Certain crayfish store gastroliths in their stomachs. Crayfish living in freshwater store these gastroliths as the presence of calcium is limited in freshwater. These gastroliths serve as a calcium source for molting. [ 4 ] [ 5 ] [ 6 ]


In 1906,  George Reber Weiland  reported the presence of worn and polished quartz pebbles associated with the remains of  plesiosaurs  and  sauropod   dinosaurs  and interpreted these stones as gastroliths. [ 7 ]  In 1907,  Barnum Brown  found gravel in close association with the fossil remains of the duck-billed  hadrosaur   Claosaurus  and interpreted it as gastroliths.  Brown was among the first paleontologists to recognize that dinosaurs used gastroliths in their digestive systems to aid in the grinding of food. [ 8 ]   Other paleontologists over the years were unconvinced. In 1932,  Friedrich von Huene  found stones in Late Triassic sediments, in association with the fossil remains of the  prosauropod   Sellosaurus  and interpreted them as gastroliths. [ 9 ]   In 1934, the Howe Quarry, a fossil location in northwestern Wyoming also yielded dinosaur bones with their associated gastroliths.  In 1942,  William Lee Stokes  recognized the presence of gastroliths in the remains of sauropod dinosaurs recovered from Late Jurassic  strata .


Geologists  usually require several pieces of evidence before they will accept that a rock was used by a dinosaur to aid its  digestion .  First, it should be rounded on all edges (and some are polished) because inside a dinosaur's gizzard any genuine gastrolith would have been acted upon by other stones and fibrous materials in a process similar to the action of a  rock tumbler . Second, the stone must be unlike the rock found in its geological vicinity, i.e., its geologic context. Many gastroliths have been found in fine grained lake, mud, and swamp deposits. These environs are calm water deposits and could not carry pebbles and cobbles (unlike a river or beach). Oliver Wings also argues that the stone must be found with the  fossils  of the dinosaur which ingested it. [ citation needed ]  It is this last criterion that causes trouble in identification, as smooth stones found without context can (possibly erroneously in some cases) be dismissed as having been polished by water or wind.  Christopher H. Whittle  (1988,9) pioneered  scanning electron microscope  analysis of wear patterns on gastroliths. Wings (2003) found that  ostrich  gastroliths would be deposited outside the skeleton if the carcass was deposited in an aquatic environment for as little as a few days following death. He concludes that this is likely to hold true for all birds (with the possible exception of  moa ) due to their air-filled bones which would cause a carcass deposited in water to float for the time it needs to rot sufficiently to allow gastroliths to escape.


Gastroliths can be distinguished from stream- or beach-rounded rocks by several criteria: gastroliths are highly polished on the higher surfaces, with little or no polish in depressions or crevices, often strongly resembling the surface of worn animal teeth. Stream- or beach-worn rocks, particularly in a high-impact environment, show less polishing on higher surfaces, often with many small pits or cracks on these higher surfaces. Finally, highly polished gastroliths often show long microscopic rilles, defined by Whittle as "longitudinal gashes, deeper than one millimeter and longer than one centimeter at a magnification of 50 times". [ 10 ]  These are presumably caused by contact with stomach acid. Since most gastroliths were scattered when the animal died and many entered a stream or beach environment, some gastroliths show a mixture of these wear features. Others were undoubtedly swallowed by other dinosaurs and highly polished gastroliths may have been swallowed repeatedly.


None of the gastroliths examined in a 2001 study of  Cedarosaurus  gastroliths had the "soapy" texture popularly used to distinguish gastroliths from other types of clast. [ 11 ]  The researchers dismissed using a soapy texture to identify gastroliths as "unreliable". [ 11 ]  Gastroliths tended to be universally dull, although the colors represented were varied including black, dark brown, purplish red and grey-blue. [ 11 ]  Reflectance values greater than 50% are very diagnostic for identifying gastroliths. [ 11 ]  Clasts from beaches and streams tended to have reflectance values of less than 35%. [ 12 ]  Less than ten percent of beach clasts have reflectance values lying between 50 and 80%. [ 13 ]


The American Museum of Natural History  Photograph # 311488 demonstrates an articulated skeleton of a  Psittacosaurus mongoliensis , from the  Ondai Sair Formation , Lower  Cretaceous   Period  of  Mongolia , showing a collection of about 40 gastroliths inside the  rib cage , about midway between shoulder and pelvis.


Gastroliths have sometimes been called  Morrison stones  because they are often found in the  Morrison Formation  (named after the town of  Morrison , west of  Denver ,  Colorado ), a late  Jurassic  formation roughly 150 million years old. Some gastroliths are made of  petrified wood . Most known instances of preserved  sauropod  gastroliths are from  Jurassic  animals. [ 14 ]


The  Early Cretaceous   Cedar Mountain Formation  of Central  Utah  is full of highly polished red and black  cherts , and other rounded quartzose clasts, which may partly represent gastroliths. The cherts may themselves contain fossils of ancient animals, such as corals. These stones do not appear to be associated with stream deposits and are rarely more than fist-sized, which is consistent with the idea that they are gastroliths.


Most known instances of preserved  sauropod  gastroliths are from  Jurassic  animals. [ 14 ]  The largest known gastroliths found in association with sauropod skeletons are approximately ten centimeters in length. [ 15 ]


In 2001  Frank Sanders ,  Kim Manley , and  Kenneth Carpenter  published a study on 115 gastroliths discovered in association with a  Cedarosaurus  specimen. [ 16 ]  The stones were identified as gastroliths on the basis of their tight spatial distribution, partial matrix support, and an edge-on orientation indicative of their being deposited while the carcass still had soft tissue. [ 16 ]  Their high surface  reflectance  values are consistent with other known dinosaur gastroliths. [ 16 ]   Nearly all of the  Cedarosaurus  gastroliths were found within a .06 m volume [ clarification needed ]  of space in the gut region of the skeleton. [ 17 ]


The total mass of the gastroliths themselves was 7 kilograms (15 lb). [ 18 ]  Most were less than 10 millilitres (0.35 imp fl oz; 0.34 US fl oz) in volume. [ 19 ]  The least massive clast was 0.1 grams (0.0035 oz) and the most was 715 grams (25.2 oz), with most of them being toward the smaller end of that range. [ 19 ]  The clasts tended to be close to spherical in shape, although the largest specimens were also the most irregular. [ 19 ]  The largest gastroliths contributed the most to the total surface area of the set. [ 20 ]  Some gastroliths were so large and irregularly shaped that they may have been difficult to swallow. [ 20 ]  The gastroliths were mostly composed of  chert , with some  sandstone ,  siltstone , and  quartzite  clasts also included. [ 11 ]


Since some of the most irregular gastroliths are also the largest, it is unlikely that they were ingested by accident. [ 20 ]   Cedarosaurus  may have found irregular clasts to be attractive potential gastroliths or was not selective about shape. [ 20 ]  The clasts were generally of dull coloration, suggesting that color was not a major factor for the sauropod's decision making. [ 16 ]  The high surface area to volume ratio of the largest clasts suggests that the gastroliths may have broken down ingested plant material by grinding or crushing it. [ 13 ]  The sandstone clasts tended to be fragile and some broke in the process of collection. [ 11 ]  The sandstone gastroliths may have been rendered fragile after deposition by loss of cement caused by the external chemical environment. [ 21 ]  If the clasts had been that fragile while the animal was alive, they probably rolled and tumbled in the digestive tract. [ 13 ]  If they were more robust, they could have served as part of a ball-mill system. [ 13 ]


Paleontologists  and geologists are researching new methods of identifying gastroliths that have been found disassociated from animal remains, because of the important information they can provide, if indeed they are trace fossils. If the validity of such gastroliths can be verified, it may be possible to trace gastrolithic rocks back to their original source area where the dinosaur first swallowed the rock. This may provide important information on how dinosaurs migrated. Because the number of suspected gastroliths is substantial, they might provide significant new information and insights into the lives and behaviour of dinosaurs.


The  gastrovascular cavity  is the primary organ of  digestion  and  circulation  in two major animal phyla: the  Coelenterates  or cnidarians (including  jellyfish  and  corals ) and  Platyhelminthes  (flatworms). The cavity may be extensively branched into a system of canals. In cnidarians, the gastrovascular system is also known as the  coelenteron , and is commonly known as a "blind gut" or "blind sac", since food enters and waste exits through the same orifice.


The  radially symmetrical  cnidarians have a sac-like body in two distinct layers, the epidermis and  gastrodermis , with a jellylike layer called the  mesoglea  between. Extracellular digestion takes place within the central cavity of the sac-like body.  This cavity has only one opening to the outside which, in most cnidarians, is surrounded by  tentacles  for capturing prey.


This article about anatomy of the phylum  Cnidaria  is a  stub . You can help Wikipedia by  expanding it .


This  flatworm - (or platyhelminth-) related article is a  stub . You can help Wikipedia by  expanding it .


Gulp: Adventures on the Alimentary Canal  is a nonfiction work by science author  Mary Roach , published in April 2013 by  W.W. Norton & Company .


The book covers 17 topics:


Gut microbiota ,  gut microbiome , or  gut flora  are the  microorganisms , including  bacteria ,  archaea ,  fungi , and  viruses , that live in the  digestive tracts  of  animals . [ 1 ] [ 2 ]  The gastrointestinal  metagenome  is the aggregate of all the  genomes  of the gut  microbiota . [ 3 ] [ 4 ]  The  gut  is the main location of the  human microbiome . [ 5 ]  The gut microbiota has broad impacts, including effects on  colonization , resistance to  pathogens , maintaining the  intestinal epithelium , metabolizing dietary and pharmaceutical compounds, controlling immune function, and even behavior through the  gut–brain axis . [ 4 ]


The microbial composition of the gut microbiota varies across regions of the digestive tract. The  colon  contains the highest microbial density of any human-associated microbial community studied so far, representing between 300 and 1000 different  species . [ 6 ]  Bacteria are the largest and to date, best studied component and 99% of gut bacteria come from about 30 or 40 species. [ 7 ]  About 55% of the dry mass of  feces  is bacteria. [ 8 ]  Over 99% of the bacteria in the gut are  anaerobes , but in the  cecum ,  aerobic bacteria  reach high densities. [ 5 ]  It is estimated that the human gut microbiota have around a hundred times as many  genes  as there are in the  human genome .


