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By the end of this section, you will be able to:
- Label on a diagram the four main regions of the stomach, its curvatures, and its sphincter
- Identify the four main types of secreting cells in gastric glands, and their important products
- Explain why the stomach does not digest itself
- Describe the mechanical and chemical digestion of food entering the stomach
Although a minimal amount of carbohydrate digestion occurs in the mouth, chemical digestion really gets underway in the stomach. An expansion of the alimentary canal that lies immediately inferior to the esophagus, the stomach links the esophagus to the first part of the small intestine (the duodenum) and is relatively fixed in place at its esophageal and duodenal ends. In between, however, it can be a highly active structure, contracting and continually changing position and size. These contractions provide mechanical assistance to digestion. The empty stomach is only about the size of your fist, but can stretch to hold as much as 4 liters of food and fluid, or more than 75 times its empty volume, and then return to its resting size when empty. Although you might think that the size of a person’s stomach is related to how much food that individual consumes, body weight does not correlate with stomach size. Rather, when you eat greater quantities of food—such as at holiday dinner—you stretch the stomach more than when you eat less.
Popular culture tends to refer to the stomach as the location where all digestion takes place. Of course, this is not true. An important function of the stomach is to serve as a temporary holding chamber. You can ingest a meal far more quickly than it can be digested and absorbed by the small intestine. Thus, the stomach holds food and parses only small amounts into the small intestine at a time. Foods are not processed in the order they are eaten; rather, they are mixed together with digestive juices in the stomach until they are converted into chyme, which is released into the small intestine.
As you will see in the sections that follow, the stomach plays several important roles in chemical digestion, including the continued digestion of carbohydrates and the initial digestion of proteins and triglycerides. Little if any nutrient absorption occurs in the stomach, with the exception of the negligible amount of nutrients in alcohol.
There are four main regions in the stomach: the cardia, fundus, body, and pylorus. The cardia (or cardiac region) is the point where the esophagus connects to the stomach and through which food passes into the stomach. Located inferior to the diaphragm, above and to the left of the cardia, is the dome-shaped fundus. Below the fundus is the body, the main part of the stomach. The funnel-shaped pylorus connects the stomach to the duodenum. The wider end of the funnel, the pyloric antrum, connects to the body of the stomach. The narrower end is called the pyloric canal, which connects to the duodenum. The smooth muscle pyloric sphincter is located at this latter point of connection and controls stomach emptying. In the absence of food, the stomach deflates inward, and its mucosa and submucosa fall into a large fold called a ruga.
The convex lateral surface of the stomach is called the greater curvature; the concave medial border is the lesser curvature. The stomach is held in place by the lesser omentum, which extends from the liver to the lesser curvature, and the greater omentum, which runs from the greater curvature to the posterior abdominal wall.
The wall of the stomach is made of the same four layers as most of the rest of the alimentary canal, but with adaptations to the mucosa and muscularis for the unique functions of this organ. In addition to the typical circular and longitudinal smooth muscle layers, the muscularis has an inner oblique smooth muscle layer. As a result, in addition to moving food through the canal, the stomach can vigorously churn food, mechanically breaking it down into smaller particles.
The stomach mucosa’s epithelial lining consists only of surface mucus cells, which secrete a protective coat of alkaline mucus. A vast number of gastric pits dot the surface of the epithelium, giving it the appearance of a well-used pincushion, and mark the entry to each gastric gland, which secretes a complex digestive fluid referred to as gastric juice.
Although the walls of the gastric pits are made up primarily of mucus cells, the gastric glands are made up of different types of cells. The glands of the cardia and pylorus are composed primarily of mucus-secreting cells. Cells that make up the pyloric antrum secrete mucus and a number of hormones, including the majority of the stimulatory hormone, gastrin. The much larger glands of the fundus and body of the stomach, the site of most chemical digestion, produce most of the gastric secretions. These glands are made up of a variety of secretory cells. These include parietal cells, chief cells, mucous neck cells, and enteroendocrine cells.
- Parietal cells—Located primarily in the middle region of the gastric glands are parietal cells, which are among the most highly differentiated of the body’s epithelial cells. These relatively large cells produce both hydrochloric acid (HCl) and intrinsic factor. HCl is responsible for the high acidity (pH 1.5 to 3.5) of the stomach contents and is needed to activate the protein-digesting enzyme, pepsin. The acidity also kills much of the bacteria you ingest with food and helps to denature proteins, making them more available for enzymatic digestion. Intrinsic factor is a glycoprotein necessary for the absorption of vitamin B12 in the small intestine.
- Chief cells—Located primarily in the basal regions of gastric glands are chief cells, which secrete pepsinogen, the inactive proenzyme form of pepsin. HCl is necessary for the conversion of pepsinogen to pepsin.
- Mucous neck cells—Gastric glands in the upper part of the stomach contain mucous neck cells that secrete thin, acidic mucus that is much different from the mucus secreted by the goblet cells of the surface epithelium. The role of this mucus is not currently known.
- Enteroendocrine cells—Finally, enteroendocrine cells found in the gastric glands secrete various hormones into the interstitial fluid of the lamina propria. These include gastrin, which is released mainly by enteroendocrine G cells.
Table 1 describes the digestive functions of important hormones secreted by the stomach.
|Table 1. Hormones Secreted by the Stomach|
|Hormone||Production site||Production stimulus||Target organ||Action|
|Gastrin||Stomach mucosa, mainly G cells of the pyloric antrum||Presence of peptides and amino acids in stomach||Stomach||Increases secretion by gastric glands; promotes gastric emptying|
|Gastrin||Stomach mucosa, mainly G cells of the pyloric antrum||Presence of peptides and amino acids in stomach||Small intestine||Promotes intestinal muscle contraction|
|Gastrin||Stomach mucosa, mainly G cells of the pyloric antrum||Presence of peptides and amino acids in stomach||Ileocecal valve||Relaxes valve|
|Gastrin||Stomach mucosa, mainly G cells of the pyloric antrum||Presence of peptides and amino acids in stomach||Large intestine||Triggers mass movements|
|Ghrelin||Stomach mucosa, mainly fundus||Fasting state (levels increase just prior to meals)||Hypothalamus||Regulates food intake, primarily by stimulating hunger and satiety|
|Histamine||Stomach mucosa||Presence of food in the stomach||Stomach||Stimulates parietal cells to release HCl|
|Serotonin||Stomach mucosa||Presence of food in the stomach||Stomach||Contracts stomach muscle|
|Somatostatin||Mucosa of stomach, especially pyloric antrum; also duodenum||Presence of food in the stomach; sympathetic axon stimulation||Stomach||Restricts all gastric secretions, gastric motility, and emptying|
|Somatostatin||Mucosa of stomach, especially pyloric antrum; also duodenum||Presence of food in the stomach; sympathetic axon stimulation||Pancreas||Restricts pancreatic secretions|
|Somatostatin||Mucosa of stomach, especially pyloric antrum; also duodenum||Presence of food in the stomach; sympathetic axon stimulation||Small intestine||Reduces intestinal absorption by reducing blood flow|
Watch this animation that depicts the structure of the stomach and how this structure functions in the initiation of protein digestion. This view of the stomach shows the characteristic rugae. What is the function of these rugae?
The secretion of gastric juice is controlled by both nerves and hormones. Stimuli in the brain, stomach, and small intestine activate or inhibit gastric juice production. This is why the three phases of gastric secretion are called the cephalic, gastric, and intestinal phases. However, once gastric secretion begins, all three phases can occur simultaneously.
The cephalic phase (reflex phase) of gastric secretion, which is relatively brief, takes place before food enters the stomach. The smell, taste, sight, or thought of food triggers this phase. For example, when you bring a piece of sushi to your lips, impulses from receptors in your taste buds or the nose are relayed to your brain, which returns signals that increase gastric secretion to prepare your stomach for digestion. This enhanced secretion is a conditioned reflex, meaning it occurs only if you like or want a particular food. Depression and loss of appetite can suppress the cephalic reflex.
The gastric phase of secretion lasts 3 to 4 hours, and is set in motion by local neural and hormonal mechanisms triggered by the entry of food into the stomach. For example, when your sushi reaches the stomach, it creates distention that activates the stretch receptors. This stimulates parasympathetic neurons to release acetylcholine, which then provokes increased secretion of gastric juice. Partially digested proteins, caffeine, and rising pH stimulate the release of gastrin from enteroendocrine G cells, which in turn induces parietal cells to increase their production of HCl, which is needed to create an acidic environment for the conversion of pepsinogen to pepsin, and protein digestion. Additionally, the release of gastrin activates vigorous smooth muscle contractions. However, it should be noted that the stomach does have a natural means of avoiding excessive acid secretion and potential heartburn. Whenever pH levels drop too low, cells in the stomach react by suspending HCl secretion and increasing mucous secretions.
The intestinal phase of gastric secretion has both excitatory and inhibitory elements. The duodenum has a major role in regulating the stomach and its emptying. When partially digested food fills the duodenum, intestinal mucosal cells release a hormone called intestinal (enteric) gastrin, which further excites gastric juice secretion. This stimulatory activity is brief, however, because when the intestine distends with chyme, the enterogastric reflex inhibits secretion. One of the effects of this reflex is to close the pyloric sphincter, which blocks additional chyme from entering the duodenum.
The Mucosal Barrier
The mucosa of the stomach is exposed to the highly corrosive acidity of gastric juice. Gastric enzymes that can digest protein can also digest the stomach itself. The stomach is protected from self-digestion by the mucosal barrier. This barrier has several components. First, the stomach wall is covered by a thick coating of bicarbonate-rich mucus. This mucus forms a physical barrier, and its bicarbonate ions neutralize acid. Second, the epithelial cells of the stomach’s mucosa meet at tight junctions, which block gastric juice from penetrating the underlying tissue layers. Finally, stem cells located where gastric glands join the gastric pits quickly replace damaged epithelial mucosal cells, when the epithelial cells are shed. In fact, the surface epithelium of the stomach is completely replaced every 3 to 6 days.
Homeostatic Imbalances: Ulcers
When the Mucosal Barrier Breaks Down
As effective as the mucosal barrier is, it is not a “fail-safe” mechanism. Sometimes, gastric juice eats away at the superficial lining of the stomach mucosa, creating erosions, which mostly heal on their own. Deeper and larger erosions are called ulcers.
Why does the mucosal barrier break down? A number of factors can interfere with its ability to protect the stomach lining. The majority of all ulcers are caused by either excessive intake of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, or Helicobacter pylori infection.
Antacids help relieve symptoms of ulcers such as “burning” pain and indigestion. When ulcers are caused by NSAID use, switching to other classes of pain relievers allows healing. When caused by H. pylori infection, antibiotics are effective.
A potential complication of ulcers is perforation: Perforated ulcers create a hole in the stomach wall, resulting in peritonitis (inflammation of the peritoneum). These ulcers must be repaired surgically.
Digestive Functions of the Stomach
The stomach participates in virtually all the digestive activities with the exception of ingestion and defecation. Although almost all absorption takes place in the small intestine, the stomach does absorb some nonpolar substances, such as alcohol and aspirin.
Within a few moments after food after enters your stomach, mixing waves begin to occur at intervals of approximately 20 seconds. A mixing wave is a unique type of peristalsis that mixes and softens the food with gastric juices to create chyme. The initial mixing waves are relatively gentle, but these are followed by more intense waves, starting at the body of the stomach and increasing in force as they reach the pylorus. It is fair to say that long before your sushi exits through the pyloric sphincter, it bears little resemblance to the sushi you ate.
The pylorus, which holds around 30 mL (1 fluid ounce) of chyme, acts as a filter, permitting only liquids and small food particles to pass through the mostly, but not fully, closed pyloric sphincter. In a process called gastric emptying, rhythmic mixing waves force about 3 mL of chyme at a time through the pyloric sphincter and into the duodenum. Release of a greater amount of chyme at one time would overwhelm the capacity of the small intestine to handle it. The rest of the chyme is pushed back into the body of the stomach, where it continues mixing. This process is repeated when the next mixing waves force more chyme into the duodenum.
Gastric emptying is regulated by both the stomach and the duodenum. The presence of chyme in the duodenum activates receptors that inhibit gastric secretion. This prevents additional chyme from being released by the stomach before the duodenum is ready to process it.
The fundus plays an important role, because it stores both undigested food and gases that are released during the process of chemical digestion. Food may sit in the fundus of the stomach for a while before being mixed with the chyme. While the food is in the fundus, the digestive activities of salivary amylase continue until the food begins mixing with the acidic chyme. Ultimately, mixing waves incorporate this food with the chyme, the acidity of which inactivates salivary amylase and activates lingual lipase. Lingual lipase then begins breaking down triglycerides into free fatty acids, and mono- and diglycerides.
The breakdown of protein begins in the stomach through the actions of HCl and the enzyme pepsin. During infancy, gastric glands also produce rennin, an enzyme that helps digest milk protein.
Its numerous digestive functions notwithstanding, there is only one stomach function necessary to life: the production of intrinsic factor. The intestinal absorption of vitamin B12, which is necessary for both the production of mature red blood cells and normal neurological functioning, cannot occur without intrinsic factor. People who undergo total gastrectomy (stomach removal)—for life-threatening stomach cancer, for example—can survive with minimal digestive dysfunction if they receive vitamin B12 injections.
The contents of the stomach are completely emptied into the duodenum within 2 to 4 hours after you eat a meal. Different types of food take different amounts of time to process. Foods heavy in carbohydrates empty fastest, followed by high-protein foods. Meals with a high triglyceride content remain in the stomach the longest. Since enzymes in the small intestine digest fats slowly, food can stay in the stomach for 6 hours or longer when the duodenum is processing fatty chyme. However, note that this is still a fraction of the 24 to 72 hours that full digestion typically takes from start to finish.
The stomach participates in all digestive activities except ingestion and defecation. It vigorously churns food. It secretes gastric juices that break down food and absorbs certain drugs, including aspirin and some alcohol. The stomach begins the digestion of protein and continues the digestion of carbohydrates and fats. It stores food as an acidic liquid called chyme, and releases it gradually into the small intestine through the pyloric sphincter.
Answer the question(s) below to see how well you understand the topics covered in the previous section.
Critical Thinking Questions
- Explain how the stomach is protected from self-digestion and why this is necessary.
- Describe unique anatomical features that enable the stomach to perform digestive functions.
[reveal-answer q=”827487″]Show Answers[/reveal-answer]
- The mucosal barrier protects the stomach from self-digestion. It includes a thick coating of bicarbonate-rich mucus; the mucus is physically protective, and bicarbonate neutralizes gastric acid. Epithelial cells meet at tight junctions, which block gastric juice from penetrating the underlying tissue layers, and stem cells quickly replace sloughed off epithelial mucosal cells.