In humans, the gut microbiota has the highest numbers and species of bacteria compared to other areas of the body. [ 9 ]  The approximate number of bacteria composing the gut microbiota is about 10 13 –10 14  (10,000 to 100,000 billion). [ 10 ]   In humans, the gut flora is established at birth and gradually transitions towards a state resembling that of adults by the age of two, [ 11 ]  coinciding with the development and maturation of the  intestinal epithelium  and  intestinal mucosal barrier . This barrier is essential for supporting a symbiotic relationship with the gut flora while providing protection against pathogenic organisms. [ 12 ] [ 13 ]


The relationship between some gut microbiota and humans is not merely  commensal  (a non-harmful coexistence), but rather a  mutualistic  relationship. [ 5 ] : 700   Some human gut microorganisms benefit the host by  fermenting   dietary fiber  into  short-chain fatty acids  (SCFAs), such as  acetic acid  and  butyric acid , which are then absorbed by the host. [ 9 ] [ 14 ]  Intestinal  bacteria  also play a role in synthesizing certain  B vitamins  and  vitamin K  as well as metabolizing  bile acids ,  sterols , and  xenobiotics . [ 5 ] [ 14 ]  The systemic importance of the SCFAs and other compounds they produce are like  hormones  and the gut flora itself appears to function like an  endocrine organ . [ 14 ]  Dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions. [ 9 ] [ 15 ]


The composition of human gut microbiota changes over time, when the diet changes, and as overall health changes. [ 9 ] [ 15 ]  A  systematic review  from 2016 examined the preclinical and small human trials that have been conducted with certain commercially available strains of probiotic bacteria and identified those that had the most potential to be useful for certain  central nervous system disorders . [ 16 ]  It should also be highlighted that the Mediterranean diet, rich in vegetables and fibers, stimulates the activity and growth of beneficial bacteria for the brain. [ 17 ]


The microbial composition of the gut microbiota varies across the digestive tract. In the  stomach  and  small intestine , relatively few species of bacteria are generally present. [ 6 ] [ 18 ]   Fungi ,  protists ,  archaea , and  viruses  are also present in the gut flora, but less is known about their activities. [ 19 ]


Many species in the gut have not been studied outside of their hosts because they cannot be  cultured . [ 18 ] [ 7 ] [ 20 ]  While there are a small number of core microbial species shared by most individuals, populations of microbes can vary widely. [ 21 ]  Within an individual, their microbial populations stay fairly constant over time, with some alterations occurring due to changes in lifestyle, diet and age. [ 6 ] [ 22 ]  The  Human Microbiome Project  has set out to better describe the  microbiota  of the human gut and other body locations. [ citation needed ]


The four dominant  bacterial phyla  in the human gut are  Bacillota  (Firmicutes),  Bacteroidota ,  Actinomycetota , and  Pseudomonadota . [ 23 ]  Most bacteria belong to the genera  Bacteroides ,  Clostridium ,  Faecalibacterium , [ 6 ] [ 7 ]   Eubacterium ,  Ruminococcus ,  Peptococcus ,  Peptostreptococcus , and  Bifidobacterium . [ 6 ] [ 7 ]  Other genera, such as  Escherichia  and  Lactobacillus , are present to a lesser extent. [ 6 ]  Species from the genus  Bacteroides  alone constitute about 30% of all bacteria in the gut, suggesting that this genus is especially important in the functioning of the host. [ 18 ]


Fungal genera that have been detected in the gut include  Candida ,  Saccharomyces ,  Aspergillus ,  Penicillium ,  Rhodotorula ,  Trametes ,  Pleospora ,  Sclerotinia ,  Bullera , and  Galactomyces , among others. [ 24 ] [ 25 ]   Rhodotorula  is most frequently found in individuals with  inflammatory bowel disease  while  Candida  is most frequently found in individuals with hepatitis B cirrhosis and chronic hepatitis B. [ 24 ]


Due to the prevalence of fungi in the natural environment, determining which genera and species are permanent members of the gut  mycobiome  is difficult. [ 26 ] [ 27 ]  Research is underway as to whether  Penicillium  is a permanent or transient member of the gut flora, obtained from dietary sources such as  cheese , though several species in the genus are known to survive at temperatures around 37°C, around the same as the  core body temperature . [ 27 ]   Saccharomyces cerevisiae , brewer's yeast, is known to reach the intestines after being ingested and can be responsible for the condition  auto-brewery syndrome  in cases where it is overabundant, [ 27 ] [ 28 ] [ 29 ]  while  Candida albicans  is likely a permanent member, and is believed to be acquired at birth through  vertical transmission . [ 30 ] [ medical citation needed ]


Archaea  constitute another large class of gut flora which are important in the metabolism of the bacterial products of fermentation.


Industrialization  is associated with changes in the microbiota and the reduction of diversity could drive certain species to extinction; in 2018, researchers proposed a  biobank  repository of human microbiota. [ 31 ]


An  enterotype  is a classification of living organisms based on its bacteriological  ecosystem  in the human gut microbiome not dictated by age, gender, body weight, or national divisions. [ 32 ]  There are indications that long-term diet influences enterotype. [ 33 ]  Three human enterotypes have been proposed, [ 32 ] [ 34 ]  but their value has been questioned. [ 35 ]


Due to the high acidity of the  stomach , most microorganisms cannot survive there. The main bacteria of the  gastric microbiota  belong to five major phyla:  Firmicutes ,  Bacteroidetes ,  Actinobacteria ,  Fusobacteriota , and  Proteobacteria . The dominant genera are  Prevotella ,  Streptococcus ,  Veillonella ,  Rothia  , and  Haemophilus . [ 36 ]  The interaction between the pre-existing gastric microbiota with the introduction of  H. pylori  may influence  disease progression . [ 36 ]  When there is a presence of  H. pylori  it becomes the dominant of the microbiota. [ 37 ]


The small intestine contains a trace amount of microorganisms due to the proximity and influence of the stomach.  Gram-positive   cocci  and  rod-shaped bacteria  are the predominant microorganisms found in the small intestine. [ 5 ]  However, in the distal portion of the small intestine alkaline conditions support gram-negative bacteria of the  Enterobacteriaceae . [ 5 ]  The bacterial flora of the small intestine aid in a wide range of intestinal functions. The bacterial flora provide regulatory signals that enable the development and utility of the gut. Overgrowth of bacteria in the small intestine can lead to intestinal failure. [ 39 ]  In addition the large intestine contains the largest bacterial ecosystem in the human body. [ 5 ]  About 99% of the large intestine and feces flora are made up of obligate anaerobes such as  Bacteroides  and  Bifidobacterium. [ 40 ]  Factors that disrupt the microorganism population of the large intestine include antibiotics, stress, and parasites. [ 5 ]


Bacteria make up most of the flora in the  colon [ 41 ]  and accounts for 60%  of  fecal  nitrogen. [ 6 ]  This fact makes feces an ideal source of gut flora for any tests and experiments by extracting the nucleic acid from fecal specimens, and bacterial 16S rRNA gene sequences are generated with bacterial primers. This form of testing is also often preferable to more invasive techniques, such as biopsies.


Five  phyla  dominate the intestinal microbiota:  Bacteroidota ,  Bacillota  (Firmicutes),  Actinomycetota ,  Pseudomonadota , and  Verrucomicrobiota  – with Bacteroidota and Bacillota constituting 90% of the composition. [ 42 ]  Somewhere between 300 [ 6 ]  and 1000 different  species  live in the gut, [ 18 ]  with most estimates at about 500. [ 43 ] [ 44 ]  However, it is probable that 99% of the bacteria come from about 30 or 40 species, with  Faecalibacterium prausnitzii  (phylum firmicutes) being the most common species in healthy adults. [ 7 ] [ 45 ]


Research suggests that the relationship between gut  flora  and humans is not merely  commensal  (a non-harmful coexistence), but rather is a  mutualistic ,  symbiotic  relationship. [ 18 ]  Though people can survive with no gut flora, [ 43 ]  the microorganisms perform a host of useful functions, such as  fermenting  unused energy substrates, training the  immune system  via end products of metabolism like  propionate  and  acetate , preventing growth of harmful species, regulating the development of the gut, producing vitamins for the host (such as  biotin  and  vitamin K ), and producing hormones to direct the host to store fats. [ 5 ]  Extensive modification and imbalances of the gut microbiota and its microbiome or gene collection are associated with obesity. [ 46 ]  However, in certain conditions, some species are thought to be capable of causing  disease  by causing  infection  or increasing  cancer  risk for the host. [ 6 ] [ 41 ]


Fungi  and  protists  also make up a part of the gut flora, but less is known about their activities. [ 47 ]


The  human virome  is mostly  bacteriophages . [ 48 ]


There are common patterns of microbiome composition evolution during life. [ 49 ]  In general, the diversity of microbiota composition of fecal samples is significantly higher in adults than in children, although interpersonal differences are higher in children than in adults. [ 50 ]  Much of the maturation of microbiota into an adult-like configuration happens during the first three years of life. [ 50 ]