- The stomach has an additional inner oblique smooth muscle layer that helps the muscularis churn and mix food. The epithelium includes gastric glands that secrete gastric fluid. The gastric fluid consists mainly of mucous, HCl, and the enzyme pepsin released as pepsinogen.
body: mid-portion of the stomach
cardia: (also, cardiac region) part of the stomach surrounding the cardiac orifice (esophageal hiatus)
cephalic phase: (also, reflex phase) initial phase of gastric secretion that occurs before food enters the stomach
chief cell: gastric gland cell that secretes pepsinogen
enteroendocrine cell: gastric gland cell that releases hormones
fundus: dome-shaped region of the stomach above and to the left of the cardia
G cell: gastrin-secreting enteroendocrine cell
gastric emptying: process by which mixing waves gradually cause the release of chyme into the duodenum
gastric gland: gland in the stomach mucosal epithelium that produces gastric juice
gastric phase: phase of gastric secretion that begins when food enters the stomach
gastric pit: narrow channel formed by the epithelial lining of the stomach mucosa
gastrin: peptide hormone that stimulates secretion of hydrochloric acid and gut motility
hydrochloric acid (HCl): digestive acid secreted by parietal cells in the stomach
intrinsic factor: glycoprotein required for vitamin B12 absorption in the small intestine
intestinal phase: phase of gastric secretion that begins when chyme enters the intestine
mixing wave: unique type of peristalsis that occurs in the stomach
mucosal barrier: protective barrier that prevents gastric juice from destroying the stomach itself
mucous neck cell: gastric gland cell that secretes a uniquely acidic mucus
parietal cell: gastric gland cell that secretes hydrochloric acid and intrinsic factor
pepsinogen: inactive form of pepsin
pyloric antrum: wider, more superior part of the pylorus
pyloric canal: narrow, more inferior part of the pylorus
pyloric sphincter: sphincter that controls stomach emptying
pylorus: lower, funnel-shaped part of the stomach that is continuous with the duodenum
ruga: fold of alimentary canal mucosa and submucosa in the empty stomach and other organs
stomach: alimentary canal organ that contributes to chemical and mechanical digestion of food from the esophagus before releasing it, as chyme, to the small intestine
Gastric cancer: Classification, histology and application of molecular pathology
Gastric cancer remains one of the deadly diseases with poor prognosis. New classification of gastric cancers based on histologic features, genotypes and molecular phenotypes helps better understand the characteristics of each subtype, and improve early diagnosis, prevention and treatment. The objective of this article is to review the new classification of gastric cancers and the up-to-date guidance in the application of molecular testing.
The gastrointestinal (GI) tract of most metazoans, including that of humans, is lined by a series of highly compartmentalized epithelia that perform localized functions. These epithelia also share certain characteristics that support interactions with commensal bacteria (see Box 1 for Glossary), enhance immune responses to infections and maintain the barrier function of the intestine. These epithelia undergo regeneration in homeostatic conditions as well as in response to tissue damage. During recurring regenerative episodes, and for the lifetime of the animal, the functional diversity of newly formed intestinal cells has to be sustained – an achievement that is only beginning to be understood, via the use of animal models (Barker et al., 2010a Buchon et al., 2013b Li et al., 2013a Marianes and Spradling, 2013 Strand and Micchelli, 2011).
Conditions that negatively impact epithelial compartmentalization can have substantial deleterious consequences. In the human GI tract, for example, the development of epithelial metaplastic lesions (see Box 1) can place individuals at a high risk of developing intestinal cancer (Slack, 2007). In these lesions, one differentiated cell type is replaced by a cell with a different identity. One example is Barrett's metaplasia (see Box 1), in which the esophageal squamous epithelium acquires properties that are reminiscent of the gastric or intestinal columnar epithelium. This transformation has been associated with acid reflux disease and is believed to be a cause of esophageal adenocarcinomas (Falk, 2002 Hvid-Jensen et al., 2011). Dysplasia (see Box 1), another type of epithelial lesion that commonly affects the human GI tract, is characterized by aberrant cell proliferation and differentiation. Dysplastic changes are often found at later stages during epithelial carcinogenesis than are metaplasias, and eventually lead to invasive carcinoma (see Box 1) (Correa and Houghton, 2007 Ullman et al., 2009). Much remains to be learnt about intestinal metaplasias and dysplasias, not least because of their clinical significance, such as the exact cellular origins of metaplastic cells and the molecular pathways that underpin epithelial dysfunction. Because intestinal epithelia are regenerated by local intestinal stem cell (ISC) populations, which have been characterized in the GI tract of flies and mice in the past decade (Barker et al., 2007 Micchelli and Perrimon, 2006 Ohlstein and Spradling, 2006), deregulation of these stem cell functions, including proliferation and differentiation, has been associated with metaplastic and dysplastic lesions. To better understand the molecular changes underlying epithelial carcinogenesis, it is thus crucial to pinpoint the mechanisms that regulate ISC function.
In this Review, we highlight recent insights into the maintenance of GI compartmentalization and regulation of diverse stem cell lineages, focusing on advances made by analysis of the GI tract of Drosophila and mice. We then summarize findings about signaling pathways that control these stem cell functions, drawing parallels between the fly and mammalian systems. Finally, we discuss how these findings inform our current understanding of the pathogenesis of epithelial dysfunctions that can predispose humans to cancer.
The stomachs of some other animals differ considerably from that of humans many have multiple-chambered organs or special adaptations. The stomachs of cows and most cud-chewing (ruminant) animals are divided into four separate parts. Food is received first in the rumen, where mucus is added and cellulose is broken down. Next, it goes back to the mouth to be thoroughly rechewed. When swallowed again, it is passed to the second and third chambers, the reticulum and omasum, where water is extracted and absorbed. The food then goes to a final chamber, the abomasum, to receive the digestive enzymes.
Birds have a three-chambered stomach: the first chamber, the crop, receives the food initially and either stores or begins to moisten and soften (macerate) it the true stomach area adds digestive juices and the gizzard, with its stones, or toothlike structures, grinds the food.
Rodents have only one stomach area, and many must eat their food twice before absorption takes place. Food is eaten and passed through the lower digestive tract, where it is coated with metabolites to help break it down. The fecal material is then re-eaten and mixed with additional food. Enzymes and water are removed from the once-passed material by the stomach and used to help digest new nutritional substances. Dry fecal pellets are finally excreted.
The starfish can turn its stomach inside out and extrude it partly from the body to eat the soft contents of shelled animals such as clams. Camels and llamas can regurgitate their stomach contents and spit this material at approaching enemies. Crayfish produce stones of calcium salts in their stomach. These are stored until the animal sheds its external shell, when the stones are reabsorbed by the stomach and used in forming a new shell.
The Editors of Encyclopaedia Britannica This article was most recently revised and updated by Adam Augustyn, Managing Editor, Reference Content.
Why does your stomach growl when you are hungry?
Though stomach growling is commonly heard and associated with hunger and an absence of food in the stomach, it can occur at any time, on an empty or full stomach. Furthermore, growling doesn't only come from the stomach but, just as often, can be heard coming from the small intestines. Growling is more commonly associated with hunger because it is typically louder when the stomach and intestines are empty and so the organs' contents don't muffle the noise.
This growling has been of interest for so many years that the ancient Greeks came up with the rather interesting name for it: borborygmi (the plural of borborygmus). The etymology of the term relies on onomatopoeia it is an attempt to put the rumbling sound into words. Borborygmi actually translates as "rumbling."
The physiological origin of this rumbling involves muscular activity in the stomach and small intestines. In general, the gastrointestinal tract is a hollow tube that runs from mouth to anus and its walls are primarily composed of layers of smooth muscle. When the walls are activated and squeeze the tract's contents to mix and propel food, gas and fluids through the stomach and small intestines, it generates a rumbling noise. This squeezing of the muscular walls is termed peristalsis and involves a ring of contraction moving aborally (away from the oral cavity) towards the anus a few inches at a time.
The generation of these waves of peristalsis results from a rhythmic fluctuation of electrical potential in the smooth muscle cells, which, all other conditions being appropriate, will cause the muscle to contract. This fluctuation is called the basic electrical rhythm (BER) and is a result of inherent activity of the enteric nervous system, which is found in the walls of the gut. The BER causes the muscle cells of the stomach and small intestines to activate at a regular rhythm (three and 12 times per minute, respectively), in a manner similar to, but slower than, the rhythmicity of cardiac muscle in the heart. The autonomic nervous system and hormonal factors can modulate this BER.
Though the rate and force of peristalsis typically increases in the presence of food, activity also increases after the stomach and small intestines have been empty for approximately two hours. In the latter case, receptors in the walls of the stomach sense the absence of food, causing a reflex generation of waves of electrical activity (migrating myoelectric complexes, or MMCs) in the enteric nervous system. These MMCs travel along the stomach and small intestines and lead to hunger contractions. Such hunger contractions start in the antrum, or lower region, of the stomach and propagate along the entire length of the gut, sweeping to the terminal ileum. They clear out any and all stomach contentsincluding mucus, remaining foodstuffs and bacteriaand keep them from accumulating at any one site.
The contractions also produce vibrations and the rumbling noise associated with hunger. Hunger contractions may continue for 10 to 20 minutes once initiated, and then repeat every one to two hours until the next meal is ingested. These are not the same as hunger pangs, which start 12 to 24 hours after the last meal and may continue for a few days before gradually subsiding. (It is possible such pangs are important in the hunger sensation that drives animals to eat.) Low blood sugar enhances this activity, which can also be induced using an intravenous infusion of the hormone motilin. After feeding, the MMCs subside.
Gastric cancer: epidemiology, biology, and prevention: a mini review
Gastric cancer is one of the most common causes of cancer-related mortality worldwide. The objective of this article is to review the epidemiology and biology of gastric cancer risk. This literature review explores the biological, clinical, and environmental factors that influence the rates of this disease and discuss the different intervention methods that may not only increase the awareness of gastric cancer but also increase screening in efforts to reduce the risk of gastric cancer. Helicobacter pylori infection is the primary risk factor for gastric cancer. Additional risk factors include geographical location, age, sex, smoking, socioeconomic status, dietary intake, and genetics. Primary and secondary prevention strategies such as dietary modifications and screenings are important measures for reducing the risk of gastric cancer. Interventions, such as H. pylori eradication through chemoprevention trials, have shown some potential as a preventative strategy. Although knowledge about gastric cancer risk has greatly increased, future research is warranted on the differentiation of gastric cancer epidemiology by subsite and exploring the interactions between H. pylori infection, genetics, and environmental factors. Better understanding of these relationships can help researchers determine the most effective intervention strategies for reducing the risk of this disease.
Helicobacter pylori infection and gastric cancer biology: tempering a double-edged sword
Helicobacter pylori (H. pylori) infection affects an estimated 4.4 billion people globally. Moreover, H. pylori presents the most significant risk factor for gastric cancer and low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, and it is the first example of bacterial infection linked to carcinogenesis. Here, we contend that H. pylori research, which focuses on a cancer-causing pathogen resident in a relatively accessible organ, the stomach, could constitute an exemplar for microbial-related carcinogenesis in less tractable organs, such as the pancreas and lung. In this context, molecular biological approaches that could reap rewards are reviewed, including: (1) gastric cancer dynamics, particularly the role of stem cells and the heterogeneity of neoplastic cells, which are currently being investigated at the single-cell sequencing level (2) mechanobiology, and the role of three-dimensional organoids and matrix metalloproteases and (3) the connection between H. pylori and host pathophysiology and the gut microbiome. In the context of H. pylori's contribution to gastric cancer, several important conundrums remain to be fully elucidated. From among them, this article discusses (1) why H. pylori infection, which causes both gastric and duodenal inflammation, is only linked to gastric cancer (2) whether a "precision oncomicrobiology" approach could enable a fine-tuning of the expression of only cancer-implicated H. pylori genes while maintaining beneficial H. pylori-mediated factors in extra-gastric tissues and (3) the feasibility of using antibiotics targeting the microbial DNA damage system, which shares commonalities with mechanisms for human cell replication, as chemopreventives. Additional therapeutic perspectives are also discussed.
Keywords: CagA protein DNA damage Gastric cancer Helicobacter pylori Mechanobiology Stem cells.
Up to 90% of people infected with H. pylori never experience symptoms or complications.  However, individuals infected with H. pylori have a 10% to 20% lifetime risk of developing peptic ulcers.   Acute infection may appear as an acute gastritis with abdominal pain (stomach ache) or nausea.  Where this develops into chronic gastritis, the symptoms, if present, are often those of non-ulcer dyspepsia: Stomach pains, nausea, bloating, belching, and sometimes vomiting.   Pain typically occurs when the stomach is empty, between meals, and in the early morning hours, but it can also occur at other times. Less common ulcer symptoms include nausea, vomiting, and loss of appetite.
Bleeding in the stomach can also occur as evidenced by the passage of black stools prolonged bleeding may cause anemia leading to weakness and fatigue. If bleeding is heavy, hematemesis, hematochezia, or melena may occur. Inflammation of the pyloric antrum, which connects the stomach to the duodenum, is more likely to lead to duodenal ulcers, while inflammation of the corpus (i.e. body of the stomach) is more likely to lead to gastric ulcers.   Individuals infected with H. pylori may also develop colorectal   or gastric  polyps, i.e. non-cancerous growths of tissue projecting from the mucous membranes of these organs. Usually, these polyps are asymptomatic but gastric polyps may be the cause of dyspepsia, heartburn, bleeding from the upper gastrointestinal tract, and, rarely, gastric outlet obstruction  while colorectal polyps may be the cause of rectal bleeding, anemia, constipation, diarrhea, weight loss, and abdominal pain. 
Individuals with chronic H. pylori infection have an increased risk of acquiring a cancer that is directly related to this infection.     These cancers are stomach adenocarcinoma, less commonly diffuse large B-cell lymphoma of the stomach,  or extranodal marginal zone B-cell lymphomas of the stomach,   or, more rarely, of the colon,   rectum,  esophagus,  or ocular adenexa (i.e. orbit, conjunctiva, and/or eyelids).   The signs, symptoms, pathophysiology, and diagnoses of these cancers are given in the cited linkages.
Helicobacter pylori is a helix-shaped (classified as a curved rod, not spirochaete) Gram-negative bacterium about 3 μm long with a diameter of about 0.5 μm . H. pylori can be demonstrated in tissue by Gram stain, Giemsa stain, haematoxylin–eosin stain, Warthin–Starry silver stain, acridine orange stain, and phase-contrast microscopy. It is capable of forming biofilms  and can convert from spiral to a possibly viable but nonculturable coccoid form. 
Helicobacter pylori has four to six flagella at the same location all gastric and enterohepatic Helicobacter species are highly motile owing to flagella.  The characteristic sheathed flagellar filaments of Helicobacter are composed of two copolymerized flagellins, FlaA and FlaB. 
Helicobacter pylori is microaerophilic – that is, it requires oxygen, but at lower concentration than in the atmosphere. It contains a hydrogenase that can produce energy by oxidizing molecular hydrogen (H2) made by intestinal bacteria.  It produces oxidase, catalase, and urease.
H. pylori possesses five major outer membrane protein families.  The largest family includes known and putative adhesins. The other four families are porins, iron transporters, flagellum-associated proteins, and proteins of unknown function. Like other typical Gram-negative bacteria, the outer membrane of H. pylori consists of phospholipids and lipopolysaccharide (LPS). The O antigen of LPS may be fucosylated and mimic Lewis blood group antigens found on the gastric epithelium.  The outer membrane also contains cholesterol glucosides, which are present in few other bacteria. 
Helicobacter pylori consists of a large diversity of strains, and hundreds of genomes have been completely sequenced.       The genome of the strain "26695" consists of about 1.7 million base pairs, with some 1,576 genes. The pan-genome, that is a combined set of 30 sequenced strains, encodes 2,239 protein families (orthologous groups, OGs). Among them, 1,248 OGs are conserved in all the 30 strains, and represent the universal core. The remaining 991 OGs correspond to the accessory genome in which 277 OGs are unique (i.e., OGs present in only one strain). 