As the microbiome composition changes, so does the composition of bacterial proteins produced in the gut. In adult microbiomes, a high prevalence of enzymes involved in  fermentation ,  methanogenesis  and the metabolism of  arginine ,  glutamate ,  aspartate  and  lysine  have been found. In contrast, in infant microbiomes the dominant enzymes are involved in  cysteine  metabolism and fermentation pathways. [ 50 ]


Gut microbiome composition depends on the geographic origin of populations. Variations in a trade-off of  Prevotella , the representation of the  urease  gene, and the representation of genes encoding glutamate synthase/degradation or other enzymes involved in amino acids degradation or vitamin biosynthesis show significant differences between populations from the US,  Malawi , or Amerindian origin. [ 50 ]


The US population has a high representation of enzymes encoding the degradation of  glutamine  and enzymes involved in vitamin and  lipoic acid  biosynthesis; whereas Malawi and Amerindian populations have a high representation of enzymes encoding glutamate synthase and they also have an overrepresentation of  α-amylase  in their microbiomes. As the US population has a diet richer in fats than Amerindian or Malawian populations which have a corn-rich diet, the diet is probably the main determinant of the gut bacterial composition. [ 50 ]


Further studies have indicated a large difference in the composition of microbiota between European and rural African children. The fecal bacteria of children from  Florence  were compared to that of children from the small rural village of  Boulpon  in  Burkina Faso . The diet of a typical child living in this village is largely lacking in fats and animal proteins and rich in polysaccharides and plant proteins. The fecal bacteria of European children were dominated by  Firmicutes  and showed a marked reduction in biodiversity, while the fecal bacteria of the Boulpon children was dominated by  Bacteroidetes . The increased biodiversity and different composition of the gut microbiome in African populations may aid in the digestion of normally indigestible plant polysaccharides and also may result in a reduced incidence of non-infectious colonic diseases. [ 51 ]


On a smaller scale, it has been shown that sharing numerous common environmental exposures in a family is a strong determinant of individual microbiome composition. This effect has no genetic influence and it is consistently observed in culturally different populations. [ 50 ]


Malnourished  children have less mature and less diverse gut microbiota than healthy children, and changes in the microbiome associated with nutrient scarcity can in turn be a pathophysiological cause of malnutrition. [ 52 ] [ 53 ]  Malnourished children also typically have more potentially pathogenic gut flora, and more  yeast  in their mouths and throats. [ 54 ]  Altering diet may lead to changes in gut microbiota composition and diversity. [ 55 ]


Researchers with the American Gut Project and Human Microbiome Project found that twelve microbe families varied in abundance based on the race or ethnicity of the individual. The strength of these associations is limited by the small sample size: the American Gut Project collected data from 1,375 individuals, 90% of whom were white. [ 56 ]  The Healthy Life in an Urban Setting (HELIUS) study in Amsterdam found that those of Dutch ancestry had the highest level of gut microbiota diversity, while those of South Asian and  Surinamese  descent had the lowest diversity. The study results suggested that individuals of the same race or ethnicity have more similar microbiomes than individuals of different racial backgrounds. [ 56 ]


As of 2020, at least two studies have demonstrated a link between an individual's  socioeconomic status  (SES) and their gut microbiota. A study in  Chicago  found that individuals in higher SES neighborhoods had greater microbiota diversity. People from higher SES neighborhoods also had more abundant  Bacteroides  bacteria. Similarly, a study of  twins  in the United Kingdom found that higher SES was also linked with a greater gut diversity. [ 56 ]


As of 2023, a study suggests that antibiotics, especially those used in the treatment of broad-spectrum bacterial infections, have negative effects on the gut microbiota. [ 57 ]  The study also states that there are many experts on intestinal health concerned that antibody usage has reduced the diversity of the gut microbiota, many of the strains are lost, and if there is a re-emergence of the bacteria, is gradual and long-term.  [ 58 ]


The establishment of a gut flora is crucial to the health of an adult, as well as the functioning of the gastrointestinal tract. [ 59 ]  In humans, a gut flora similar to an adult's is formed within one to two years of birth as microbiota are acquired through parent-to-child transmission and transfer from food, water, and other environmental sources. [ 60 ] [ 12 ]


The traditional view of the  gastrointestinal tract  of a normal  fetus  is that it is sterile, although this view has been challenged in the past few years. [ timeframe? ] [ 61 ]  Multiple lines of evidence have begun to emerge that suggest there may be bacteria in the intrauterine environment. In humans, research has shown that microbial colonization may occur in the fetus [ 62 ]  with one study showing  Lactobacillus  and  Bifidobacterium  species were present in placental biopsies. [ 63 ]  Several  rodent studies  have demonstrated the presence of bacteria in the amniotic fluid and placenta, as well as in the  meconium  of babies born by sterile cesarean section. [ 64 ] [ 65 ]  In another study, researchers administered a culture of bacteria orally to pregnant mice, and detected the bacteria in the offspring, likely resulting from transmission between the digestive tract and amniotic fluid via the blood stream. [ 66 ]  However, researchers caution that the source of these intrauterine bacteria, whether they are alive, and their role, is not yet understood. [ 67 ] [ 63 ]


During birth and rapidly thereafter, bacteria from the mother and the surrounding environment colonize the infant's gut. [ 12 ]  The exact sources of bacteria are not fully understood, but may include the birth canal, other people (parents, siblings, hospital workers), breastmilk, food, and the general environment with which the infant interacts. [ 68 ]  Research has shown that the microbiome of babies born  vaginally  differs significantly from that of babies delivered by  caesarean section  and that vaginally born babies got most of their gut bacteria from their mother, while the microbiota of babies born by caesarean section had more bacteria associated with hospital environments. [ 69 ]


During the first year of life, the composition of the gut flora is generally simple and changes a great deal with time and is not the same across individuals. [ 12 ]  The initial bacterial population are generally  facultative anaerobic organisms ; investigators believe that these initial colonizers decrease the oxygen concentration in the gut, which in turn allows obligately anaerobic bacteria like  Bacteroidota ,  Actinomycetota , and  Bacillota  to become established and thrive. [ 12 ]  Breast-fed babies become dominated by  bifidobacteria , possibly due to the contents of  bifidobacterial growth factors  in breast milk, and by the fact that breast milk carries prebiotic components, allowing for healthy bacterial growth. [ 63 ] [ 70 ]  Breast milk also contains higher levels of Immunoglobulin A (IgA) to help with the tolerance and regulation of the baby's immune system. [ 71 ]  In contrast, the microbiota of  formula-fed  infants is more diverse, with high numbers of  Enterobacteriaceae ,  enterococci , bifidobacteria,  Bacteroides , and clostridia. [ 72 ]


Caesarean section,  antibiotics , and  formula feeding  may alter the gut microbiome composition. [ 63 ]  Children treated with antibiotics have less stable, and less diverse floral communities. [ 73 ]  Caesarean sections have been shown to be disruptive to mother-offspring transmission of bacteria, which impacts the overall health of the offspring by raising risks of disease such as  celiac disease ,  asthma , and  type   1 diabetes . [ 63 ]  This further evidences the importance of a healthy gut microbiome. Various methods of microbiome restoration are being explored, typically involving exposing the infant to maternal vaginal contents, and oral probiotics. [ 63 ]


When the study of gut flora began in 1995, [ 74 ]  it was thought to have three key roles: direct defense against  pathogens , fortification of host defense by its role in developing and maintaining the  intestinal epithelium  and inducing antibody production there, and metabolizing otherwise indigestible compounds in food.  Subsequent work discovered its role in training the developing immune system, and yet further work focused on its role in the  gut–brain axis . [ 75 ]


The gut flora community plays a direct role in defending against pathogens by fully colonising the space, making use of all available nutrients, and by secreting compounds known as  cytokines  that kill or inhibit unwelcome organisms that would compete for nutrients with it. [ 76 ]  Different strains of gut bacteria cause the production of different cytokines. Cytokines are chemical compounds produced by our immune system for initiating the  inflammatory response  against infections. Disruption of the gut flora allows competing organisms like  Clostridioides difficile  to become established that otherwise are kept in abeyance. [ 76 ]


In humans, a gut flora similar to an adult's is formed within one to two years of birth. [ 12 ]  As the gut flora gets established, the lining of the intestines – the intestinal epithelium and the intestinal mucosal barrier that it secretes – develop as well, in a way that is tolerant to, and even supportive of, commensalistic microorganisms to a certain extent and also provides a barrier to pathogenic ones. [ 12 ]  Specifically,  goblet cells  that produce the mucosa proliferate, and the mucosa layer thickens, providing an outside mucosal layer in which "friendly" microorganisms can anchor and feed, and an inner layer that even these organisms cannot penetrate. [ 12 ] [ 13 ]  Additionally, the development of  gut-associated lymphoid tissue  (GALT), which forms part of the intestinal epithelium and which detects and reacts to pathogens, appears and develops during the time that the gut flora develops and established. [ 12 ]  The GALT that develops is tolerant to gut flora species, but not to other microorganisms. [ 12 ]  GALT also normally becomes tolerant to food to which the infant is exposed, as well as digestive products of food, and gut flora's  metabolites  (molecules formed from metabolism) produced from food. [ 12 ]


The human  immune system  creates  cytokines  that can drive the immune system to produce inflammation in order to protect itself, and that can tamp down the immune response to maintain  homeostasis  and allow healing after insult or injury. [ 12 ]  Different bacterial species that appear in gut flora have been shown to be able to drive the immune system to create cytokines selectively; for example  Bacteroides fragilis  and some  Clostridia  species appear to drive an anti-inflammatory response, while some  segmented filamentous bacteria  drive the production of inflammatory cytokines. [ 12 ] [ 77 ]  Gut flora can also regulate the production of  antibodies  by the immune system. [ 12 ] [ 78 ]  One function of this regulation is to cause  B cells  to class switch to  IgA . In most cases B cells need activation from  T helper cells  to induce  class switching ; however, in another pathway, gut flora cause  NF-kB  signaling by intestinal epithelial cells which results in further signaling molecules being secreted. [ 79 ]  These signaling molecules interact with B cells to induce class switching to IgA. [ 79 ]  IgA is an important type of antibody that is used in mucosal environments like the gut. It has been shown that IgA can help diversify the gut community and helps in getting rid of bacteria that cause inflammatory responses. [ 80 ]  Ultimately, IgA maintains a healthy environment between the host and gut bacteria. [ 80 ]  These cytokines and antibodies can have effects outside the gut, in the lungs and other tissues. [ 12 ]


The immune system can also be altered due to the gut bacteria's ability to produce  metabolites  that can affect cells in the immune system. For example  short-chain fatty acids  (SCFA) can be produced by some gut bacteria through  fermentation . [ 81 ]  SCFAs stimulate a rapid increase in the production of innate immune cells like  neutrophils ,  basophils  and  eosinophils . [ 81 ]  These cells are part of the innate immune system that try to limit the spread of infection.


Without gut flora, the human body would be unable to utilize some of the undigested  carbohydrates  it consumes, because some types of gut flora have  enzymes  that human cells lack for breaking down certain  polysaccharides . [ 14 ]  Rodents raised in a  sterile  environment and lacking in gut flora need to eat 30% more  calories  just to remain the same weight as their normal counterparts. [ 14 ]  Carbohydrates that humans cannot  digest  without bacterial help include certain  starches ,  fiber ,  oligosaccharides , and  sugars  that the body failed to digest and absorb like  lactose  in the case of  lactose intolerance  and  sugar alcohols ,  mucus  produced by the gut, and proteins. [ 9 ] [ 14 ]


Bacteria turn carbohydrates they ferment into  short-chain fatty acids  by a form of fermentation called  saccharolytic fermentation . [ 44 ]  Products include  acetic acid ,  propionic acid  and  butyric acid . [ 7 ] [ 44 ]  These materials can be used by host cells, providing a major source of energy and nutrients. [ 44 ]  Gases (which are involved in  signaling [ 86 ]  and may cause  flatulence ) and  organic acids , such as  lactic acid , are also produced by fermentation. [ 7 ]  Acetic acid is used by  muscle , propionic acid facilitates  liver  production of  ATP , and butyric acid provides energy to gut cells. [ 44 ]


Gut flora also synthesize vitamins like  biotin  and  folate , and facilitate absorption of  dietary minerals , including magnesium, calcium, and iron. [ 6 ] [ 22 ]   Methanobrevibacter smithii  is unique because it is not a species of bacteria, but rather a member of  domain   Archaea , and is the most abundant  methane -producing archaeal species in the human gastrointestinal microbiota. [ 87 ]


Gut microbiota also serve as a source of vitamins K and B 12 , which are not produced by the body or produced in little amount. [ 88 ] [ 89 ]


Bacteria that degrade cellulose (such as  Ruminococcus ) are prevalent among  great apes , ancient human societies,  hunter-gatherer  communities, and even modern rural populations. However, they are rare in industrialized societies. Human-associated strains have acquired genes that can degrade specific plant fibers such as  maize ,  rice , and  wheat . Bacterial strains found in primates can also degrade  chitin , a polymer abundant in insects, which are part of the diet of many nonhuman  primates . The decline of these bacteria in the human gut were likely influenced by the shift toward western lifestyles. [ 90 ]


The human  metagenome  (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals. [ 91 ] [ 92 ]  Since the total number of microbial cells in the human body (over 100 trillion) greatly outnumbers  Homo sapiens  cells (tens of trillions), [ note 1 ] [ 91 ] [ 93 ]  there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the  human microbiome ,  drug metabolism  by microbial enzymes modifying the drug's  pharmacokinetic  profile, and microbial drug metabolism affecting a drug's clinical efficacy and  toxicity  profile. [ 91 ] [ 92 ] [ 94 ]


Apart from carbohydrates, gut microbiota can also metabolize other  xenobiotics  such as drugs,  phytochemicals , and food toxicants. More than 30 drugs have been shown to be metabolized by gut microbiota. [ 95 ]  The microbial metabolism of drugs can sometimes inactivate the drug. [ 96 ]


The gut microbiota is an enriched community that contains diverse genes with huge biochemical capabilities to modify drugs, especially those taken by mouth. [ 97 ]  Gut microbiota can affect drug metabolism via direct and indirect mechanisms. [ 98 ]  The direct mechanism is mediated by the microbial enzymes that can modify the chemical structure of the administered drugs. [ 99 ]  Conversely, the indirect pathway is mediated by the microbial metabolites which affect the expression of host metabolizing enzymes such as  cytochrome P450 . [ 100 ] [ 98 ]  The effects of the gut microbiota on the pharmacokinetics and bioavailability of the drug have been investigated a few decades ago. [ 101 ] [ 102 ] [ 103 ]  These effects can be varied; it could activate the inactive drugs such as lovastatin, [ 104 ]  inactivate the active drug such as  digoxin [ 105 ]  or induce drug toxicity as in  irinotecan . [ 106 ]  Since then, the impacts of the gut microbiota on the pharmacokinetics of many drugs were heavily studied. [ 107 ] [ 97 ]


The human gut microbiota plays a crucial role in modulating the effect of the administered drugs on the human. Directly, gut microbiota can synthesize and release a series of enzymes with the capability to metabolize drugs such as microbial biotransformation of L-dopa by decarboxylase and dehydroxylase enzymes. [ 99 ]  On the contrary, gut microbiota may also alter the metabolism of the drugs by modulating the host drug metabolism. This mechanism can be mediated by microbial metabolites or by modifying host metabolites which in turn change the expression of host metabolizing enzymes. [ 100 ]


A large number of studies have demonstrated the metabolism of over 50 drugs by the gut microbiota. [ 107 ] [ 98 ]  For example, lovastatin (a cholesterol-lowering agent) which is a lactone prodrug is partially activated by the human gut microbiota forming active acid hydroxylated metabolites. [ 104 ]  Conversely, digoxin (a drug used to treat Congestive Heart Failure) is inactivated by a member of the gut microbiota (i.e.  Eggerthella   lanta ). [ 108 ]   Eggerthella   lanta  has a cytochrome-encoding operon up-regulated by digoxin and associated with digoxin-inactivation. [ 108 ]  Gut microbiota can also modulate the efficacy and toxicity of chemotherapeutic agents such as irinotecan. [ 109 ]  This effect is derived from the microbiome-encoded β-glucuronidase enzymes which recover the active form of the irinotecan causing gastrointestinal toxicity. [ 110 ]


This microbial community in the gut has a huge biochemical capability to produce distinct secondary metabolites that are sometimes produced from the metabolic conversion of dietary foods such as  fibers , endogenous biological compounds such as  indole  or  bile acids . [ 111 ] [ 112 ] [ 113 ]  Microbial metabolites especially short chain fatty acids (SCFAs) and secondary bile acids (BAs) play important roles for the human in health and disease states. [ 114 ] [ 115 ] [ 116 ]


One of the most important bacterial metabolites produced by the gut microbiota is secondary bile acids (BAs). [ 113 ]  These metabolites are produced by the bacterial biotransformation of the primary bile acids such as cholic acid  (CA) and chenodeoxycholic acid (CDCA) into secondary bile acids (BAs) lithocholic acid (LCA) and deoxy cholic acid (DCA) respectively. [ 117 ]  Primary bile acids which are synthesized by hepatocytes and stored in the gall bladder possess hydrophobic characters. These metabolites are subsequently metabolized by the gut microbiota into secondary metabolites with increased hydrophobicity. [ 117 ]  Bile salt hydrolases (BSH) which are conserved across gut microbiota phyla such as  Bacteroides ,  Firmicutes , and  Actinobacteria  responsible for the first step of secondary bile acids metabolism. [ 117 ]  Secondary bile acids (BAs) such as DCA and LCA have been demonstrated to inhibit both  Clostridioides difficile  germination and outgrowth. [ 116 ]


The gut microbiota is important for maintaining homeostasis in the intestine. Development of  intestinal cancer  is associated with an imbalance in the natural microflora (dysbiosis). [ 118 ]   The secondary bile acid  deoxycholic acid  is associated with alterations of the microbial community that lead to increased intestinal carcinogenesis. [ 118 ]   Increased exposure of the colon to secondary bile acids resulting from dysbiosis can cause  DNA damage , and such damage can produce carcinogenic mutations in cells of the colon. [ 119 ]  The high density of bacteria in the  colon  (about 10 12  per ml.) that are subject to dysbiosis compared to the relatively low density in the  small intestine  (about 10 2  per ml.) may account for the greater than 10-fold higher incidence of cancer in the colon compared to the small intestine. [ 119 ]


The gut microbiota contributes to digestion and immune modulation, as it plays a role in the gut-brain axis, where microbial metabolites such as short-chain fatty acids and neurotransmitters influence brain function and behavior. The gut–brain axis is the biochemical signaling that takes place between the  gastrointestinal tract  and the  central nervous system . [ 75 ]  That term has been expanded to include the role of the gut flora in the interplay; the term "microbiome––brain axis" is sometimes used to describe paradigms explicitly including the gut flora. [ 75 ] [ 120 ] [ 121 ]  Broadly defined, the gut–brain axis includes the central nervous system,  neuroendocrine  and  neuroimmune  systems including the  hypothalamic–pituitary–adrenal axis  (HPA axis), sympathetic and parasympathetic arms of the  autonomic nervous system  including the  enteric nervous system , the  vagus nerve , and the gut  microbiota . [ 75 ] [ 121 ]  Studies show links between gut dysbiosis and mental health conditions, indicating a complex interaction that impacts mood and cognitive functions.