In 2010, Sharma et al. presented a comprehensive analysis of transcription at single-nucleotide resolution by differential RNA-seq that confirmed the known acid induction of major virulence loci, such as the urease (ure) operon or the cag pathogenicity island (see below).  More importantly, this study identified a total of 1,907 transcriptional start sites, 337 primary operons, and 126 additional suboperons, and 66 monocistrons. Until 2010, only about 55 transcriptional start sites (TSSs) were known in this species. Notably, 27% of the primary TSSs are also antisense TSSs, indicating that – similar to E. coli – antisense transcription occurs across the entire H. pylori genome. At least one antisense TSS is associated with about 46% of all open reading frames, including many housekeeping genes.  Most (about 50%) of the 5′ UTRs are 20–40 nucleotides (nt) in length and support the AAGGag motif located about 6 nt (median distance) upstream of start codons as the consensus Shine–Dalgarno sequence in H. pylori. 
Genes involved in virulence and pathogenesis Edit
Study of the H. pylori genome is centered on attempts to understand pathogenesis, the ability of this organism to cause disease. About 29% of the loci have a colonization defect when mutated. Two of sequenced strains have an around 40 kb-long Cag pathogenicity island (a common gene sequence believed responsible for pathogenesis) that contains over 40 genes. This pathogenicity island is usually absent from H. pylori strains isolated from humans who are carriers of H. pylori, but remain asymptomatic. 
The cagA gene codes for one of the major H. pylori virulence proteins. Bacterial strains with the cagA gene are associated with an ability to cause ulcers.  The cagA gene codes for a relatively long (1186-amino acid) protein. The cag pathogenicity island (PAI) has about 30 genes, part of which code for a complex type IV secretion system. The low GC-content of the cag PAI relative to the rest of the Helicobacter genome suggests the island was acquired by horizontal transfer from another bacterial species.  The serine protease HtrA also plays a major role in the pathogenesis of H. pylori. The HtrA protein enables the bacterium to transmigrate across the host cells' epithelium, and is also needed for the translocation of CagA. 
The vacA ( Q48245 ) gene codes for another major H. pylori virulence protein. There are four main subtypes of vacA: s1/m1, s1/m2, s2/m1, and s2/m2. s1/m1 and s1/m2 subtypes are known to cause increased risk of gastric cancer.  This has been linked to the ability for toxigenic vacA to promote the generation of intracellular reservoirs of H. pylori via disruption of calcium channel TRPML1. 
Adaptation to the stomach Edit
To avoid the acidic environment of the interior of the stomach (lumen), H. pylori uses its flagella to burrow into the mucus lining of the stomach to reach the epithelial cells underneath, where it is less acidic.  H. pylori is able to sense the pH gradient in the mucus and move towards the less acidic region (chemotaxis). This also keeps the bacteria from being swept away into the lumen with the bacteria's mucus environment, which is constantly moving from its site of creation at the epithelium to its dissolution at the lumen interface. 
H. pylori is found in the mucus, on the inner surface of the epithelium, and occasionally inside the epithelial cells themselves.  It adheres to the epithelial cells by producing adhesins, which bind to lipids and carbohydrates in the epithelial cell membrane. One such adhesin, BabA, binds to the Lewis b antigen displayed on the surface of stomach epithelial cells.  H. pylori adherence via BabA is acid sensitive and can be fully reversed by decreased pH. It has been proposed that BabA's acid responsiveness enables adherence while also allowing an effective escape from unfavorable environment at pH that is harmful to the organism.  Another such adhesin, SabA, binds to increased levels of sialyl-Lewis x antigen expressed on gastric mucosa. 
In addition to using chemotaxis to avoid areas of low pH, H. pylori also neutralizes the acid in its environment by producing large amounts of urease, which breaks down the urea present in the stomach to carbon dioxide and ammonia. These react with the strong acids in the environment to produce a neutralized area around H. pylori.  Urease knockout mutants are incapable of colonization. In fact, urease expression is not only required for establishing initial colonization but also for maintaining chronic infection. 
As mentioned above, H. pylori produce large amounts of urease to produce ammonia as one of its adaptation methods to overcome stomach acidity. Helicobacter pylori arginase, a bimetallic enzyme binuclear Mn2-metalloenzyme arginase, crucial for pathogenesis of the bacterium in human stomach,  a member of the ureohydrolase family, catalyzes the conversion of L-arginine to L-ornithine and urea, where ornithine is further converted into polyamines, which are essential for various critical metabolic processes. 
This provides acid resistance and is thus important for colonization of the bacterium in the gastric epithelial cells. Arginase of H. pylori also plays a role in evasion of the pathogen from the host immune system mainly by various proposed mechanisms, arginase competes with host-inducible nitric oxide (NO) synthase for the common substrate L-arginine, and thus reduces the synthesis of NO, an important component of innate immunity and an effective antimicrobial agent that is able to kill the invading pathogens directly. 
Alterations in the availability of L-arginine and its metabolism into polyamines contribute significantly to the dysregulation of the host immune response to H. pylori infection. 
Inflammation, gastritis and ulcer Edit
Helicobacter pylori harms the stomach and duodenal linings by several mechanisms. The ammonia produced to regulate pH is toxic to epithelial cells, as are biochemicals produced by H. pylori such as proteases, vacuolating cytotoxin A (VacA) (this damages epithelial cells, disrupts tight junctions and causes apoptosis), and certain phospholipases.  Cytotoxin associated gene CagA can also cause inflammation and is potentially a carcinogen. 
Colonization of the stomach by H. pylori can result in chronic gastritis, an inflammation of the stomach lining, at the site of infection. Helicobacter cysteine-rich proteins (Hcp), particularly HcpA (hp0211), are known to trigger an immune response, causing inflammation.  H. pylori has been shown to increase the levels of COX2 in H. pylori positive gastritis.  Chronic gastritis is likely to underlie H. pylori-related diseases. 
Ulcers in the stomach and duodenum result when the consequences of inflammation allow stomach acid and the digestive enzyme pepsin to overwhelm the mechanisms that protect the stomach and duodenal mucous membranes. The location of colonization of H. pylori, which affects the location of the ulcer, depends on the acidity of the stomach.  In people producing large amounts of acid, H. pylori colonizes near the pyloric antrum (exit to the duodenum) to avoid the acid-secreting parietal cells at the fundus (near the entrance to the stomach).  In people producing normal or reduced amounts of acid, H. pylori can also colonize the rest of the stomach.
The inflammatory response caused by bacteria colonizing near the pyloric antrum induces G cells in the antrum to secrete the hormone gastrin, which travels through the bloodstream to parietal cells in the fundus.  Gastrin stimulates the parietal cells to secrete more acid into the stomach lumen, and over time increases the number of parietal cells, as well.  The increased acid load damages the duodenum, which may eventually result in ulcers forming in the duodenum.
When H. pylori colonizes other areas of the stomach, the inflammatory response can result in atrophy of the stomach lining and eventually ulcers in the stomach. This also may increase the risk of stomach cancer. 
Cag pathogenicity island Edit
The pathogenicity of H. pylori may be increased by genes of the cag pathogenicity island about 50–70% of H. pylori strains in Western countries carry it, but it's virtually absent in East Asian strains.  Western people infected with strains carrying the cag PAI have a stronger inflammatory response in the stomach and are at a greater risk of developing peptic ulcers or stomach cancer than those infected with strains lacking the island.  Following attachment of H. pylori to stomach epithelial cells, the type IV secretion system expressed by the cag PAI "injects" the inflammation-inducing agent, peptidoglycan, from their own cell walls into the epithelial cells. The injected peptidoglycan is recognized by the cytoplasmic pattern recognition receptor (immune sensor) Nod1, which then stimulates expression of cytokines that promote inflammation. 
The type-IV secretion apparatus also injects the cag PAI-encoded protein CagA into the stomach's epithelial cells, where it disrupts the cytoskeleton, adherence to adjacent cells, intracellular signaling, cell polarity, and other cellular activities.  Once inside the cell, the CagA protein is phosphorylated on tyrosine residues by a host cell membrane-associated tyrosine kinase (TK). CagA then allosterically activates protein tyrosine phosphatase/protooncogene Shp2.  Pathogenic strains of H. pylori have been shown to activate the epidermal growth factor receptor (EGFR), a membrane protein with a TK domain. Activation of the EGFR by H. pylori is associated with altered signal transduction and gene expression in host epithelial cells that may contribute to pathogenesis. A C-terminal region of the CagA protein (amino acids 873–1002) has also been suggested to be able to regulate host cell gene transcription, independent of protein tyrosine phosphorylation.   A great deal of diversity exists between strains of H. pylori, and the strain that infects a person can predict the outcome.
Two related mechanisms by which H. pylori could promote cancer are under investigation. One mechanism involves the enhanced production of free radicals near H. pylori and an increased rate of host cell mutation. The other proposed mechanism has been called a "perigenetic pathway",  and involves enhancement of the transformed host cell phenotype by means of alterations in cell proteins, such as adhesion proteins. H. pylori has been proposed to induce inflammation and locally high levels of TNF-α and/or interleukin 6 (IL-6). According to the proposed perigenetic mechanism, inflammation-associated signaling molecules, such as TNF-α, can alter gastric epithelial cell adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations in tumor suppressor genes, such as genes that code for cell adhesion proteins. 
The strain of H. pylori a person is exposed to may influence the risk of developing gastric cancer. Strains of H. pylori that produce high levels of two proteins, vacuolating toxin A (VacA) and the cytotoxin-associated gene A (CagA), appear to cause greater tissue damage than those that produce lower levels or that lack those genes completely.  These proteins are directly toxic to cells lining the stomach and signal strongly to the immune system that an invasion is under way. As a result of the bacterial presence, neutrophils and macrophages set up residence in the tissue to fight the bacteria assault. 
H. pylori is a major source of worldwide cancer mortality.  Although the data varies between different countries, overall about 1% to 3% of people infected with Helicobacter pylori develop gastric cancer in their lifetime compared to 0.13% of individuals who have had no H. pylori infection.   H. pylori infection is very prevalent. As evaluated in 2002, it is present in the gastric tissues of 74% of middle-aged adults in developing countries and 58% in developed countries.  Since 1% to 3% of infected individuals are likely to develop gastric cancer,  H. pylori-induced gastric cancer is the third highest cause of worldwide cancer mortality as of 2018. 
Infection by H. pylori causes no symptoms in about 80% of those infected.  About 75% of individuals infected with H. pylori develop gastritis.  Thus, the usual consequence of H. pylori infection is chronic asymptomatic gastritis.  Because of the usual lack of symptoms, when gastric cancer is finally diagnosed it is often fairly advanced. More than half of gastric cancer patients have lymph node metastasis when they are initially diagnosed. 
The gastritis caused by H. pylori is accompanied by inflammation, characterized by infiltration of neutrophils and macrophages to the gastric epithelium, which favors the accumulation of pro-inflammatory cytokines and reactive oxygen species/reactive nitrogen species (ROS/RNS).  The substantial presence of ROS/RNS causes DNA damage including 8-oxo-2'-deoxyguanosine (8-OHdG).  If the infecting H. pylori carry the cytotoxic cagA gene (present in about 60% of Western isolates and a higher percentage of Asian isolates), they can increase the level of 8-OHdG in gastric cells by 8-fold, while if the H. pylori do not carry the cagA gene, the increase in 8-OHdG is about 4-fold.  In addition to the oxidative DNA damage 8-OHdG, H. pylori infection causes other characteristic DNA damages including DNA double-strand breaks. 
H. pylori also causes many epigenetic alterations linked to cancer development.   These epigenetic alterations are due to H. pylori-induced methylation of CpG sites in promoters of genes  and H. pylori-induced altered expression of multiple microRNAs. 
As reviewed by Santos and Ribeiro  H. pylori infection is associated with epigenetically reduced efficiency of the DNA repair machinery, which favors the accumulation of mutations and genomic instability as well as gastric carcinogenesis. In particular, Raza et al.  showed that expression of two DNA repair proteins, ERCC1 and PMS2, was severely reduced once H. pylori infection had progressed to cause dyspepsia. Dyspepsia occurs in about 20% of infected individuals.  In addition, as reviewed by Raza et al.,  human gastric infection with H. pylori causes epigenetically reduced protein expression of DNA repair proteins MLH1, MGMT and MRE11. Reduced DNA repair in the presence of increased DNA damage increases carcinogenic mutations and is likely a significant cause of H. pylori carcinogenesis.
Survival of Helicobacter pylori Edit
The pathogenesis of H. pylori depends on its ability to survive in the harsh gastric environment characterized by acidity, peristalsis, and attack by phagocytes accompanied by release of reactive oxygen species.  In particular, H. pylori elicits an oxidative stress response during host colonization. This oxidative stress response induces potentially lethal and mutagenic oxidative DNA adducts in the H. pylori genome. 
Vulnerability to oxidative stress and oxidative DNA damage occurs commonly in many studied bacterial pathogens, including Neisseria gonorrhoeae, Hemophilus influenzae, Streptococcus pneumoniae, S. mutans, and H. pylori.  For each of these pathogens, surviving the DNA damage induced by oxidative stress appears supported by transformation-mediated recombinational repair. Thus, transformation and recombinational repair appear to contribute to successful infection.
Transformation (the transfer of DNA from one bacterial cell to another through the intervening medium) appears to be part of an adaptation for DNA repair. H. pylori is naturally competent for transformation. While many organisms are competent only under certain environmental conditions, such as starvation, H. pylori is competent throughout logarithmic growth.  All organisms encode genetic programs for response to stressful conditions including those that cause DNA damage.  In H. pylori, homologous recombination is required for repairing DNA double-strand breaks (DSBs). The AddAB helicase-nuclease complex resects DSBs and loads RecA onto single-strand DNA (ssDNA), which then mediates strand exchange, leading to homologous recombination and repair. The requirement of RecA plus AddAB for efficient gastric colonization suggests, in the stomach, H. pylori is either exposed to double-strand DNA damage that must be repaired or requires some other recombination-mediated event. In particular, natural transformation is increased by DNA damage in H. pylori, and a connection exists between the DNA damage response and DNA uptake in H. pylori,  suggesting natural competence contributes to persistence of H. pylori in its human host and explains the retention of competence in most clinical isolates.
RuvC protein is essential to the process of recombinational repair, since it resolves intermediates in this process termed Holliday junctions. H. pylori mutants that are defective in RuvC have increased sensitivity to DNA-damaging agents and to oxidative stress, exhibit reduced survival within macrophages, and are unable to establish successful infection in a mouse model.  Similarly, RecN protein plays an important role in DSB repair in H. pylori.  An H. pylori recN mutant displays an attenuated ability to colonize mouse stomachs, highlighting the importance of recombinational DNA repair in survival of H. pylori within its host. 
Colonization with H. pylori is not a disease in and of itself, but a condition associated with a number of disorders of the upper gastrointestinal tract.  Testing for H. pylori is not routinely recommended.  Testing is recommended if peptic ulcer disease or low-grade gastric MALT lymphoma (MALToma) is present, after endoscopic resection of early gastric cancer, for first-degree relatives with gastric cancer, and in certain cases of dyspepsia.  Several methods of testing exist, including invasive and noninvasive testing methods.
Noninvasive tests for H. pylori infection may be suitable and include blood antibody tests, stool antigen tests, or the carbon urea breath test (in which the patient drinks 14 C – or 13 C-labelled urea, which the bacterium metabolizes, producing labelled carbon dioxide that can be detected in the breath).   It is not known which non-invasive test is more accurate for diagnosing a H. pylori infection, and the clinical significance of the levels obtained with these tests is not clear. 
An endoscopic biopsy is an invasive means to test for H. pylori infection. Low-level infections can be missed by biopsy, so multiple samples are recommended. The most accurate method for detecting H. pylori infection is with a histological examination from two sites after endoscopic biopsy, combined with either a rapid urease test or microbial culture. 
Helicobacter pylori is contagious, although the exact route of transmission is not known.   Person-to-person transmission by either the oral–oral or fecal–oral route is most likely. Consistent with these transmission routes, the bacteria have been isolated from feces, saliva, and dental plaque of some infected people. Findings suggest H. pylori is more easily transmitted by gastric mucus than saliva.  Transmission occurs mainly within families in developed nations, yet can also be acquired from the community in developing countries.  H. pylori may also be transmitted orally by means of fecal matter through the ingestion of waste-tainted water, so a hygienic environment could help decrease the risk of H. pylori infection. 
Due to H. pylori’s role as a major cause of certain diseases (particularly cancers) and its consistently increasing antibiotic resistance, there is a clear need for new therapeutic strategies to prevent or remove the bacterium from colonizing humans.  Much work has been done on developing viable vaccines aimed at providing an alternative strategy to control H. pylori infection and related diseases.  Researchers are studying different adjuvants, antigens, and routes of immunization to ascertain the most appropriate system of immune protection however, most of the research only recently moved from animal to human trials.  An economic evaluation of the use of a potential H. pylori vaccine in babies found its introduction could, at least in the Netherlands, prove cost-effective for the prevention of peptic ulcer and stomach adenocarcinoma.  A similar approach has also been studied for the United States.  Notwithstanding this proof-of-concept (i.e. vaccination protects children from acquisition of infection with H. pylori), as of late 2019 there have been no advanced vaccine candidates and only one vaccine in a Phase I clinical trial. Furthermore, development of a vaccine against H. pylori has not been a current priority of major pharmaceutical companies. 
Many investigations have attempted to prevent the development of Helicobacter pylori-related diseases by eradicating the bacterium during the early stages of its infestation using antibiotic-based drug regimens. Studies find that such treatments, when effectively eradicating H. pylori from the stomach, reduce the inflammation and some of the histopathological abnormalities associated with the infestation. However studies disagree on the ability of these treatments to alleviate the more serious histopathological abnormalities in H. pylori infections, e.g. gastric atrophy and metaplasia, both of which are precursors to gastric adenocarcinoma.  There is similar disagreement on the ability of antibiotic-based regiments to prevent gastric adenocarcinoma. A meta-analysis (i.e. a statistical analysis that combines the results of multiple randomized controlled trials) published in 2014 found that these regimens did not appear to prevent development of this adenocarcinoma.  However, two subsequent prospective cohort studies conducted on high-risk individuals in China and Taiwan found that eradication of the bacterium produced a significant decrease in the number of individuals developing the disease. These results agreed with a retrospective cohort study done in Japan and published in 2016  as well as a meta-analysis, also published in 2016, of 24 studies conducted on individuals with varying levels of risk for developing the disease.  These more recent studies suggest that the eradication of H. pylori infection reduces the incidence of H. pylori-related gastric adenocarcinoma in individuals at all levels of baseline risk.  Further studies will be required to clarify this issue. In all events, studies agree that antibiotic-based regimens effectively reduce the occurrence of metachronous H. pylori-associated gastric adenocarcinoma.  (Metachronous cancers are cancers that reoccur 6 months or later after resection of the original cancer.) It is suggested that antibiotic-based drug regimens be used after resecting H. pylori-associated gastric adenocarcinoma in order to reduce its metachronus reoccurrence. 
Superficial gastritis, either acute or chronic, is the most common manifestation of H. pylori infection. The signs and symptoms of this gastritis have been found to remit spontaneously in many individuals without resorting to Helicobacter pylori eradication protocols. The H. pylori bacterial infection persists after remission in these cases. Various antibiotic plus proton pump inhibitor drug regimens are used to eradicate the bacterium and thereby successfully treat the disorder  with triple-drug therapy consisting of clarithromycin, amoxicillin, and a proton-pump inhibitor given for 14–21 days often being considered first line treatment. 
Peptic ulcers Edit
Once H. pylori is detected in a person with a peptic ulcer, the normal procedure is to eradicate it and allow the ulcer to heal. The standard first-line therapy is a one-week "triple therapy" consisting of proton-pump inhibitors such as omeprazole and the antibiotics clarithromycin and amoxicillin.  (The actions of proton pump inhibitors against H. pylori may reflect their direct bacteriostatic effect due to inhibition of the bacterium's P-type ATPase and/or urease.  ) Variations of the triple therapy have been developed over the years, such as using a different proton pump inhibitor, as with pantoprazole or rabeprazole, or replacing amoxicillin with metronidazole for people who are allergic to penicillin.  In areas with higher rates of clarithromycin resistance, other options are recommended.  Such a therapy has revolutionized the treatment of peptic ulcers and has made a cure to the disease possible. Previously, the only option was symptom control using antacids, H2-antagonists or proton pump inhibitors alone.  
Antibiotic-resistant disease Edit
An increasing number of infected individuals are found to harbor antibiotic-resistant bacteria. This results in initial treatment failure and requires additional rounds of antibiotic therapy or alternative strategies, such as a quadruple therapy, which adds a bismuth colloid, such as bismuth subsalicylate.    For the treatment of clarithromycin-resistant strains of H. pylori, the use of levofloxacin as part of the therapy has been suggested.  
Ingesting lactic acid bacteria exerts a suppressive effect on H. pylori infection in both animals and humans, and supplementing with Lactobacillus- and Bifidobacterium-containing yogurt improved the rates of eradication of H. pylori in humans.  Symbiotic butyrate-producing bacteria which are normally present in the intestine are sometimes used as probiotics to help suppress H. pylori infections as an adjunct to antibiotic therapy.  Butyrate itself is an antimicrobial which destroys the cell envelope of H. pylori by inducing regulatory T cell expression (specifically, FOXP3) and synthesis of an antimicrobial peptide called LL-37, which arises through its action as a histone deacetylase inhibitor. [a]  
The substance sulforaphane, which occurs in broccoli and cauliflower, has been proposed as a treatment.    Periodontal therapy or scaling and root planing has also been suggested as an additional treatment. 
Extranodal marginal zone B-cell lymphomas Edit
Extranodal marginal zone B-cell lymphomas (also termed MALT lymphomas) are generally indolent malignancies. Recommended treatment of H. pylori-positive extranodal marginal zone B-cell lymphoma of the stomach, when localized (i.e. Ann Arbor stage I and II), employs one of the antibiotic-proton pump inhibitor regiments listed in the H. pylori eradication protocols. If the initial regimen fails to eradicate the pathogen, patients are treated with an alternate protocol. Eradication of the pathogen is successful in 70–95% of cases.  Some 50-80% of patients who experience eradication of the pathogen develop within 3–28 months a remission and long-term clinical control of their lymphoma. Radiation therapy to the stomach and surrounding (i.e. peri-gastric) lymph nodes has also been used to successfully treat these localized cases. Patients with non-localized (i.e. systemic Ann Arbor stage III and IV) disease who are free of symptoms have been treated with watchful waiting or, if symptomatic, with the immunotherapy drug, rituximab, (given for 4 weeks) combined with the chemotherapy drug, chlorambucil, for 6–12 months 58% of these patients attain a 58% progression-free survival rate at 5 years. Frail stage III/IV patients have been successfully treated with rituximab or the chemotherapy drug, cyclophosphamide, alone.  Only rare cases of H. pylori-positive extranodal marginal zone B-cell lymphoma of the colon have been successfully treated with an antibiotic-proton pump inhibitor regimen the currently recommended treatments for this disease are surgical resection, endoscopic resection, radiation, chemotherapy, or, more recently, rituximab.  In the few reported cases of H. pylori-positive extranodal marginal zone B-cell lymphoma of the esophagus, localized disease has been successfully treated with antibiotic-proton pump inhibitor regimens however, advanced disease appears less responsive or unresponsive to these regimens but partially responsive to rituximab.  Antibiotic-proton pump inhibitor eradication therapy and localized radiation therapy have been used successfully to treat H. pylori-positive extranodal marginal zone B-cell lymphomas of the rectum however radiation therapy has given slightly better results and therefore been suggested to be the disease' preferred treatment.  The treatment of localized H. pylori-positive extranodal marginal zone B-cell lymphoma of the ocular adenexa with antibiotic/proton pump inhibitor regimens has achieved 2 year and 5 year failure-free survival rates of 67% and 55%, respectively, and a 5 year progression-free rate of 61%.  However, the generally recognized treatment of choice for patients with systemic involvement uses various chemotherapy drugs often combined with rituximab. 
Diffuse large B-cell lymphoma Edit
Diffuse large B-cell lymphoma is a far more aggressive cancer than extranodal marginal zone B-cell lymphoma. Cases of this malignancy that are H. pylori-positive may be derived from the latter lymphoma  and are less aggressive as well as more susceptible to treatment than H. pylori negative cases.   Several recent studies strongly suggest that localized, early-stage diffuse Helicobacter pylori positive diffuse large B-cell lymphoma, when limited to the stomach, can be successfully treated with antibiotic-proton pump inhibitor regimens.     However, these studies also agree that, given the aggressiveness of diffuse large B-cell lymphoma, patients treated with one of these H. pylori eradication regimes need to be carefully followed. If found unresponsive to or clinically worsening on these regimens, these patients should be switched to more conventional therapy such as chemotherapy (e.g. CHOP or a CHOP-like regimen), immunotherapy (e.g. rituximab), surgery, and/or local radiotherapy.  H. pylori positive diffuse large B-cell lymphoma has been successfully treated with one or a combination of these methods. 
Stomach adenocarcinoma Edit
Helicobacter pylori is linked to the majority of gastric adenocarcinoma cases, particularly those that are located outside of the stomach's cardia (i.e. esophagus-stomach junction).  The treatment for this cancer is highly aggressive with even localized disease being treated sequentially with chemotherapy and radiotherapy before surgical resection.  Since this cancer, once developed, is independent of H. pylori infection, antibiotic-proton pump inhibitor regimens are not used in its treatment. 
Helicobacter pylori colonizes the stomach and induces chronic gastritis, a long-lasting inflammation of the stomach. The bacterium persists in the stomach for decades in most people. Most individuals infected by H. pylori never experience clinical symptoms, despite having chronic gastritis. About 10–20% of those colonized by H. pylori ultimately develop gastric and duodenal ulcers.  H. pylori infection is also associated with a 1–2% lifetime risk of stomach cancer and a less than 1% risk of gastric MALT lymphoma. 
In the absence of treatment, H. pylori infection – once established in its gastric niche – is widely believed to persist for life.  In the elderly, however, infection likely can disappear as the stomach's mucosa becomes increasingly atrophic and inhospitable to colonization. The proportion of acute infections that persist is not known, but several studies that followed the natural history in populations have reported apparent spontaneous elimination.  
Mounting evidence suggests H. pylori has an important role in protection from some diseases.  The incidence of acid reflux disease, Barrett's esophagus, and esophageal cancer have been rising dramatically at the same time as H. pylori ' s presence decreases.  In 1996, Martin J. Blaser advanced the hypothesis that H. pylori has a beneficial effect by regulating the acidity of the stomach contents.   The hypothesis is not universally accepted as several randomized controlled trials failed to demonstrate worsening of acid reflux disease symptoms following eradication of H. pylori.   Nevertheless, Blaser has reasserted his view that H. pylori is a member of the normal flora of the stomach.  He postulates that the changes in gastric physiology caused by the loss of H. pylori account for the recent increase in incidence of several diseases, including type 2 diabetes, obesity, and asthma.   His group has recently shown that H. pylori colonization is associated with a lower incidence of childhood asthma. 
At least half the world's population is infected by the bacterium, making it the most widespread infection in the world.  Actual infection rates vary from nation to nation the developing world has much higher infection rates than the West (Western Europe, North America, Australasia), where rates are estimated to be around 25%. 
The age when someone acquires this bacterium seems to influence the pathologic outcome of the infection. People infected at an early age are likely to develop more intense inflammation that may be followed by atrophic gastritis with a higher subsequent risk of gastric ulcer, gastric cancer, or both. Acquisition at an older age brings different gastric changes more likely to lead to duodenal ulcer.  Infections are usually acquired in early childhood in all countries.  However, the infection rate of children in developing nations is higher than in industrialized nations, probably due to poor sanitary conditions, perhaps combined with lower antibiotics usage for unrelated pathologies. In developed nations, it is currently uncommon to find infected children, but the percentage of infected people increases with age, with about 50% infected for those over the age of 60 compared with around 10% between 18 and 30 years.  The higher prevalence among the elderly reflects higher infection rates in the past when the individuals were children rather than more recent infection at a later age of the individual.  In the United States, prevalence appears higher in African-American and Hispanic populations, most likely due to socioeconomic factors.   The lower rate of infection in the West is largely attributed to higher hygiene standards and widespread use of antibiotics. Despite high rates of infection in certain areas of the world, the overall frequency of H. pylori infection is declining.  However, antibiotic resistance is appearing in H. pylori many metronidazole- and clarithromycin-resistant strains are found in most parts of the world. 
Helicobacter pylori migrated out of Africa along with its human host circa 60,000 years ago.  Recent research states that genetic diversity in H. pylori, like that of its host, decreases with geographic distance from East Africa. Using the genetic diversity data, researchers have created simulations that indicate the bacteria seem to have spread from East Africa around 58,000 years ago. Their results indicate modern humans were already infected by H. pylori before their migrations out of Africa, and it has remained associated with human hosts since that time. 
H. pylori was first discovered in the stomachs of patients with gastritis and ulcers in 1982 by Drs. Barry Marshall and Robin Warren of Perth, Western Australia. At the time, the conventional thinking was that no bacterium could live in the acid environment of the human stomach. In recognition of their discovery, Marshall and Warren were awarded the 2005 Nobel Prize in Physiology or Medicine. 
Before the research of Marshall and Warren, German scientists found spiral-shaped bacteria in the lining of the human stomach in 1875, but they were unable to culture them, and the results were eventually forgotten.  The Italian researcher Giulio Bizzozero described similarly shaped bacteria living in the acidic environment of the stomach of dogs in 1893.  Professor Walery Jaworski of the Jagiellonian University in Kraków investigated sediments of gastric washings obtained by lavage from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic spiral shape, which he called Vibrio rugula. He was the first to suggest a possible role of this organism in the pathogenesis of gastric diseases. His work was included in the Handbook of Gastric Diseases, but it had little impact, as it was written in Polish.  Several small studies conducted in the early 20th century demonstrated the presence of curved rods in the stomachs of many people with peptic ulcers and stomach cancers.  Interest in the bacteria waned, however, when an American study published in 1954 failed to observe the bacteria in 1180 stomach biopsies. 
Interest in understanding the role of bacteria in stomach diseases was rekindled in the 1970s, with the visualization of bacteria in the stomachs of people with gastric ulcers.  The bacteria had also been observed in 1979, by Robin Warren, who researched it further with Barry Marshall from 1981. After unsuccessful attempts at culturing the bacteria from the stomach, they finally succeeded in visualizing colonies in 1982, when they unintentionally left their Petri dishes incubating for five days over the Easter weekend. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by bacterial infection and not by stress or spicy food, as had been assumed before. 