A  systematic review  from 2016 examined the preclinical and small human trials that have been conducted with certain commercially available strains of  probiotic  bacteria and found that among those tested,  Bifidobacterium  and  Lactobacillus   genera  ( B. longum ,  B. breve ,  B. infantis ,  L. helveticus ,  L. rhamnosus ,  L. plantarum , and  L. casei ), had the most potential to be useful for certain  central nervous system disorders . [ 16 ]


Altering the numbers of gut bacteria, for example by taking  broad-spectrum antibiotics , may affect the host's health and ability to digest food. [ 122 ]  Antibiotics can cause  antibiotic-associated diarrhea  by irritating the  bowel  directly, changing the levels of microbiota, or allowing  pathogenic  bacteria to grow. [ 7 ]  Another harmful effect of antibiotics is the increase in numbers of  antibiotic-resistant bacteria  found after their use, which, when they invade the host, cause illnesses that are difficult to treat with antibiotics. [ 122 ]


Changing the numbers and species of gut microbiota can reduce the body's ability to ferment carbohydrates and metabolize  bile  acids and may cause  diarrhea . Carbohydrates that are not broken down may absorb too much water and cause runny stools, or lack of SCFAs produced by gut microbiota could cause diarrhea. [ 7 ]


A reduction in levels of native bacterial species also disrupts their ability to inhibit the growth of harmful species such as  C. difficile  and  Salmonella  Kedougou, and these species can get out of hand, though their overgrowth may be incidental and not be the true cause of diarrhea. [ 6 ] [ 7 ] [ 122 ]  Emerging treatment protocols for C. difficile infections involve fecal microbiota transplantation of donor feces (see  Fecal transplant ). [ 123 ]  Initial reports of treatment describe success rates of 90%, with few side effects. Efficacy is speculated to result from restoring bacterial balances of bacteroides and firmicutes classes of bacteria. [ 124 ]


The composition of the gut microbiome also changes in severe illnesses, due not only to antibiotic use but also to such factors as  ischemia  of the gut, failure to eat, and  immune compromise . Negative effects from this have led to interest in  selective digestive tract decontamination , a treatment to kill only pathogenic bacteria and allow the re-establishment of healthy ones. [ 125 ]


Antibiotics alter the population of the microbiota in the  gastrointestinal tract , and this may change the intra-community metabolic interactions, modify caloric intake by using carbohydrates, and globally affect host metabolic, hormonal, and immune homeostasis. [ 126 ]


There is reasonable evidence that taking probiotics containing  Lactobacillus  species may help prevent antibiotic-associated diarrhea and that taking probiotics with  Saccharomyces  (e.g.,  Saccharomyces boulardii   ) may help to prevent  Clostridioides difficile  infection following systemic antibiotic treatment. [ 127 ]


The gut microbiota of a woman changes as  pregnancy  advances, with the changes similar to those seen in  metabolic syndromes  such as diabetes. The change in gut microbiota causes no ill effects. The newborn's gut microbiota resemble the mother's first-trimester samples. The diversity of the microbiome decreases from the first to third trimester, as the numbers of certain species go up. [ 63 ] [ 128 ]


Probiotics  contain live  microorganisms . When consumed, they are believed to provide health benefits by altering the microbiome composition. [ 129 ] [ 130 ] [ 131 ]  Current research explores using probiotics as a way to restore the microbial balance of the  intestine  by stimulating the immune system and inhibiting pro-inflammatory  cytokines . [ 129 ]


With regard to gut microbiota,  prebiotics  are typically non-digestible,  fiber  compounds that pass undigested through the upper part of the  gastrointestinal tract  and stimulate the growth or activity of advantageous gut flora by acting as  substrate  for them. [ 44 ] [ 132 ]


Synbiotics  refers to  food ingredients  or  dietary supplements  combining probiotics and prebiotics in a form of  synergism . [ 133 ]


The term "pharmabiotics" is used in various ways, to mean:  pharmaceutical formulations  (standardized manufacturing that can obtain regulatory approval as a drug) of probiotics,  prebiotics , or  synbiotics ; [ 134 ]  probiotics that have been genetically engineered or otherwise optimized for best performance (shelf life, survival in the digestive tract, etc.); [ 135 ]  and the natural products of gut flora metabolism (vitamins, etc.). [ 136 ]


There is some evidence that treatment with some probiotic strains of bacteria may be effective in  irritable bowel syndrome , [ 137 ] [ 138 ]  abdominal bloating  [ 139 ] and  chronic idiopathic constipation . Those organisms most likely to result in a decrease of symptoms have included:


Feces of about 10–15% of people consistently floats in toilet water ('floaters'), while the rest produce feces that sinks ('sinkers') and production of gas causes feces to float. [ 143 ]  While conventional mice often produce 'floaters', gnotobiotic germfree mice no gut microbiota (bred in germfree isolator) produce 'sinkers', and gut microbiota colonization in germfree mice leads to food transformation to microbial biomass and enrichment of multiple gasogenic bacterial species that turns the 'sinkers' into 'floaters'. [ 144 ]


Tests for whether non-antibiotic drugs may impact human gut-associated bacteria were performed by  in vitro  analysis on more than 1000 marketed drugs against 40 gut bacterial strains, demonstrating that 24% of the drugs inhibited the growth of at least one of the bacterial strains. [ 145 ]


Bacteria in the digestive tract can contribute to and be affected by disease in various ways. The presence or overabundance of some kinds of bacteria may contribute to inflammatory disorders such as  inflammatory bowel disease . [ 6 ]  Additionally, metabolites from certain members of the gut flora may influence host signalling pathways, contributing to disorders such as  obesity  and  colon cancer . [ 6 ]  Some gut bacteria may also cause  infections  and  sepsis , for example when they are allowed to  pass from the gut into the rest of the body . [ 6 ]


Helicobacter pylori  infection can initiate formation of stomach ulcers when the bacteria penetrate the stomach epithelial lining, then causing an  inflammatory phagocytotic response . [ 146 ]  In turn, the inflammation damages parietal cells which release excessive  hydrochloric acid  into the stomach and produce less of the protective mucus. [ 147 ]  Injury to the stomach lining, leading to  ulcers , develops when gastric acid overwhelms the defensive properties of cells and inhibits endogenous  prostaglandin  synthesis,  reduces mucus and bicarbonate secretion, reduces mucosal blood flow, and lowers resistance to injury. [ 147 ]  Reduced protective properties of the stomach lining increase vulnerability to further injury and ulcer formation by stomach acid,  pepsin , and bile salts. [ 146 ] [ 147 ]


Normally- commensal bacteria  can harm the host if they extrude from the intestinal tract. [ 12 ] [ 13 ]   Translocation , which occurs when bacteria leave the gut through its  mucosal  lining, can occur in a number of different diseases. [ 13 ]  If the gut is perforated, bacteria invade the  interstitium , causing a potentially fatal  infection . [ 5 ] : 715


The two main types of  inflammatory bowel diseases ,  Crohn's disease  and  ulcerative colitis , are  chronic  inflammatory disorders of the gut; the causes of these diseases are unknown and issues with the gut flora and its relationship with the host have been implicated in these conditions. [ 15 ] [ 148 ] [ 149 ] [ 150 ]  Additionally, it appears that interactions of gut flora with the gut–brain axis have a role in IBD, with physiological stress mediated through the  hypothalamic–pituitary–adrenal axis  driving changes to intestinal epithelium and the gut flora in turn releasing factors and metabolites that trigger signaling in the  enteric nervous system  and the  vagus nerve . [ 4 ]


The diversity of gut flora appears to be significantly diminished in people with inflammatory bowel diseases compared to healthy people; additionally, in people with ulcerative colitis, Proteobacteria and Actinobacteria appear to dominate; in people with Crohn's,  Enterococcus faecium  and several Proteobacteria appear to be over-represented. [ 4 ]


There is reasonable evidence that correcting gut flora imbalances by taking probiotics with  Lactobacilli  and  Bifidobacteria  can reduce visceral pain and gut inflammation in IBD. [ 127 ]


Irritable bowel syndrome  is a result of stress and chronic activation of the HPA axis; its symptoms include abdominal pain, changes in bowel movements, and an increase in proinflammatory cytokines. Overall, studies have found that the luminal and mucosal microbiota are changed in irritable bowel syndrome individuals, and these changes can relate to the type of irritation such as diarrhea or  constipation . Also, there is a decrease in the diversity of the microbiome with low levels of fecal Lactobacilli and Bifidobacteria, high levels of facultative  anaerobic bacteria  such as  Escherichia coli , and increased ratios of Firmicutes: Bacteroidetes. [ 121 ]


With asthma, two hypotheses have been posed to explain its rising prevalence in the developed world. The  hygiene hypothesis  posits that children in the developed world are not exposed to enough microbes and thus may contain lower prevalence of specific bacterial taxa that play protective roles. [ 151 ]  The second hypothesis focuses on the  Western pattern diet , which lacks  whole grains  and  fiber  and has an overabundance of  simple sugars . [ 15 ]  Both hypotheses converge on the role of short-chain fatty acids (SCFAs) in  immunomodulation . These bacterial fermentation metabolites are involved in immune signalling that prevents the triggering of asthma and lower SCFA levels are associated with the disease. [ 151 ] [ 152 ]  Lacking protective genera such as  Lachnospira ,  Veillonella ,  Rothia  and  Faecalibacterium  has been linked to reduced SCFA levels. [ 151 ]  Further, SCFAs are the product of bacterial fermentation of fiber, which is low in the Western pattern diet. [ 15 ] [ 152 ]  SCFAs offer a link between gut flora and immune disorders, and as of 2016, this was an active area of research. [ 15 ]  Similar hypotheses have also been posited for the rise of food and other allergies. [ 153 ]