Some skepticism was expressed initially, but within a few years multiple research groups had verified the association of H. pylori with gastritis and, to a lesser extent, ulcers.  To demonstrate H. pylori caused gastritis and was not merely a bystander, Marshall drank a beaker of H. pylori culture. He became ill with nausea and vomiting several days later. An endoscopy 10 days after inoculation revealed signs of gastritis and the presence of H. pylori. These results suggested H. pylori was the causative agent. Marshall and Warren went on to demonstrate antibiotics are effective in the treatment of many cases of gastritis. In 1987, the Sydney gastroenterologist Thomas Borody invented the first triple therapy for the treatment of duodenal ulcers.  In 1994, the National Institutes of Health stated most recurrent duodenal and gastric ulcers were caused by H. pylori, and recommended antibiotics be included in the treatment regimen. 
The bacterium was initially named Campylobacter pyloridis, then renamed C. pylori in 1987 (pylori being the genitive of pylorus, the circular opening leading from the stomach into the duodenum, from the Ancient Greek word πυλωρός, which means gatekeeper.  ).  When 16S ribosomal RNA gene sequencing and other research showed in 1989 that the bacterium did not belong in the genus Campylobacter, it was placed in its own genus, Helicobacter from the ancient Greek έλιξ (hělix) "spiral" or "coil".  
In October 1987, a group of experts met in Copenhagen to found the European Helicobacter Study Group (EHSG), an international multidisciplinary research group and the only institution focused on H. pylori.  The Group is involved with the Annual International Workshop on Helicobacter and Related Bacteria,  the Maastricht Consensus Reports (European Consensus on the management of H. pylori),     and other educational and research projects, including two international long-term projects:
- European Registry on H. pylori Management (Hp-EuReg) – a database systematically registering the routine clinical practice of European gastroenterologists. 
- Optimal H. pylori management in primary care (OptiCare) – a long-term educational project aiming to disseminate the evidence based recommendations of the Maastricht IV Consensus to primary care physicians in Europe, funded by an educational grant from United European Gastroenterology. 
Results from in vitro studies suggest that fatty acids, mainly polyunsaturated fatty acids, have a bactericidal effect against H. pylori, but their in vivo effects have not been proven. 
Control of the Digestive Process
The process of digestion is controlled by both hormones and nerves. Hormonal control is mainly by endocrine hormones secreted by cells in the lining of the stomach and small intestine. These hormones stimulate the production of digestive enzymes, bicarbonate, and bile. The hormone secretin, for example, is produced by endocrine cells lining the duodenum of the small intestine. Acidic chyme entering the duodenum from the stomach triggers the release of secretin into the bloodstream. When the secretin returns via the circulation to the digestive system, it signals the release of bicarbonate from the pancreas. The bicarbonate neutralizes the acidic chyme. See Table 15.3.2 for a summary of the major hormones governing the process of chemical digestion.
Nerves involved in digestion include those that connect digestive organs to the central nervous system , as well as nerves inside the walls of the digestive organs. Nerves connecting the digestive organs to the central nervous system cause smooth muscles in the walls of digestive organs to contract or relax as needed, depending on whether or not there is food to be digested. Nerves within digestive organs are stimulated when food enters the organs and stretches their walls. These nerves trigger the release of substances that speed up or slow down the movement of food through the GI tract and the secretion of digestive enzymes.
Mammal classification has been through several revisions since Carl Linnaeus initially defined the class, and at present, no classification system is universally accepted. McKenna & Bell (1997) and Wilson & Reader (2005) provide useful recent compendiums.  Simpson (1945)  provides systematics of mammal origins and relationships that had been taught universally until the end of the 20th century. However, since 1945, a large amount of new and more detailed information has gradually been found: The paleontological record has been recalibrated, and the intervening years have seen much debate and progress concerning the theoretical underpinnings of systematization itself, partly through the new concept of cladistics. Though fieldwork and lab work progressively outdated Simpson's classification, it remains the closest thing to an official classification of mammals, despite its known issues. 
Most mammals, including the six most species-rich orders, belong to the placental group. The three largest orders in numbers of species are Rodentia: mice, rats, porcupines, beavers, capybaras, and other gnawing mammals Chiroptera: bats and Soricomorpha: shrews, moles, and solenodons. The next three biggest orders, depending on the biological classification scheme used, are the Primates: apes, monkeys, and lemurs the Cetartiodactyla: whales and even-toed ungulates and the Carnivora which includes cats, dogs, weasels, bears, seals, and allies.  According to Mammal Species of the World, 5,416 species were identified in 2006. These were grouped into 1,229 genera, 153 families and 29 orders.  In 2008, the International Union for Conservation of Nature (IUCN) completed a five-year Global Mammal Assessment for its IUCN Red List, which counted 5,488 species.  According to research published in the Journal of Mammalogy in 2018, the number of recognized mammal species is 6,495, including 96 recently extinct. 
The word "mammal" is modern, from the scientific name Mammalia coined by Carl Linnaeus in 1758, derived from the Latin mamma ("teat, pap"). In an influential 1988 paper, Timothy Rowe defined Mammalia phylogenetically as the crown group of mammals, the clade consisting of the most recent common ancestor of living monotremes (echidnas and platypuses) and Therian mammals (marsupials and placentals) and all descendants of that ancestor.  Since this ancestor lived in the Jurassic period, Rowe's definition excludes all animals from the earlier Triassic, despite the fact that Triassic fossils in the Haramiyida have been referred to the Mammalia since the mid-19th century.  If Mammalia is considered as the crown group, its origin can be roughly dated as the first known appearance of animals more closely related to some extant mammals than to others. Ambondro is more closely related to monotremes than to therian mammals while Amphilestes and Amphitherium are more closely related to the therians as fossils of all three genera are dated about 167 million years ago in the Middle Jurassic, this is a reasonable estimate for the appearance of the crown group. 
T.S. Kemp has provided a more traditional definition: "Synapsids that possess a dentary–squamosal jaw articulation and occlusion between upper and lower molars with a transverse component to the movement" or, equivalently in Kemp's view, the clade originating with the last common ancestor of Sinoconodon and living mammals.  The earliest known synapsid satisfying Kemp's definitions is Tikitherium, dated 225 Ma , so the appearance of mammals in this broader sense can be given this Late Triassic date.  
In 1997, the mammals were comprehensively revised by Malcolm C. McKenna and Susan K. Bell, which has resulted in the McKenna/Bell classification. The authors worked together as paleontologists at the American Museum of Natural History. McKenna inherited the project from Simpson and, with Bell, constructed a completely updated hierarchical system, covering living and extinct taxa, that reflects the historical genealogy of Mammalia.  Their 1997 book, Classification of Mammals above the Species Level,  is a comprehensive work on the systematics, relationships and occurrences of all mammal taxa, living and extinct, down through the rank of genus, though molecular genetic data challenge several of the higher-level groupings.
In the following list, extinct groups are labelled with a dagger (†).
- Subclass Prototheria: monotremes: echidnas and the platypus
- Subclass Theriiformes: live-bearing mammals and their prehistoric relatives
- Infraclass †Allotheria: multituberculates
- Infraclass †Eutriconodonta: eutriconodonts
- Infraclass Holotheria: modern live-bearing mammals and their prehistoric relatives
- Superlegion †Kuehneotheria
- Supercohort Theria: live-bearing mammals
- Cohort Marsupialia: marsupials
- Magnorder Australidelphia: Australian marsupials and the monito del monte
- Magnorder Ameridelphia: New World marsupials. Now considered paraphyletic, with shrew opossums being closer to australidelphians. 
- Magnorder Xenarthra: xenarthrans
- Magnorder Epitheria: epitheres
- Superorder †Leptictida
- Superorder Preptotheria
- Grandorder Anagalida: lagomorphs, rodents and elephant shrews
- Grandorder Ferae: carnivorans, pangolins, †creodonts and relatives
- Grandorder Lipotyphla: insectivorans
- Grandorder Archonta: bats, primates, colugos and treeshrews
- Grandorder Ungulata: ungulates
- Order Tubulidentataincertae sedis: aardvark
- Mirorder Eparctocyona: †condylarths, whales and artiodactyls (even-toed ungulates)
- Mirorder †Meridiungulata: South American ungulates
- Mirorder Altungulata: perissodactyls (odd-toed ungulates), elephants, manatees and hyraxes
Molecular classification of placentals
As of the early 21st century, molecular studies based on DNA analysis have suggested new relationships among mammal families. Most of these findings have been independently validated by retrotransposon presence/absence data.  Classification systems based on molecular studies reveal three major groups or lineages of placental mammals—Afrotheria, Xenarthra and Boreoeutheria—which diverged in the Cretaceous. The relationships between these three lineages is contentious, and all three possible hypotheses have been proposed with respect to which group is basal. These hypotheses are Atlantogenata (basal Boreoeutheria), Epitheria (basal Xenarthra) and Exafroplacentalia (basal Afrotheria).  Boreoeutheria in turn contains two major lineages—Euarchontoglires and Laurasiatheria.
Estimates for the divergence times between these three placental groups range from 105 to 120 million years ago, depending on the type of DNA used (such as nuclear or mitochondrial)  and varying interpretations of paleogeographic data. 
The cladogram above is based on Tarver et al. (2016) 
- Clade Afroinsectiphilia
- Order Macroscelidea: elephant shrews (Africa)
- Order Afrosoricida: tenrecs and golden moles (Africa)
- Order Tubulidentata: aardvark (Africa south of the Sahara)
- Order Hyracoidea: hyraxes or dassies (Africa, Arabia)
- Order Proboscidea: elephants (Africa, Southeast Asia)
- Order Sirenia: dugong and manatees (cosmopolitan tropical)
- Order Pilosa: sloths and anteaters (neotropical)
- Order Cingulata: armadillos and extinct relatives (Americas)
Group III: Magnaorder Boreoeutheria 
- Superorder: Euarchontoglires (Supraprimates)
- Grandorder Euarchonta
- Order Scandentia: treeshrews (Southeast Asia).
- Order Dermoptera: flying lemurs or colugos (Southeast Asia)
- Order Primates: lemurs, bushbabies, monkeys, apes, humans (cosmopolitan)
- Order Lagomorpha: pikas, rabbits, hares (Eurasia, Africa, Americas)
- Order Rodentia: rodents (cosmopolitan)
- Order Eulipotyphla: shrews, hedgehogs, moles, solenodons
- Order Chiroptera: bats (cosmopolitan)
- Order Pholidota: pangolins or scaly anteaters (Africa, South Asia)
- Order Carnivora: carnivores (cosmopolitan), including cats and dogs
- Order Cetartiodactyla: cetaceans (whales, dolphins and porpoises) and even-toed ungulates, including pigs, cattle, deer and giraffes
- Order Perissodactyla: odd-toed ungulates, including horses, donkeys, zebras, tapirs and rhinoceroses
Synapsida, a clade that contains mammals and their extinct relatives, originated during the Pennsylvanian subperiod (
300 million years ago), when they split from reptilian and avian lineages. Crown group mammals evolved from earlier mammaliaforms during the Early Jurassic. The cladogram takes Mammalia to be the crown group. 
Evolution from older amniotes
The first fully terrestrial vertebrates were amniotes. Like their amphibious tetrapod predecessors, they had lungs and limbs. Amniotic eggs, however, have internal membranes that allow the developing embryo to breathe but keep water in. Hence, amniotes can lay eggs on dry land, while amphibians generally need to lay their eggs in water.
The first amniotes apparently arose in the Pennsylvanian subperiod of the Carboniferous. They descended from earlier reptiliomorph amphibious tetrapods,  which lived on land that was already inhabited by insects and other invertebrates as well as ferns, mosses and other plants. Within a few million years, two important amniote lineages became distinct: the synapsids, which would later include the common ancestor of the mammals and the sauropsids, which now include turtles, lizards, snakes, crocodilians and dinosaurs (including birds).  Synapsids have a single hole (temporal fenestra) low on each side of the skull. One synapsid group, the pelycosaurs, included the largest and fiercest animals of the early Permian.  Nonmammalian synapsids are sometimes (inaccurately) called "mammal-like reptiles".  
Therapsids, a group of synapsids, descended from pelycosaurs in the Middle Permian, about 265 million years ago, and became the dominant land vertebrates.  They differ from basal eupelycosaurs in several features of the skull and jaws, including: larger skulls and incisors which are equal in size in therapsids, but not for eupelycosaurs.  The therapsid lineage leading to mammals went through a series of stages, beginning with animals that were very similar to their pelycosaur ancestors and ending with probainognathian cynodonts, some of which could easily be mistaken for mammals. Those stages were characterized by: 
- The gradual development of a bony secondary palate.
- Progression towards an erect limb posture, which would increase the animals' stamina by avoiding Carrier's constraint. But this process was slow and erratic: for example, all herbivorous nonmammaliaform therapsids retained sprawling limbs (some late forms may have had semierect hind limbs) Permian carnivorous therapsids had sprawling forelimbs, and some late Permian ones also had semisprawling hindlimbs. In fact, modern monotremes still have semisprawling limbs.
- The dentary gradually became the main bone of the lower jaw which, by the Triassic, progressed towards the fully mammalian jaw (the lower consisting only of the dentary) and middle ear (which is constructed by the bones that were previously used to construct the jaws of reptiles).
The Permian–Triassic extinction event about 252 million years ago, which was a prolonged event due to the accumulation of several extinction pulses, ended the dominance of carnivorous therapsids.  In the early Triassic, most medium to large land carnivore niches were taken over by archosaurs  which, over an extended period (35 million years), came to include the crocodylomorphs,  the pterosaurs and the dinosaurs  however, large cynodonts like Trucidocynodon and traversodontids still occupied large sized carnivorous and herbivorous niches respectively. By the Jurassic, the dinosaurs had come to dominate the large terrestrial herbivore niches as well. 
The first mammals (in Kemp's sense) appeared in the Late Triassic epoch (about 225 million years ago), 40 million years after the first therapsids. They expanded out of their nocturnal insectivore niche from the mid-Jurassic onwards  The Jurassic Castorocauda, for example, was a close relative of true mammals that had adaptations for swimming, digging and catching fish.  Most, if not all, are thought to have remained nocturnal (the nocturnal bottleneck), accounting for much of the typical mammalian traits.  The majority of the mammal species that existed in the Mesozoic Era were multituberculates, eutriconodonts and spalacotheriids.  The earliest known metatherian is Sinodelphys, found in 125 million-year-old Early Cretaceous shale in China's northeastern Liaoning Province. The fossil is nearly complete and includes tufts of fur and imprints of soft tissues. 
The oldest known fossil among the Eutheria ("true beasts") is the small shrewlike Juramaia sinensis, or "Jurassic mother from China", dated to 160 million years ago in the late Jurassic.  A later eutherian relative, Eomaia, dated to 125 million years ago in the early Cretaceous, possessed some features in common with the marsupials but not with the placentals, evidence that these features were present in the last common ancestor of the two groups but were later lost in the placental lineage.  In particular, the epipubic bones extend forwards from the pelvis. These are not found in any modern placental, but they are found in marsupials, monotremes, other nontherian mammals and Ukhaatherium, an early Cretaceous animal in the eutherian order Asioryctitheria. This also applies to the multituberculates.  They are apparently an ancestral feature, which subsequently disappeared in the placental lineage. These epipubic bones seem to function by stiffening the muscles during locomotion, reducing the amount of space being presented, which placentals require to contain their fetus during gestation periods. A narrow pelvic outlet indicates that the young were very small at birth and therefore pregnancy was short, as in modern marsupials. This suggests that the placenta was a later development. 
One of the earliest known monotremes was Teinolophos, which lived about 120 million years ago in Australia.  Monotremes have some features which may be inherited from the original amniotes such as the same orifice to urinate, defecate and reproduce (cloaca)—as lizards and birds also do—  and they lay eggs which are leathery and uncalcified. 
Earliest appearances of features
Hadrocodium, whose fossils date from approximately 195 million years ago, in the early Jurassic, provides the first clear evidence of a jaw joint formed solely by the squamosal and dentary bones there is no space in the jaw for the articular, a bone involved in the jaws of all early synapsids. 
The earliest clear evidence of hair or fur is in fossils of Castorocauda and Megaconus, from 164 million years ago in the mid-Jurassic. In the 1950s, it was suggested that the foramina (passages) in the maxillae and premaxillae (bones in the front of the upper jaw) of cynodonts were channels which supplied blood vessels and nerves to vibrissae (whiskers) and so were evidence of hair or fur   it was soon pointed out, however, that foramina do not necessarily show that an animal had vibrissae, as the modern lizard Tupinambis has foramina that are almost identical to those found in the nonmammalian cynodont Thrinaxodon.   Popular sources, nevertheless, continue to attribute whiskers to Thrinaxodon.  Studies on Permian coprolites suggest that non-mammalian synapsids of the epoch already had fur, setting the evolution of hairs possibly as far back as dicynodonts. 
When endothermy first appeared in the evolution of mammals is uncertain, though it is generally agreed to have first evolved in non-mammalian therapsids.   Modern monotremes have lower body temperatures and more variable metabolic rates than marsupials and placentals,  but there is evidence that some of their ancestors, perhaps including ancestors of the therians, may have had body temperatures like those of modern therians.  Likewise, some modern therians like afrotheres and xenarthrans have secondarily developed lower body temperatures. 
The evolution of erect limbs in mammals is incomplete—living and fossil monotremes have sprawling limbs. The parasagittal (nonsprawling) limb posture appeared sometime in the late Jurassic or early Cretaceous it is found in the eutherian Eomaia and the metatherian Sinodelphys, both dated to 125 million years ago.  Epipubic bones, a feature that strongly influenced the reproduction of most mammal clades, are first found in Tritylodontidae, suggesting that it is a synapomorphy between them and mammaliformes. They are omnipresent in non-placental mammaliformes, though Megazostrodon and Erythrotherium appear to have lacked them. 
It has been suggested that the original function of lactation (milk production) was to keep eggs moist. Much of the argument is based on monotremes, the egg-laying mammals.   In human females, mammary glands become fully developed during puberty, regardless of pregnancy. 
Rise of the mammals
Therian mammals took over the medium- to large-sized ecological niches in the Cenozoic, after the Cretaceous–Paleogene extinction event approximately 66 million years ago emptied ecological space once filled by non-avian dinosaurs and other groups of reptiles, as well as various other mammal groups,  and underwent an exponential increase in body size (megafauna).  Then mammals diversified very quickly both birds and mammals show an exponential rise in diversity.  For example, the earliest known bat dates from about 50 million years ago, only 16 million years after the extinction of the non-avian dinosaurs. 
Molecular phylogenetic studies initially suggested that most placental orders diverged about 100 to 85 million years ago and that modern families appeared in the period from the late Eocene through the Miocene.  However, no placental fossils have been found from before the end of the Cretaceous.  The earliest undisputed fossils of placentals comes from the early Paleocene, after the extinction of the non-avian dinosaurs.  In particular, scientists have identified an early Paleocene animal named Protungulatum donnae as one of the first placental mammals.  however it has been reclassified as a non-placental eutherian.  Recalibrations of genetic and morphological diversity rates have suggested a Late Cretaceous origin for placentals, and a Paleocene origin for most modern clades. 
The earliest known ancestor of primates is Archicebus achilles  from around 55 million years ago.  This tiny primate weighed 20–30 grams (0.7–1.1 ounce) and could fit within a human palm. 
Living mammal species can be identified by the presence of sweat glands, including those that are specialized to produce milk to nourish their young.  In classifying fossils, however, other features must be used, since soft tissue glands and many other features are not visible in fossils. 
Many traits shared by all living mammals appeared among the earliest members of the group:
- Jaw joint – The dentary (the lower jaw bone, which carries the teeth) and the squamosal (a small cranial bone) meet to form the joint. In most gnathostomes, including early therapsids, the joint consists of the articular (a small bone at the back of the lower jaw) and quadrate (a small bone at the back of the upper jaw). 
- Middle ear – In crown-group mammals, sound is carried from the eardrum by a chain of three bones, the malleus, the incus and the stapes. Ancestrally, the malleus and the incus are derived from the articular and the quadrate bones that constituted the jaw joint of early therapsids. 
- Tooth replacement – Teeth can be replaced once (diphyodonty) or (as in toothed whales and murid rodents) not at all (monophyodonty).  Elephants, manatees, and kangaroos continually grow new teeth throughout their life (polyphyodonty). 
- Prismatic enamel – The enamel coating on the surface of a tooth consists of prisms, solid, rod-like structures extending from the dentin to the tooth's surface. 
- Occipital condyles – Two knobs at the base of the skull fit into the topmost neck vertebra most other tetrapods, in contrast, have only one such knob. 
For the most part, these characteristics were not present in the Triassic ancestors of the mammals.  Nearly all mammaliaforms possess an epipubic bone, the exception being modern placentals. 
On average, male mammals are larger than females, with males being at least 10% larger than females in over 45% of investigated species. Most mammalian orders also exhibit male-biased sexual dimorphism, although some orders do not show any bias or are significantly female-biased (Lagomorpha). Sexual size dimorphism increases with body size across mammals (Rensch's rule), suggesting that there are parallel selection pressures on both male and female size. Male-biased dimorphism relates to sexual selection on males through male–male competition for females, as there is a positive correlation between the degree of sexual selection, as indicated by mating systems, and the degree of male-biased size dimorphism. The degree of sexual selection is also positively correlated with male and female size across mammals. Further, parallel selection pressure on female mass is identified in that age at weaning is significantly higher in more polygynous species, even when correcting for body mass. Also, the reproductive rate is lower for larger females, indicating that fecundity selection selects for smaller females in mammals. Although these patterns hold across mammals as a whole, there is considerable variation across orders. 
The majority of mammals have seven cervical vertebrae (bones in the neck). The exceptions are the manatee and the two-toed sloth, which have six, and the three-toed sloth which has nine.  All mammalian brains possess a neocortex, a brain region unique to mammals.  Placental brains have a corpus callosum, unlike monotremes and marsupials. 
The lungs of mammals are spongy and honeycombed. Breathing is mainly achieved with the diaphragm, which divides the thorax from the abdominal cavity, forming a dome convex to the thorax. Contraction of the diaphragm flattens the dome, increasing the volume of the lung cavity. Air enters through the oral and nasal cavities, and travels through the larynx, trachea and bronchi, and expands the alveoli. Relaxing the diaphragm has the opposite effect, decreasing the volume of the lung cavity, causing air to be pushed out of the lungs. During exercise, the abdominal wall contracts, increasing pressure on the diaphragm, which forces air out quicker and more forcefully. The rib cage is able to expand and contract the chest cavity through the action of other respiratory muscles. Consequently, air is sucked into or expelled out of the lungs, always moving down its pressure gradient.   This type of lung is known as a bellows lung due to its resemblance to blacksmith bellows. 
The mammalian heart has four chambers, two upper atria, the receiving chambers, and two lower ventricles, the discharging chambers.  The heart has four valves, which separate its chambers and ensures blood flows in the correct direction through the heart (preventing backflow). After gas exchange in the pulmonary capillaries (blood vessels in the lungs), oxygen-rich blood returns to the left atrium via one of the four pulmonary veins. Blood flows nearly continuously back into the atrium, which acts as the receiving chamber, and from here through an opening into the left ventricle. Most blood flows passively into the heart while both the atria and ventricles are relaxed, but toward the end of the ventricular relaxation period, the left atrium will contract, pumping blood into the ventricle. The heart also requires nutrients and oxygen found in blood like other muscles, and is supplied via coronary arteries. 
The integumentary system (skin) is made up of three layers: the outermost epidermis, the dermis and the hypodermis. The epidermis is typically 10 to 30 cells thick its main function is to provide a waterproof layer. Its outermost cells are constantly lost its bottommost cells are constantly dividing and pushing upward. The middle layer, the dermis, is 15 to 40 times thicker than the epidermis. The dermis is made up of many components, such as bony structures and blood vessels. The hypodermis is made up of adipose tissue, which stores lipids and provides cushioning and insulation. The thickness of this layer varies widely from species to species  : 97 marine mammals require a thick hypodermis (blubber) for insulation, and right whales have the thickest blubber at 20 inches (51 cm).  Although other animals have features such as whiskers, feathers, setae, or cilia that superficially resemble it, no animals other than mammals have hair. It is a definitive characteristic of the class, though some mammals have very little.  : 61
Herbivores have developed a diverse range of physical structures to facilitate the consumption of plant material. To break up intact plant tissues, mammals have developed teeth structures that reflect their feeding preferences. For instance, frugivores (animals that feed primarily on fruit) and herbivores that feed on soft foliage have low-crowned teeth specialized for grinding foliage and seeds. Grazing animals that tend to eat hard, silica-rich grasses, have high-crowned teeth, which are capable of grinding tough plant tissues and do not wear down as quickly as low-crowned teeth.  Most carnivorous mammals have carnassialiforme teeth (of varying length depending on diet), long canines and similar tooth replacement patterns. 
The stomach of even-toed ungulates (Artiodactyla) is divided into four sections: the rumen, the reticulum, the omasum and the abomasum (only ruminants have a rumen). After the plant material is consumed, it is mixed with saliva in the rumen and reticulum and separates into solid and liquid material. The solids lump together to form a bolus (or cud), and is regurgitated. When the bolus enters the mouth, the fluid is squeezed out with the tongue and swallowed again. Ingested food passes to the rumen and reticulum where cellulolytic microbes (bacteria, protozoa and fungi) produce cellulase, which is needed to break down the cellulose in plants.  Perissodactyls, in contrast to the ruminants, store digested food that has left the stomach in an enlarged cecum, where it is fermented by bacteria.  Carnivora have a simple stomach adapted to digest primarily meat, as compared to the elaborate digestive systems of herbivorous animals, which are necessary to break down tough, complex plant fibers. The caecum is either absent or short and simple, and the large intestine is not sacculated or much wider than the small intestine. 
The mammalian excretory system involves many components. Like most other land animals, mammals are ureotelic, and convert ammonia into urea, which is done by the liver as part of the urea cycle.  Bilirubin, a waste product derived from blood cells, is passed through bile and urine with the help of enzymes excreted by the liver.  The passing of bilirubin via bile through the intestinal tract gives mammalian feces a distinctive brown coloration.  Distinctive features of the mammalian kidney include the presence of the renal pelvis and renal pyramids, and of a clearly distinguishable cortex and medulla, which is due to the presence of elongated loops of Henle. Only the mammalian kidney has a bean shape, although there are some exceptions, such as the multilobed reniculate kidneys of pinnipeds, cetaceans and bears.   Most adult placental mammals have no remaining trace of the cloaca. In the embryo, the embryonic cloaca divides into a posterior region that becomes part of the anus, and an anterior region that has different fates depending on the sex of the individual: in females, it develops into the vestibule that receives the urethra and vagina, while in males it forms the entirety of the penile urethra.  However, the tenrecs, golden moles, and some shrews retain a cloaca as adults.  In marsupials, the genital tract is separate from the anus, but a trace of the original cloaca does remain externally.  Monotremes, which translates from Greek into "single hole", have a true cloaca. 
As in all other tetrapods, mammals have a larynx that can quickly open and close to produce sounds, and a supralaryngeal vocal tract which filters this sound. The lungs and surrounding musculature provide the air stream and pressure required to phonate. The larynx controls the pitch and volume of sound, but the strength the lungs exert to exhale also contributes to volume. More primitive mammals, such as the echidna, can only hiss, as sound is achieved solely through exhaling through a partially closed larynx. Other mammals phonate using vocal folds, as opposed to the vocal cords seen in birds and reptiles. The movement or tenseness of the vocal folds can result in many sounds such as purring and screaming. Mammals can change the position of the larynx, allowing them to breathe through the nose while swallowing through the mouth, and to form both oral and nasal sounds nasal sounds, such as a dog whine, are generally soft sounds, and oral sounds, such as a dog bark, are generally loud. 
Some mammals have a large larynx and thus a low-pitched voice, namely the hammer-headed bat (Hypsignathus monstrosus) where the larynx can take up the entirety of the thoracic cavity while pushing the lungs, heart, and trachea into the abdomen.  Large vocal pads can also lower the pitch, as in the low-pitched roars of big cats.  The production of infrasound is possible in some mammals such as the African elephant (Loxodonta spp.) and baleen whales.   Small mammals with small larynxes have the ability to produce ultrasound, which can be detected by modifications to the middle ear and cochlea. Ultrasound is inaudible to birds and reptiles, which might have been important during the Mesozoic, when birds and reptiles were the dominant predators. This private channel is used by some rodents in, for example, mother-to-pup communication, and by bats when echolocating. Toothed whales also use echolocation, but, as opposed to the vocal membrane that extends upward from the vocal folds, they have a melon to manipulate sounds. Some mammals, namely the primates, have air sacs attached to the larynx, which may function to lower the resonances or increase the volume of sound. 
The vocal production system is controlled by the cranial nerve nuclei in the brain, and supplied by the recurrent laryngeal nerve and the superior laryngeal nerve, branches of the vagus nerve. The vocal tract is supplied by the hypoglossal nerve and facial nerves. Electrical stimulation of the periaqueductal gray (PEG) region of the mammalian midbrain elicit vocalizations. The ability to learn new vocalizations is only exemplified in humans, seals, cetaceans, elephants and possibly bats in humans, this is the result of a direct connection between the motor cortex, which controls movement, and the motor neurons in the spinal cord. 
The primary function of the fur of mammals is thermoregulation. Others include protection, sensory purposes, waterproofing, and camouflage.  Different types of fur serve different purposes:  : 99
- Definitive – which may be shed after reaching a certain length
- Vibrissae – sensory hairs, most commonly whiskers
- Pelage – guard hairs, under-fur, and awn hair – stiff guard hair used for defense (such as in porcupines) – long hairs usually used in visual signals. (such as a lion's mane) – often called "down fur" which insulates newborn mammals – long, soft and often curly
Hair length is not a factor in thermoregulation: for example, some tropical mammals such as sloths have the same length of fur length as some arctic mammals but with less insulation and, conversely, other tropical mammals with short hair have the same insulating value as arctic mammals. The denseness of fur can increase an animal's insulation value, and arctic mammals especially have dense fur for example, the musk ox has guard hairs measuring 30 cm (12 in) as well as a dense underfur, which forms an airtight coat, allowing them to survive in temperatures of −40 °C (−40 °F).  : 162–163 Some desert mammals, such as camels, use dense fur to prevent solar heat from reaching their skin, allowing the animal to stay cool a camel's fur may reach 70 °C (158 °F) in the summer, but the skin stays at 40 °C (104 °F).  : 188 Aquatic mammals, conversely, trap air in their fur to conserve heat by keeping the skin dry.  : 162–163
Mammalian coats are colored for a variety of reasons, the major selective pressures including camouflage, sexual selection, communication, and thermoregulation. Coloration in both the hair and skin of mammals is mainly determined by the type and amount of melanin eumelanins for brown and black colors and pheomelanin for a range of yellowish to reddish colors, giving mammals an earth tone.   Some mammals have more vibrant colors the mandrill has bright blue ridges on its muzzle which are produced by diffraction in facial collagen fibers.  Many sloths appear green because their fur hosts green algae this may be a symbiotic relation that affords camouflage to the sloths. 