The connection between the gut microbiota and  diabetes mellitus type 1  has also been linked to SCFAs, such as  butyrate  and acetate. Diets yielding butyrate and acetate from bacterial fermentation show increased  T reg  expression. [ 154 ]   T reg  cells  downregulate   effector T cells , which in turn reduces the  inflammatory response  in the gut. [ 155 ]  Butyrate is an energy source for colon cells. butyrate-yielding diets thus decrease  gut permeability  by providing sufficient energy for the formation of  tight junctions . [ 156 ]  Additionally, butyrate has also been shown to decrease insulin resistance, suggesting gut communities low in butyrate-producing microbes may increase chances of acquiring  diabetes mellitus type 2 . [ 157 ]  Butyrate-yielding diets may also have potential  colorectal cancer  suppression effects. [ 156 ]


The gut flora have been implicated in obesity and  metabolic syndrome  due to a key role in the digestive process; the Western pattern diet appears to drive and maintain changes in the gut flora that in turn change how much energy is derived from food and how that energy is used. [ 150 ] [ 158 ]  One aspect of a  healthy diet  that is often lacking in the  Western-pattern diet  is fiber and other complex carbohydrates that a healthy gut flora require flourishing; changes to gut flora in response to a Western-pattern diet appear to increase the amount of energy generated by the gut flora which may contribute to obesity and metabolic syndrome. [ 127 ]  There is also evidence that microbiota influence eating behaviours based on the preferences of the microbiota, which can lead to the host consuming more food eventually resulting in obesity. It has generally been observed that with higher gut microbiome diversity, the microbiota will spend energy and resources on competing with other microbiota and less on manipulating the host. The opposite is seen with lower gut microbiome diversity, and these microbiotas may work together to create host food cravings. [ 55 ]


Additionally, the liver plays a dominant role in  blood glucose  homeostasis by maintaining a balance between the uptake and storage of glucose through the metabolic pathways of  glycogenesis  and  gluconeogenesis . Intestinal lipids regulate glucose homeostasis involving a gut–brain–liver axis. The direct administration of lipids into the upper intestine increases the long chain fatty  acyl-coenzyme A  (LCFA-CoA) levels in the upper intestines and suppresses glucose production even under subdiaphragmatic  vagotomy  or gut vagal  deafferentation . This interrupts the neural connection between the brain and the gut and blocks the upper intestinal lipids' ability to inhibit glucose production. The gut–brain–liver axis and gut microbiota composition can regulate the glucose homeostasis in the liver and provide potential therapeutic methods to treat obesity and diabetes. [ 159 ]


Just as gut flora can function in a feedback loop that can drive the development of obesity, there is evidence that restricting intake of calories (i.e.,  dieting ) can drive changes to the composition of the gut flora. [ 150 ]


The composition of the human gut microbiome is similar to that of the other great apes. However, humans' gut biota has decreased in diversity and changed in composition since our evolutionary split from  Pan . [ 160 ]  Humans display increases in Bacteroidetes, a bacterial phylum associated with diets high in animal protein and fat, and decreases in Methanobrevibacter and Fibrobacter, groups that ferment complex plant polysaccharides. [ 160 ]  These changes are the result of the combined dietary, genetic, and cultural changes humans have undergone since evolutionary divergence from  Pan . [ citation needed ]


In addition to humans and vertebrates, some insects also have complex and diverse gut microbiota that play key nutritional roles. [ 2 ]  Microbial communities associated with  termites  can constitute a majority of the weight of the individuals and perform important roles in the digestion of  lignocellulose  and  nitrogen fixation . [ 161 ]  It is known that the disruption of gut microbiota of termites using agents like antibiotics [ 162 ]  or  boric acid [ 163 ]  (a common agent used in preventative treatment) causes severe damage to digestive function and leads to the rise of opportunistic pathogens. [ 163 ]  These communities are host-specific, and closely related insect species share comparable similarities in gut microbiota composition. [ 164 ] [ 165 ]  In  cockroaches , gut microbiota have been shown to assemble in a deterministic fashion, irrespective of the  inoculum ; [ 166 ]  the reason for this host-specific assembly remains unclear. Bacterial communities associated with insects like termites and cockroaches are determined by a combination of forces, primarily diet, but there is some indication that host  phylogeny  may also be playing a role in the selection of lineages. [ 164 ] [ 165 ]


For more than 51 years it has been known that the administration of low doses of antibacterial agents promotes the growth of farm animals to increase weight gain. [ 126 ]


In a study carried out on  mice  the ratio of  Firmicutes  and  Lachnospiraceae  was significantly elevated in animals treated with subtherapeutic doses of different antibiotics. By analyzing the caloric content of faeces and the concentration of small chain fatty acids (SCFAs) in the GI tract, it was concluded that the changes in the composition of microbiota lead to an increased capacity to extract calories from otherwise indigestible constituents, and to an increased production of SCFAs. These findings provide evidence that antibiotics perturb not only the composition of the GI microbiome but also its metabolic capabilities, specifically with respect to SCFAs. [ 126 ]


The  gut–brain axis  is the two-way biochemical signaling that takes place between the  gastrointestinal tract  (GI tract) and the  central nervous system  (CNS). [ 2 ]  The term " microbiota–gut–brain axis " highlights the role of  gut microbiota  in these  biochemical signaling  . [ 3 ] [ 2 ]  Broadly defined, the gut–brain axis includes the  central nervous system ,  neuroendocrine  system,  neuroimmune systems , the  hypothalamic–pituitary–adrenal axis  (HPA axis),  sympathetic  and  parasympathetic  arms of the  autonomic nervous system , the  enteric nervous system ,  vagus nerve , and the gut microbiota. [ 2 ]


Chemicals released by the  gut microbiome  can influence  brain  development, starting from birth. A review from 2015 states that the gut microbiome influences the  CNS  by "regulating brain chemistry and influencing neuro-endocrine systems associated with stress response, anxiety and memory function". [ 4 ]  The gut, sometimes referred to as the "second brain", may use the same type of neural network as the  CNS , suggesting why it could have a role in brain function and  mental health . [ 5 ]


The bidirectional communication is done by  immune ,  endocrine ,  humoral  and neural connections between the gastrointestinal tract and the central nervous system. [ 4 ]  More research suggests that the  gut microbiome  influence the function of the brain by releasing the following chemicals:  cytokines ,  neurotransmitters ,  neuropeptides ,  chemokines , endocrine messengers and microbial  metabolites  such as "short-chain fatty acids, branched chain amino acids, and  peptidoglycans ". [ 6 ]  These chemical signals are then transported to the brain via the  blood ,  neuropod cells ,  nerves ,  endocrine cells , [ 7 ] [ 8 ]  where they impact different metabolic processes. Studies have confirmed that  gut microbiome  contribute to range of brain functions controlled by the  hippocampus ,  prefrontal cortex  and  amygdala  (responsible for  emotions  and  motivation ) and act as a key node in the gut-brain behavioral axis. [ 9 ]


While  Irritable bowel syndrome  (IBS) is the only disease confirmed to be directly influenced by the gut microbiome, many disorders (such as  anxiety ,  autism ,  depression  and  schizophrenia ) have been reportedly linked to the gut-brain axis as well. [ 6 ] [ 10 ] [ 7 ]  According to a study from 2017, " probiotics  have the ability to restore normal microbial balance, and therefore have a potential role in the treatment and prevention of anxiety and depression". [ 11 ]


The first of the brain–gut interactions shown, was the  cephalic phase of digestion , in the release of gastric and pancreatic secretions in response to sensory signals, such as the smell and sight of food. This was first demonstrated by  Pavlov  through  Nobel prize  winning research in 1904. [ 12 ] [ 13 ]


As of October 2016, most of the work done on the role of gut microbiota in the gut–brain axis had been conducted in animals, or on characterizing the various  neuroactive compounds  that gut microbiota can produce. Studies with humans – measuring variations in gut microbiota between people with various psychiatric and neurological conditions or when stressed, or measuring effects of various  probiotics  (dubbed " psychobiotics " in this context) – had generally been small and were just beginning to be generalized. [ 14 ]  Whether changes to the gut microbiota are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut–brain axis, remain unclear. [ 15 ]


The  enteric nervous system  is one of the main divisions of the  nervous system  and consists of a mesh-like system of  neurons  that governs the function of the  gastrointestinal system ; it has been described as a "second brain" for several reasons. The enteric nervous system can operate autonomously. It normally communicates with the  central nervous system  (CNS) through the  parasympathetic  (e.g., via the  vagus nerve ) and  sympathetic  (e.g., via the  prevertebral ganglia ) nervous systems. However,  vertebrate  studies show that when the  vagus nerve  is severed, the enteric nervous system continues to function. [ 16 ]


In vertebrates, the enteric nervous system includes  efferent neurons ,  afferent neurons , and  interneurons , all of which make the enteric nervous system capable of carrying reflexes in the absence of CNS input. The sensory neurons report on mechanical and chemical conditions. Through intestinal muscles, the motor neurons control  peristalsis  and churning of intestinal contents. Other neurons control the secretion of  enzymes . The enteric nervous system also makes use of more than 30  neurotransmitters , most of which are identical to the ones found in CNS, such as  acetylcholine ,  dopamine , and  serotonin . More than 90% of the body's serotonin lies in the gut, as well as about 50% of the body's dopamine; the dual function of these neurotransmitters is an active part of gut–brain research. [ 17 ] [ 18 ] [ 19 ]


The first of the gut–brain interactions was shown to be between the sight and smell of food and the release of gastric secretions, known as the  cephalic phase , or cephalic response of digestion. [ 12 ] [ 13 ]


The  gut microbiota  is the complex community of  microorganisms  that live in the  digestive tracts  of humans and other animals. The gut  metagenome  is the aggregate of all the  genomes  of gut microbiota. [ 24 ]  The gut is one niche that  human microbiota  inhabit. [ 25 ]