Camouflage is a powerful influence in a large number of mammals, as it helps to conceal individuals from predators or prey.  In arctic and subarctic mammals such as the arctic fox (Alopex lagopus), collared lemming (Dicrostonyx groenlandicus), stoat (Mustela erminea), and snowshoe hare (Lepus americanus), seasonal color change between brown in summer and white in winter is driven largely by camouflage.  Some arboreal mammals, notably primates and marsupials, have shades of violet, green, or blue skin on parts of their bodies, indicating some distinct advantage in their largely arboreal habitat due to convergent evolution. 
Aposematism, warning off possible predators, is the most likely explanation of the black-and-white pelage of many mammals which are able to defend themselves, such as in the foul-smelling skunk and the powerful and aggressive honey badger.  Coat color is sometimes sexually dimorphic, as in many primate species.  Differences in female and male coat color may indicate nutrition and hormone levels, important in mate selection.  Coat color may influence the ability to retain heat, depending on how much light is reflected. Mammals with a darker colored coat can absorb more heat from solar radiation, and stay warmer, and some smaller mammals, such as voles, have darker fur in the winter. The white, pigmentless fur of arctic mammals, such as the polar bear, may reflect more solar radiation directly onto the skin.  : 166–167  The dazzling black-and-white striping of zebras appear to provide some protection from biting flies. 
Mammals are solely gonochoric (an animal is born with either male or female genitalia, as opposed to hermaphrodites where there is no such schism).  In male placentals, the penis is used both for urination and copulation. Depending on the species, an erection may be fueled by blood flow into vascular, spongy tissue or by muscular action. A penis may be contained in a prepuce when not erect, and some placentals also have a penis bone (baculum).  Marsupials typically have forked penises,  while the echidna penis generally has four heads with only two functioning.  The testes of most mammals descend into the scrotum which is typically posterior to the penis but is often anterior in marsupials. Female mammals generally have a clitoris, labia majora and labia minora on the outside, while the internal system contains paired oviducts, 1–2 uteri, 1–2 cervices and a vagina. Marsupials have two lateral vaginas and a medial vagina. The "vagina" of monotremes is better understood as a "urogenital sinus". The uterine systems of placental mammals can vary between a duplex, were there are two uteri and cervices which open into the vagina, a bipartite, were two uterine horns have a single cervix that connects to the vagina, a bicornuate, which consists where two uterine horns that are connected distally but separate medially creating a Y-shape, and a simplex, which has a single uterus.    : 220–221, 247
The ancestral condition for mammal reproduction is the birthing of relatively undeveloped, either through direct vivipary or a short period as soft-shelled eggs. This is likely due to the fact that the torso could not expand due to the presence of epipubic bones. The oldest demonstration of this reproductive style is with Kayentatherium, which produced undeveloped perinates, but at much higher litter sizes than any modern mammal, 38 specimens.  Most modern mammals are viviparous, giving birth to live young. However, the five species of monotreme, the platypus and the four species of echidna, lay eggs. The monotremes have a sex determination system different from that of most other mammals.  In particular, the sex chromosomes of a platypus are more like those of a chicken than those of a therian mammal. 
Viviparous mammals are in the subclass Theria those living today are in the marsupial and placental infraclasses. Marsupials have a short gestation period, typically shorter than its estrous cycle and gives birth to an undeveloped newborn that then undergoes further development in many species, this takes place within a pouch-like sac, the marsupium, located in the front of the mother's abdomen. This is the plesiomorphic condition among viviparous mammals the presence of epipubic bones in all non-placental mammals prevents the expansion of the torso needed for full pregnancy.  Even non-placental eutherians probably reproduced this way.  The placentals give birth to relatively complete and developed young, usually after long gestation periods.  They get their name from the placenta, which connects the developing fetus to the uterine wall to allow nutrient uptake.  In placental mammals, the epipubic is either completely lost or converted into the baculum allowing the torso to be able to expand and thus birth developed offspring. 
The mammary glands of mammals are specialized to produce milk, the primary source of nutrition for newborns. The monotremes branched early from other mammals and do not have the nipples seen in most mammals, but they do have mammary glands. The young lick the milk from a mammary patch on the mother's belly.  Compared to placental mammals, the milk of marsupials changes greatly in both production rate and in nutrient composition, due to the underdeveloped young. In addition, the mammary glands have more autonomy allowing them to supply separate milks to young at different development stages.  Lactose is the main sugar in placental mammal milk while monotreme and marsupial milk is dominated by oligosaccharides.  Weaning is the process in which a mammal becomes less dependent on their mother's milk and more on solid food. 
Nearly all mammals are endothermic ("warm-blooded"). Most mammals also have hair to help keep them warm. Like birds, mammals can forage or hunt in weather and climates too cold for ectothermic ("cold-blooded") reptiles and insects. Endothermy requires plenty of food energy, so mammals eat more food per unit of body weight than most reptiles.  Small insectivorous mammals eat prodigious amounts for their size. A rare exception, the naked mole-rat produces little metabolic heat, so it is considered an operational poikilotherm.  Birds are also endothermic, so endothermy is not unique to mammals. 
Among mammals, species maximum lifespan varies significantly (for example the shrew has a lifespan of two years, whereas the oldest bowhead whale is recorded to be 211 years).  Although the underlying basis for these lifespan differences is still uncertain, numerous studies indicate that the ability to repair DNA damage is an important determinant of mammalian lifespan. In a 1974 study by Hart and Setlow,  it was found that DNA excision repair capability increased systematically with species lifespan among seven mammalian species. Species lifespan was observed to be robustly correlated with the capacity to recognize DNA double-strand breaks as well as the level of the DNA repair protein Ku80.  In a study of the cells from sixteen mammalian species, genes employed in DNA repair were found to be up-regulated in the longer-lived species.  The cellular level of the DNA repair enzyme poly ADP ribose polymerase was found to correlate with species lifespan in a study of 13 mammalian species.  Three additional studies of a variety of mammalian species also reported a correlation between species lifespan and DNA repair capability.   
Most vertebrates—the amphibians, the reptiles and some mammals such as humans and bears—are plantigrade, walking on the whole of the underside of the foot. Many mammals, such as cats and dogs, are digitigrade, walking on their toes, the greater stride length allowing more speed. Digitigrade mammals are also often adept at quiet movement.  Some animals such as horses are unguligrade, walking on the tips of their toes. This even further increases their stride length and thus their speed.  A few mammals, namely the great apes, are also known to walk on their knuckles, at least for their front legs. Giant anteaters  and platypuses  are also knuckle-walkers. Some mammals are bipeds, using only two limbs for locomotion, which can be seen in, for example, humans and the great apes. Bipedal species have a larger field of vision than quadrupeds, conserve more energy and have the ability to manipulate objects with their hands, which aids in foraging. Instead of walking, some bipeds hop, such as kangaroos and kangaroo rats.  
Animals will use different gaits for different speeds, terrain and situations. For example, horses show four natural gaits, the slowest horse gait is the walk, then there are three faster gaits which, from slowest to fastest, are the trot, the canter and the gallop. Animals may also have unusual gaits that are used occasionally, such as for moving sideways or backwards. For example, the main human gaits are bipedal walking and running, but they employ many other gaits occasionally, including a four-legged crawl in tight spaces.  Mammals show a vast range of gaits, the order that they place and lift their appendages in locomotion. Gaits can be grouped into categories according to their patterns of support sequence. For quadrupeds, there are three main categories: walking gaits, running gaits and leaping gaits.  Walking is the most common gait, where some feet are on the ground at any given time, and found in almost all legged animals. Running is considered to occur when at some points in the stride all feet are off the ground in a moment of suspension. 
Arboreal animals frequently have elongated limbs that help them cross gaps, reach fruit or other resources, test the firmness of support ahead and, in some cases, to brachiate (swing between trees).  Many arboreal species, such as tree porcupines, silky anteaters, spider monkeys, and possums, use prehensile tails to grasp branches. In the spider monkey, the tip of the tail has either a bare patch or adhesive pad, which provides increased friction. Claws can be used to interact with rough substrates and reorient the direction of forces the animal applies. This is what allows squirrels to climb tree trunks that are so large to be essentially flat from the perspective of such a small animal. However, claws can interfere with an animal's ability to grasp very small branches, as they may wrap too far around and prick the animal's own paw. Frictional gripping is used by primates, relying upon hairless fingertips. Squeezing the branch between the fingertips generates frictional force that holds the animal's hand to the branch. However, this type of grip depends upon the angle of the frictional force, thus upon the diameter of the branch, with larger branches resulting in reduced gripping ability. To control descent, especially down large diameter branches, some arboreal animals such as squirrels have evolved highly mobile ankle joints that permit rotating the foot into a 'reversed' posture. This allows the claws to hook into the rough surface of the bark, opposing the force of gravity. Small size provides many advantages to arboreal species: such as increasing the relative size of branches to the animal, lower center of mass, increased stability, lower mass (allowing movement on smaller branches) and the ability to move through more cluttered habitat.  Size relating to weight affects gliding animals such as the sugar glider.  Some species of primate, bat and all species of sloth achieve passive stability by hanging beneath the branch. Both pitching and tipping become irrelevant, as the only method of failure would be losing their grip. 
Bats are the only mammals that can truly fly. They fly through the air at a constant speed by moving their wings up and down (usually with some fore-aft movement as well). Because the animal is in motion, there is some airflow relative to its body which, combined with the velocity of the wings, generates a faster airflow moving over the wing. This generates a lift force vector pointing forwards and upwards, and a drag force vector pointing rearwards and upwards. The upwards components of these counteract gravity, keeping the body in the air, while the forward component provides thrust to counteract both the drag from the wing and from the body as a whole. 
The wings of bats are much thinner and consist of more bones than those of birds, allowing bats to maneuver more accurately and fly with more lift and less drag.   By folding the wings inwards towards their body on the upstroke, they use 35% less energy during flight than birds.  The membranes are delicate, ripping easily however, the tissue of the bat's membrane is able to regrow, such that small tears can heal quickly.  The surface of their wings is equipped with touch-sensitive receptors on small bumps called Merkel cells, also found on human fingertips. These sensitive areas are different in bats, as each bump has a tiny hair in the center, making it even more sensitive and allowing the bat to detect and collect information about the air flowing over its wings, and to fly more efficiently by changing the shape of its wings in response. 
Fossorial and subterranean
A fossorial (from Latin fossor, meaning "digger") is an animal adapted to digging which lives primarily, but not solely, underground. Some examples are badgers, and naked mole-rats. Many rodent species are also considered fossorial because they live in burrows for most but not all of the day. Species that live exclusively underground are subterranean, and those with limited adaptations to a fossorial lifestyle sub-fossorial. Some organisms are fossorial to aid in temperature regulation while others use the underground habitat for protection from predators or for food storage. 
Fossorial mammals have a fusiform body, thickest at the shoulders and tapering off at the tail and nose. Unable to see in the dark burrows, most have degenerated eyes, but degeneration varies between species pocket gophers, for example, are only semi-fossorial and have very small yet functional eyes, in the fully fossorial marsupial mole the eyes are degenerated and useless, talpa moles have vestigial eyes and the cape golden mole has a layer of skin covering the eyes. External ears flaps are also very small or absent. Truly fossorial mammals have short, stout legs as strength is more important than speed to a burrowing mammal, but semi-fossorial mammals have cursorial legs. The front paws are broad and have strong claws to help in loosening dirt while excavating burrows, and the back paws have webbing, as well as claws, which aids in throwing loosened dirt backwards. Most have large incisors to prevent dirt from flying into their mouth. 
Many fossorial mammals such as shrews, hedgehogs, and moles were classified under the now obsolete order Insectivora. 
Fully aquatic mammals, the cetaceans and sirenians, have lost their legs and have a tail fin to propel themselves through the water. Flipper movement is continuous. Whales swim by moving their tail fin and lower body up and down, propelling themselves through vertical movement, while their flippers are mainly used for steering. Their skeletal anatomy allows them to be fast swimmers. Most species have a dorsal fin to prevent themselves from turning upside-down in the water.   The flukes of sirenians are raised up and down in long strokes to move the animal forward, and can be twisted to turn. The forelimbs are paddle-like flippers which aid in turning and slowing. 
Semi-aquatic mammals, like pinnipeds, have two pairs of flippers on the front and back, the fore-flippers and hind-flippers. The elbows and ankles are enclosed within the body.   Pinnipeds have several adaptions for reducing drag. In addition to their streamlined bodies, they have smooth networks of muscle bundles in their skin that may increase laminar flow and make it easier for them to slip through water. They also lack arrector pili, so their fur can be streamlined as they swim.  They rely on their fore-flippers for locomotion in a wing-like manner similar to penguins and sea turtles.  Fore-flipper movement is not continuous, and the animal glides between each stroke.  Compared to terrestrial carnivorans, the fore-limbs are reduced in length, which gives the locomotor muscles at the shoulder and elbow joints greater mechanical advantage  the hind-flippers serve as stabilizers.  Other semi-aquatic mammals include beavers, hippopotamuses, otters and platypuses.  Hippos are very large semi-aquatic mammals, and their barrel-shaped bodies have graviportal skeletal structures,  adapted to carrying their enormous weight, and their specific gravity allows them to sink and move along the bottom of a river. 
Communication and vocalization
Many mammals communicate by vocalizing. Vocal communication serves many purposes, including in mating rituals, as warning calls,  to indicate food sources, and for social purposes. Males often call during mating rituals to ward off other males and to attract females, as in the roaring of lions and red deer.  The songs of the humpback whale may be signals to females  they have different dialects in different regions of the ocean.  Social vocalizations include the territorial calls of gibbons, and the use of frequency in greater spear-nosed bats to distinguish between groups.  The vervet monkey gives a distinct alarm call for each of at least four different predators, and the reactions of other monkeys vary according to the call. For example, if an alarm call signals a python, the monkeys climb into the trees, whereas the eagle alarm causes monkeys to seek a hiding place on the ground.  Prairie dogs similarly have complex calls that signal the type, size, and speed of an approaching predator.  Elephants communicate socially with a variety of sounds including snorting, screaming, trumpeting, roaring and rumbling. Some of the rumbling calls are infrasonic, below the hearing range of humans, and can be heard by other elephants up to 6 miles (9.7 km) away at still times near sunrise and sunset. 
Mammals signal by a variety of means. Many give visual anti-predator signals, as when deer and gazelle stot, honestly indicating their fit condition and their ability to escape,   or when white-tailed deer and other prey mammals flag with conspicuous tail markings when alarmed, informing the predator that it has been detected.  Many mammals make use of scent-marking, sometimes possibly to help defend territory, but probably with a range of functions both within and between species.    Microbats and toothed whales including oceanic dolphins vocalize both socially and in echolocation.   