In humans, the gut microbiota has the largest quantity of bacteria and the greatest number of species, compared to other areas of the body. [ 26 ]  In humans, the gut flora is established at one to two years after birth; by that time, the  intestinal epithelium  and the  intestinal mucosal barrier  that it secretes have co-developed in a way that is tolerant to, and even supportive of, the gut flora and that also provides a barrier to  pathogenic organisms . [ 27 ] [ 28 ]


The relationship between gut microbiota and humans is not merely  commensal  (a non-harmful coexistence), but rather a  mutualistic  relationship. [ 25 ]  Human gut microorganisms benefit the host by collecting the energy from the  fermentation  of undigested  carbohydrates  and the subsequent absorption of  short-chain fatty acids  (SCFAs),  acetate ,  butyrate , and  propionate . [ 26 ] [ 29 ]  Intestinal  bacteria  also play a role in synthesizing  vitamin B  and  vitamin K  as well as metabolizing  bile acids ,  sterols , and  xenobiotics . [ 25 ] [ 29 ]  The systemic importance of the SCFAs and other compounds they produce are like  hormones  and the gut flora itself appears to function like an  endocrine organ ; [ 29 ]  dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions. [ 26 ] [ 30 ]


The composition of human gut microbiota changes over time, when the diet changes, and as overall health changes. [ 26 ] [ 30 ]  In general, the average human has over 1000 species of bacteria in their gut microbiome, with Bacteroidetes and Firmicutes being the dominant phyla. Diets higher in processed foods and unnatural chemicals can negatively alter the ratios of these species, while diets high in whole foods can positively alter the ratios. Additional health factors that may skew the composition of the gut microbiota are  antibiotics  and  probiotics . Antibiotics have severe impacts on gut microbiota, ridding of both good and bad bacteria. Without proper rehabilitation, it can be easy for harmful bacteria to become dominant. Probiotics may help to mitigate this by supplying healthy bacteria into the gut and replenishing the richness and diversity of the gut microbiota. There are many strains of probiotics that can be administered depending on the needs of a specific individual. [ 31 ]


The gut–brain axis, a bidirectional neurohumoral communication system, is important for maintaining  homeostasis  and is regulated through the  central  and  enteric nervous systems  and the neural, endocrine, immune, and metabolic pathways, and especially including the  hypothalamic–pituitary–adrenal axis  (HPA axis). [ 2 ]  That term has been expanded to include the role of the gut microbiota as part of the "microbiome-gut-brain axis", a linkage of functions including the gut microbiota. [ 2 ]


Interest in the field was sparked by a 2004 study (Nobuyuki Sudo and Yoichi Chida) showing that germ-free mice (genetically homogeneous laboratory mice, birthed and raised in an antiseptic environment) showed an exaggerated HPA axis response to stress, compared to non-GF laboratory mice. [ 2 ]


The gut microbiota can produce a range of neuroactive molecules, such as  acetylcholine ,  catecholamines ,  γ-aminobutyric acid ,  histamine ,  melatonin , and  serotonin , which are essential for regulating peristalsis and sensation in the gut. [ 32 ]  Changes in the composition of the gut microbiota due to diet, drugs, or disease correlate with changes in levels of circulating  cytokines , some of which can affect brain function. [ 32 ]  The gut microbiota also release molecules that can directly activate the  vagus nerve , which transmits information about the state of the intestines to the brain. [ 32 ]


Likewise, chronic or acutely stressful situations activate the  hypothalamic–pituitary–adrenal axis , causing changes in the gut microbiota and  intestinal epithelium , and possibly having  systemic effects . [ 32 ]  Additionally, the  cholinergic anti-inflammatory pathway , signaling through the vagus nerve, affects the gut epithelium and microbiota. [ 32 ]   Hunger  and satiety are integrated in the brain, and the presence or absence of food in the gut and types of food present also affect the composition and activity of gut microbiota. [ 32 ]


Most of the work that has been done on the role of gut microbiota in the gut–brain axis has been conducted in animals, including the highly artificial germ-free mice. As of 2016, studies with humans measuring changes to gut microbiota in response to stress, or measuring effects of various probiotics, have generally been small and cannot be generalized; whether changes to gut microbiota are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut–brain axis, remains unclear. [ 15 ]


The concept is of special interest in  autoimmune diseases  such as  multiple sclerosis . [ 33 ]  This process is thought to be regulated via the gut microbiota, which ferment indigestible dietary fibre and resistant starch; the fermentation process produces  short chain fatty acids  (SCFAs) such as propionate, butyrate, and acetate. [ 34 ]
The history of ideas about a relationship between the gut and the mind dates from the nineteenth century.  [ 35 ]


While  Irritable bowel syndrome  (IBS) is the only disease confirmed to be directly influenced by the gut microbiome, many disorders such as  anxiety ,  autism ,  depression  and  schizophrenia  have been linked to the gut-brain axis as well. [ 6 ] [ 36 ] [ 7 ]


Skin conditions  such as  acne  were proposed as early as 1930, [ 37 ]  to be related to emotional states which altered the gut microbiome leading to  systemic inflammation . Such conditions that have been improved by the use of  probiotics . [ 38 ]  Studies have shown overlapping mechanisms in  psoriasis  and depression; psoriasis causing disturbances in the gut microbiota that reflect in the brain causing depression that in turn can cause the stress that affects the microbiome. [ 39 ]  Probiotics may reduce symptoms of depression through the vagus nerve and sympathetic pathways.


Irritable bowel syndrome (IBS) can cause many abdominal issues such as symptoms of constipation, diarrhea, gas, bloating, and abdominal pain. IBS can be stress-induced and flare-ups are associated with bouts of stress. The gut-brain axis may explain this. The use of probiotics has been shown to help to restore a balance of helpful and harmful bacteria. [ 40 ]


Brain function is dependent on multiple  neuropeptides  including  dopamine ,  GABA  and  serotonin , that are controlled in the gut microbiota. Imbalances in the gut microbiota intensifies  anxiety  as both the immune and metabolic pathways are affected. Specific microbes can lead to increased anxiety due to the activation of  c-Fos  proteins. These proteins serve as indicators of neuronal activation. Probiotics have beneficial impacts on anxiety. [ 41 ]


Studies have shown that children with  autism  are four times more likely to develop gastrointestinal disorders. The severity of their behavioral symptoms is proportional to the severity of their gastrointestinal issues. Many children with autism have high  focal levels of  HMGB1 . [ 42 ]   [ 43 ]


Different neurotrophins play a role in schizophrenia. One of the main ones is called Brain-Derived Neurotrophic Factor (BDNF). BDNF has been associated with schizophrenia and is believed to be a part of the molecular mechanism that has to do with cognitive dysfunction during neurodevelopmental changes. Those who have been diagnosed with schizophrenia tend to exhibit lower levels of BDNF in blood and levels of BDNF are also lower in the cortex and hippocampus. Levels of butyric acid have also been shown to be different between schizophrenic patients and non-schizophrenic patients. It is important to note that studies regarding the link between the gut-brain axis and schizophrenia are limited and further studies are underway.  [ 44 ]


Braak's theory  proposed that  gut dysbiosis  in Parkinson's causes the aggregation of  alpha-synuclein  in the gastrointestinal tract before its spreading to the brain. [ 45 ]


The gut-brain microbiota abnormalities that contribute to Parkinson's disease, supports the idea that it originates in the gut and spreads. The route would be from the gut to the central nervous system, through the vagus nerve. Gastrointestinal syndromes are known to be dysphagia, gastroparesis, and constipation among others, contributing to the risk of Parkinson's disease. From the understanding of these diseases, the disease modifying therapies are known to be aspects that help prevent the progress of these diseases that focus on the gut-brain axis. Relevant therapies are the Vagus nerve stimulation, the Fecal microbiota transplantation, the use of Rifaximun and other drugs directed towards the gut.
 [ 46 ]


Microbial derived secondary  bile acids  produced in the gut may influence cognitive function. [ 47 ]   Altered bile acid profiles occur in cases of  mild cognitive impairment  and  Alzheimer's disease  with an increase in  cytotoxic  secondary bile acids and a decrease in primary bile acids. [ 48 ]   These findings suggest a role of the gut  microbiome  in the progression to Alzheimer's disease. [ 48 ]  In contrast to the cytotoxic effect of secondary bile acids, the bile acid  tauroursodeoxycholic acid  may be beneficial in the treatment of  neurodegenerative diseases . [ 49 ]


As more bile acids are absorbed via apical sodium-bile acid transporters, there is a significant increase in age-related cognitive impairment. Levels of serum conjugated primary bile acids were monitored and increased levels revealed ammonia accumulation in the brain. These increased levels of ammonia led to hippocampal synapse loss. Because the hippocampus is largely responsible for memory, the loss of these synapses can have profound impacts on the memories of those affected.  [ 50 ]


4KKI ,  4KKJ


Haptocorrin  (HC) also known as  transcobalamin-1  ( TC-1 ) or  cobalophilin  is a  transcobalamin   protein  that in humans is encoded by the  TCN1   gene . [ 3 ]  One essential function of haptocorrin is protection of the acid-sensitive  vitamin B 12  while it moves through the stomach. A second function is serum HC binding of the great majority of circulating vitamin B 12 , rendering it unavailable for take-up by cells. This is conjectured to be a circulating storage function.