To maintain a high constant body temperature is energy expensive—mammals therefore need a nutritious and plentiful diet. While the earliest mammals were probably predators, different species have since adapted to meet their dietary requirements in a variety of ways. Some eat other animals—this is a carnivorous diet (and includes insectivorous diets). Other mammals, called herbivores, eat plants, which contain complex carbohydrates such as cellulose. An herbivorous diet includes subtypes such as granivory (seed eating), folivory (leaf eating), frugivory (fruit eating), nectarivory (nectar eating), gummivory (gum eating) and mycophagy (fungus eating). The digestive tract of an herbivore is host to bacteria that ferment these complex substances, and make them available for digestion, which are either housed in the multichambered stomach or in a large cecum.  Some mammals are coprophagous, consuming feces to absorb the nutrients not digested when the food was first ingested.  : 131–137 An omnivore eats both prey and plants. Carnivorous mammals have a simple digestive tract because the proteins, lipids and minerals found in meat require little in the way of specialized digestion. Exceptions to this include baleen whales who also house gut flora in a multi-chambered stomach, like terrestrial herbivores. 
The size of an animal is also a factor in determining diet type (Allen's rule). Since small mammals have a high ratio of heat-losing surface area to heat-generating volume, they tend to have high energy requirements and a high metabolic rate. Mammals that weigh less than about 18 ounces (510 g 1.1 lb) are mostly insectivorous because they cannot tolerate the slow, complex digestive process of an herbivore. Larger animals, on the other hand, generate more heat and less of this heat is lost. They can therefore tolerate either a slower collection process (carnivores that feed on larger vertebrates) or a slower digestive process (herbivores).  Furthermore, mammals that weigh more than 18 ounces (510 g 1.1 lb) usually cannot collect enough insects during their waking hours to sustain themselves. The only large insectivorous mammals are those that feed on huge colonies of insects (ants or termites). 
Some mammals are omnivores and display varying degrees of carnivory and herbivory, generally leaning in favor of one more than the other. Since plants and meat are digested differently, there is a preference for one over the other, as in bears where some species may be mostly carnivorous and others mostly herbivorous.  They are grouped into three categories: mesocarnivory (50–70% meat), hypercarnivory (70% and greater of meat), and hypocarnivory (50% or less of meat). The dentition of hypocarnivores consists of dull, triangular carnassial teeth meant for grinding food. Hypercarnivores, however, have conical teeth and sharp carnassials meant for slashing, and in some cases strong jaws for bone-crushing, as in the case of hyenas, allowing them to consume bones some extinct groups, notably the Machairodontinae, had saber-shaped canines. 
Some physiological carnivores consume plant matter and some physiological herbivores consume meat. From a behavioral aspect, this would make them omnivores, but from the physiological standpoint, this may be due to zoopharmacognosy. Physiologically, animals must be able to obtain both energy and nutrients from plant and animal materials to be considered omnivorous. Thus, such animals are still able to be classified as carnivores and herbivores when they are just obtaining nutrients from materials originating from sources that do not seemingly complement their classification.  For example, it is well documented that some ungulates such as giraffes, camels, and cattle, will gnaw on bones to consume particular minerals and nutrients.  Also, cats, which are generally regarded as obligate carnivores, occasionally eat grass to regurgitate indigestible material (such as hairballs), aid with hemoglobin production, and as a laxative. 
Many mammals, in the absence of sufficient food requirements in an environment, suppress their metabolism and conserve energy in a process known as hibernation.  In the period preceding hibernation, larger mammals, such as bears, become polyphagic to increase fat stores, whereas smaller mammals prefer to collect and stash food.  The slowing of the metabolism is accompanied by a decreased heart and respiratory rate, as well as a drop in internal temperatures, which can be around ambient temperature in some cases. For example, the internal temperatures of hibernating arctic ground squirrels can drop to −2.9 °C (26.8 °F), however the head and neck always stay above 0 °C (32 °F).  A few mammals in hot environments aestivate in times of drought or extreme heat, for example the fat-tailed dwarf lemur (Cheirogaleus medius). 
In intelligent mammals, such as primates, the cerebrum is larger relative to the rest of the brain. Intelligence itself is not easy to define, but indications of intelligence include the ability to learn, matched with behavioral flexibility. Rats, for example, are considered to be highly intelligent, as they can learn and perform new tasks, an ability that may be important when they first colonize a fresh habitat. In some mammals, food gathering appears to be related to intelligence: a deer feeding on plants has a brain smaller than a cat, which must think to outwit its prey. 
Tool use by animals may indicate different levels of learning and cognition. The sea otter uses rocks as essential and regular parts of its foraging behaviour (smashing abalone from rocks or breaking open shells), with some populations spending 21% of their time making tools.  Other tool use, such as chimpanzees using twigs to "fish" for termites, may be developed by watching others use tools and may even be a true example of animal teaching.  Tools may even be used in solving puzzles in which the animal appears to experience a "Eureka moment".  Other mammals that do not use tools, such as dogs, can also experience a Eureka moment. 
Self-awareness appears to be a sign of abstract thinking. Self-awareness, although not well-defined, is believed to be a precursor to more advanced processes such as metacognitive reasoning. The traditional method for measuring this is the mirror test, which determines if an animal possesses the ability of self-recognition.  Mammals that have passed the mirror test include Asian elephants (some pass, some do not)  chimpanzees  bonobos  orangutans  humans, from 18 months (mirror stage)  bottlenose dolphins [a]  killer whales  and false killer whales. 
Eusociality is the highest level of social organization. These societies have an overlap of adult generations, the division of reproductive labor and cooperative caring of young. Usually insects, such as bees, ants and termites, have eusocial behavior, but it is demonstrated in two rodent species: the naked mole-rat  and the Damaraland mole-rat. 
Presociality is when animals exhibit more than just sexual interactions with members of the same species, but fall short of qualifying as eusocial. That is, presocial animals can display communal living, cooperative care of young, or primitive division of reproductive labor, but they do not display all of the three essential traits of eusocial animals. Humans and some species of Callitrichidae (marmosets and tamarins) are unique among primates in their degree of cooperative care of young.  Harry Harlow set up an experiment with rhesus monkeys, presocial primates, in 1958 the results from this study showed that social encounters are necessary in order for the young monkeys to develop both mentally and sexually. 
A fission-fusion society is a society that changes frequently in its size and composition, making up a permanent social group called the "parent group". Permanent social networks consist of all individual members of a community and often varies to track changes in their environment. In a fission–fusion society, the main parent group can fracture (fission) into smaller stable subgroups or individuals to adapt to environmental or social circumstances. For example, a number of males may break off from the main group in order to hunt or forage for food during the day, but at night they may return to join (fusion) the primary group to share food and partake in other activities. Many mammals exhibit this, such as primates (for example orangutans and spider monkeys),  elephants,  spotted hyenas,  lions,  and dolphins. 
Solitary animals defend a territory and avoid social interactions with the members of its species, except during breeding season. This is to avoid resource competition, as two individuals of the same species would occupy the same niche, and to prevent depletion of food.  A solitary animal, while foraging, can also be less conspicuous to predators or prey. 
In a hierarchy, individuals are either dominant or submissive. A despotic hierarchy is where one individual is dominant while the others are submissive, as in wolves and lemurs,  and a pecking order is a linear ranking of individuals where there is a top individual and a bottom individual. Pecking orders may also be ranked by sex, where the lowest individual of a sex has a higher ranking than the top individual of the other sex, as in hyenas.  Dominant individuals, or alphas, have a high chance of reproductive success, especially in harems where one or a few males (resident males) have exclusive breeding rights to females in a group.  Non-resident males can also be accepted in harems, but some species, such as the common vampire bat (Desmodus rotundus), may be more strict. 
Some mammals are perfectly monogamous, meaning that they mate for life and take no other partners (even after the original mate's death), as with wolves, Eurasian beavers, and otters.   There are three types of polygamy: either one or multiple dominant males have breeding rights (polygyny), multiple males that females mate with (polyandry), or multiple males have exclusive relations with multiple females (polygynandry). It is much more common for polygynous mating to happen, which, excluding leks, are estimated to occur in up to 90% of mammals.  Lek mating occurs when males congregate around females and try to attract them with various courtship displays and vocalizations, as in harbor seals. 
All higher mammals (excluding monotremes) share two major adaptations for care of the young: live birth and lactation. These imply a group-wide choice of a degree of parental care. They may build nests and dig burrows to raise their young in, or feed and guard them often for a prolonged period of time. Many mammals are K-selected, and invest more time and energy into their young than do r-selected animals. When two animals mate, they both share an interest in the success of the offspring, though often to different extremes. Mammalian females exhibit some degree of maternal aggression, another example of parental care, which may be targeted against other females of the species or the young of other females however, some mammals may "aunt" the infants of other females, and care for them. Mammalian males may play a role in child rearing, as with tenrecs, however this varies species to species, even within the same genus. For example, the males of the southern pig-tailed macaque (Macaca nemestrina) do not participate in child care, whereas the males of the Japanese macaque (M. fuscata) do. 
In human culture
Non-human mammals play a wide variety of roles in human culture. They are the most popular of pets, with tens of millions of dogs, cats and other animals including rabbits and mice kept by families around the world.    Mammals such as mammoths, horses and deer are among the earliest subjects of art, being found in Upper Paleolithic cave paintings such as at Lascaux.  Major artists such as Albrecht Dürer, George Stubbs and Edwin Landseer are known for their portraits of mammals.  Many species of mammals have been hunted for sport and for food deer and wild boar are especially popular as game animals.    Mammals such as horses and dogs are widely raced for sport, often combined with betting on the outcome.   There is a tension between the role of animals as companions to humans, and their existence as individuals with rights of their own.  Mammals further play a wide variety of roles in literature,    film,  mythology, and religion.   
Uses and importance
Domestic mammals form a large part of the livestock raised for meat across the world. They include (2009) around 1.4 billion cattle, 1 billion sheep, 1 billion domestic pigs,   and (1985) over 700 million rabbits.  Working domestic animals including cattle and horses have been used for work and transport from the origins of agriculture, their numbers declining with the arrival of mechanised transport and agricultural machinery. In 2004 they still provided some 80% of the power for the mainly small farms in the third world, and some 20% of the world's transport, again mainly in rural areas. In mountainous regions unsuitable for wheeled vehicles, pack animals continue to transport goods.  Mammal skins provide leather for shoes, clothing and upholstery.  Wool from mammals including sheep, goats and alpacas has been used for centuries for clothing.   Mammals serve a major role in science as experimental animals, both in fundamental biological research, such as in genetics,  and in the development of new medicines, which must be tested exhaustively to demonstrate their safety.  Millions of mammals, especially mice and rats, are used in experiments each year.  A knockout mouse is a genetically modified mouse with an inactivated gene, replaced or disrupted with an artificial piece of DNA. They enable the study of sequenced genes whose functions are unknown.  A small percentage of the mammals are non-human primates, used in research for their similarity to humans.   
Charles Darwin, Jared Diamond and others have noted the importance of domesticated mammals in the Neolithic development of agriculture and of civilization, causing farmers to replace hunter-gatherers around the world. [b]  This transition from hunting and gathering to herding flocks and growing crops was a major step in human history. The new agricultural economies, based on domesticated mammals, caused "radical restructuring of human societies, worldwide alterations in biodiversity, and significant changes in the Earth's landforms and its atmosphere. momentous outcomes". 
Hybrids are offspring resulting from the breeding of two genetically distinct individuals, which usually will result in a high degree of heterozygosity, though hybrid and heterozygous are not synonymous. The deliberate or accidental hybridizing of two or more species of closely related animals through captive breeding is a human activity which has been in existence for millennia and has grown for economic purposes.  Hybrids between different subspecies within a species (such as between the Bengal tiger and Siberian tiger) are known as intra-specific hybrids. Hybrids between different species within the same genus (such as between lions and tigers) are known as interspecific hybrids or crosses. Hybrids between different genera (such as between sheep and goats) are known as intergeneric hybrids.  Natural hybrids will occur in hybrid zones, where two populations of species within the same genera or species living in the same or adjacent areas will interbreed with each other. Some hybrids have been recognized as species, such as the red wolf (though this is controversial). 
Artificial selection, the deliberate selective breeding of domestic animals, is being used to breed back recently extinct animals in an attempt to achieve an animal breed with a phenotype that resembles that extinct wildtype ancestor. A breeding-back (intraspecific) hybrid may be very similar to the extinct wildtype in appearance, ecological niche and to some extent genetics, but the initial gene pool of that wild type is lost forever with its extinction. As a result, bred-back breeds are at best vague look-alikes of extinct wildtypes, as Heck cattle are of the aurochs. 
Purebred wild species evolved to a specific ecology can be threatened with extinction  through the process of genetic pollution, the uncontrolled hybridization, introgression genetic swamping which leads to homogenization or out-competition from the heterosic hybrid species.  When new populations are imported or selectively bred by people, or when habitat modification brings previously isolated species into contact, extinction in some species, especially rare varieties, is possible.  Interbreeding can swamp the rarer gene pool and create hybrids, depleting the purebred gene pool. For example, the endangered wild water buffalo is most threatened with extinction by genetic pollution from the domestic water buffalo. Such extinctions are not always apparent from a morphological standpoint. Some degree of gene flow is a normal evolutionary process, nevertheless, hybridization threatens the existence of rare species.  
The loss of species from ecological communities, defaunation, is primarily driven by human activity.  This has resulted in empty forests, ecological communities depleted of large vertebrates.   In the Quaternary extinction event, the mass die-off of megafaunal variety coincided with the appearance of humans, suggesting a human influence. One hypothesis is that humans hunted large mammals, such as the woolly mammoth, into extinction.   The 2019 Global Assessment Report on Biodiversity and Ecosystem Services by IPBES states that the total biomass of wild mammals has declined by 82 percent since the beginning of human civilization.   Wild animals make up just 4% of mammalian biomass on earth, while humans and their domesticated animals make up 96%. 
Various species are predicted to become extinct in the near future,  among them the rhinoceros,  primates,  pangolins,  and giraffes.  According to the WWF's 2020 Living Planet Report, vertebrate wildlife populations have declined by 68% since 1970 as a result of human activities, particularly overconsumption, population growth and intensive farming, which is evidence that humans have triggered a sixth mass extinction event.   Hunting alone threatens hundreds of mammalian species around the world.   Scientists claim that the growing demand for meat is contributing to biodiversity loss as this is a significant driver of deforestation and habitat destruction species-rich habitats, such as significant portions of the Amazon rainforest, are being converted to agricultural land for meat production.    Another influence is over-hunting and poaching, which can reduce the overall population of game animals,  especially those located near villages,  as in the case of peccaries.  The effects of poaching can especially be seen in the ivory trade with African elephants.  Marine mammals are at risk from entanglement from fishing gear, notably cetaceans, with discard mortalities ranging from 65,000 to 86,000 individuals annually. 
Attention is being given to endangered species globally, notably through the Convention on Biological Diversity, otherwise known as the Rio Accord, which includes 189 signatory countries that are focused on identifying endangered species and habitats.  Another notable conservation organization is the IUCN, which has a membership of over 1,200 governmental and non-governmental organizations. 
Recent extinctions can be directly attributed to human influences.   The IUCN characterizes 'recent' extinction as those that have occurred past the cut-off point of 1500,  and around 80 mammal species have gone extinct since that time and 2015.  Some species, such as the Père David's deer  are extinct in the wild, and survive solely in captive populations. Other species, such as the Florida panther, are ecologically extinct, surviving in such low numbers that they essentially have no impact on the ecosystem.  : 318 Other populations are only locally extinct (extirpated), still existing elsewhere, but reduced in distribution,  : 75–77 as with the extinction of gray whales in the Atlantic. 
Watch the video: Stomach Vacuum Progress: 2 Month (May 2022).
- Grandorder Euarchonta
- Cohort Marsupialia: marsupials