Haptocorrin (HC), also commonly known as the R-protein, or the R-factor, or previously referred to as transcobalamin I, is a unique  glycoprotein  produced by the salivary glands of the oral cavity, in response to ingestion of food. This protein binds strongly to vitamin B 12  in what is an intricate and necessary mechanism to protect this vitamin from the acidic environment of the stomach. [ 4 ] : 44   Vitamin B 12  is an essential water-soluble vitamin, the deficiency of which creates anemia ( macrocytic anemia ), decreased bone marrow cell production ( anemia ,  pancytopenia ), neurological problems, as well as metabolic issues ( methylmalonyl-CoA acidosis ). [ 4 ] : 50–51


Vitamin B 12  is therefore an important vitamin for the body to absorb. Despite its vital role however, vitamin B 12  is structurally very sensitive to the  hydrochloric acid  found in the stomach secretions, and easily denatures in that environment before it has a chance to be absorbed by the small intestine.  Found in fresh animal products (such as liver), vitamin B 12  attaches haptocorrin, which has a high affinity for its molecular structure. [ 5 ]  Coupled together vitamin B 12  and haptocorrin create a complex. This haptocorrin–B 12  complex is impervious to the insult of the stomach acid, and passes on via the  pylorus  to the  duodenum . In the duodenum pancreatic  proteases  (a component of  pancreatic juice ) cleave haptocorrin, releasing vitamin B 12  in its free form.


The same cells in the stomach that produce gastric hydrochloric acid, the  parietal cells , also produce a molecule called the  intrinsic factor  (IF), which binds the B 12  after its release from haptocorrin by digestion, and without which only 1% of vitamin B 12  is absorbed. Intrinsic factor (IF) is a glycoprotein, with a molecular weight of 45 kDa. In the duodenum, the free vitamin B 12  attaches to the intrinsic factor (IF) to create a vitamin B 12 –IF complex. This complex then travels through the small bowel and reaches the terminal tertiary portion of the small intestine, called the  ileum . The ileum is the longest of all portions of the small intestine, and has on its surface specialized receptors called  cubilin  receptors, that identify the B 12 –IF complexes and take them up into the circulation via  endocytosis -mediated absorption. [ 6 ]


Separate from the digestive absorption function, serum HC binds 80-90% of circulating B 12 , rendering it unavailable for cellular delivery by  transcobalamin II . This is conjectured to be a circulating storage function. [ 7 ]  Several serious, even life-threatening diseases cause elevated serum HC, measured as abnormally high serum vitamin B 12  while at the same time manifesting as a vitamin deficiency because of insufficient vitamin bound to transcobalamin II. [ 8 ]


The  hepatopancreas ,  digestive gland  or  midgut gland  is an organ of the  digestive tract  of  arthropods  and  molluscs . It provides the functions which in  mammals  are provided separately by the  liver  and  pancreas , including the production of digestive  enzymes , and absorption of digested food. [ 2 ]


Arthropods, especially  detritivores  in the Order  Isopoda , Suborder Oniscidea ( woodlice ), have been shown to be able to store  heavy metals  in their hepatopancreas. [ 3 ]  This could lead to  bioaccumulation  through the  food chain  and implications for  food web  destruction, if the accumulation gets high enough in polluted areas; for example, high metal concentrations are seen in  spiders  of the genus  Dysdera  which feed on  woodlice , including their hepatopancreas, the major metal storage organ of isopods in  polluted  sites. [ 4 ]


The hepatopancreas is a centre for  lipid metabolism  and for storage of lipids in  gastropods . [ 6 ]


Some species in the genus  Phyllodesmium  contains active  zooxanthellae  of the genus  Symbiodinium  in the hepatopancreas. [ 7 ]


Heyndrickxia coagulans  (formerly  Bacillus coagulans ) is a  lactic acid –forming bacterial species. This species was transferred to  Weizmannia  in 2020, [ 1 ]  then to  Heyndrickxia  in 2023. [ 2 ]


H. coagulans  is a  Gram-positive ,  catalase -positive, spore-forming,  motile ,  facultative anaerobe  rod that measures approximately 0.9 μm by 3.0 μm to 5.0 μm. It may appear  Gram negative  when entering the  stationary phase  of growth. The optimum temperature for growth is 50 °C (122 °F); the range of temperatures tolerated is 30–55 °C (86–131 °F).  IMViC  tests  VP and MR ( methyl red ) are positive.


The species was first isolated and described in 1915 by B.W. Hammer at the Iowa Agricultural Experiment Station as a cause of an outbreak of coagulation in  evaporated milk  packed by an Iowa  condensary . [ 3 ]  Separately isolated in 1935 and described as  Lactobacillus sporogenes  in the fifth edition of  Bergey's Manual of Systematic Bacteriology , it exhibits characteristics typical of both genera  Lactobacillus  and  Bacillus ; its taxonomic position between the families  Lactobacillaceae  and  Bacillaceae  was often debated. However, in the seventh edition of  Bergey's , it was finally transferred to the genus  Bacillus . DNA-based technology was used in distinguishing between the two genera of bacteria, which are  morphologically  similar and possess similar  physiological  and  biochemical  characteristics. [ 4 ] [ 5 ]


In 2020, further genetic evidence shows that it is sufficiently different from other members of  Bacillus  to be transferred into its own genus. As a result, it became the  type species  of  Weizmannia . [ 1 ]  In 2023, even further genetic evidence shows that  Weizmannia  was not sufficiently distinct from  Heyndrickxia  to be an independent genus; as a result, all members of  Weizmannia  were moved to  Heyndrickxia . [ 2 ]


H. coagulans  has been added by the  EFSA  to their Qualified Presumption of Safety list [ 6 ]  and has been approved for veterinary purposes as  GRAS  by the  U.S. Food and Drug Administration 's Center for Veterinary Medicine, as well as by the  European Union , and is listed by  AAFCO  for use as a direct-fed microbial in livestock production. It is often used in veterinary applications, especially as a  probiotic  in pigs, cattle, poultry, and shrimp. Many references to use of this bacterium in humans exist, especially in improving the  vaginal flora , [ 7 ] [ 8 ] [ 9 ]  improving abdominal pain and bloating in  irritable bowel syndrome  patients, [ 10 ]  and increasing immune response to viral challenges. [ 11 ]  There is evidence from animal research that suggests that  H. coagulans  is effective in both treating as well as preventing recurrence of  Clostridioides difficile  associated diarrhea . [ 12 ]  Further, one animal research study showed that it can alter inflammatory processes in the context of  multiple sclerosis . [ 13 ]  One strain of this bacterium has also been assessed for safety as a food ingredient. [ 14 ]   Spores are activated in the acidic environment of the stomach and begin germinating and proliferating in the intestine. Sporeforming  H. coagulans  strains are used in some countries as probiotics for patients on antibiotics.


H. coagulans  is often marketed as  Lactobacillus sporogenes  or a 'sporeforming lactic acid bacterium' probiotic, but this is an outdated name due to taxonomic changes in 1939. Although  H. coagulans  does produce L+ lactic acid , the bacterium used in these products is not a lactic-acid bacterium, as  Bacillaceae  species do not belong to the  lactic acid bacteria  ( Lactobacillales ). By definition, lactic acid bacteria ( Lactobacillus ,  Bifidobacterium ) do not form spores. Therefore, using the name  Lactobacillus sporogenes  is scientifically incorrect. [ 4 ] [ 15 ]


The 2023 name  H. coagulans  is nowhere as common as the former name  Bacillus coagulans . The former name remains  valid  under the  Prokaryotic Code .


Hindgut fermentation  is a digestive process seen in  monogastric   herbivores  (animals with a simple, single-chambered  stomach ).    Cellulose  is digested with the aid of  symbiotic  microbes including  bacteria ,  archaea , and  eukaryotes . [ 1 ]  The  microbial   fermentation  occurs in the digestive organs that follow the  small intestine : the  cecum  and  large intestine .  Examples of  hindgut  fermenters include  proboscideans  and large  odd-toed ungulates  such as  horses  and  rhinos , as well as small animals such as  rodents ,  rabbits  and  koalas . [ 2 ]


In contrast,  foregut fermentation  is the form of cellulose digestion seen in  ruminants  such as  cattle  which have a four-chambered stomach, [ 3 ]  as well as in  sloths ,  macropodids , some  monkeys , and one bird, the  hoatzin . [ 4 ]


Hindgut fermenters generally have a  cecum  and large intestine that are much larger and more complex than those of a foregut or  midgut  fermenter. [ 5 ]  Research on small cecum fermenters such as  flying squirrels , rabbits and lemurs has revealed these mammals to have a GI tract about 10-13 times the length of their body. [ 6 ]   This is due to the high intake of  fiber  and other hard to digest compounds that are characteristic to the diet of monogastric herbivores. [ 7 ]


Easily digestible food is processed in the gastrointestinal tract & expelled as regular feces.  But in order to get nutrients out of hard to digest fiber, some smaller hindgut fermenters, like  lagomorphs  (rabbits, hares, pikas), ferment fiber in the cecum (at the small and large intestine junction) and then expel the contents as  cecotropes , which are reingested ( cecotrophy ).  The cecotropes are then absorbed in the small intestine to utilize the nutrients. [ 7 ]


This process is also beneficial in allowing for restoration of the microflora population, or  gut flora . These microbes are found in the gastrointestinal tract and can act as protective agents that strengthen the  immune system . Small hindgut fermenters have the ability to expel their microflora, which is useful during the acts of  hibernation ,  estivation  and  torpor .


While foregut fermentation is generally considered more efficient, and monogastric animals cannot digest cellulose as efficiently as ruminants, [ 5 ]  hindgut fermentation allows animals to consume small amounts of low-quality forage all day long and thus survive in conditions where ruminants might not be able to obtain nutrition adequate for their needs. While ruminants require a good deal of time resting between meals, hindgut fermenters are able to take in smaller meals more frequently, allowing them to eat and move more readily. [ 8 ]   The large hindgut fermenters are bulk feeders: they ingest large quantities of low-nutrient food, which they process more rapidly than would be possible for a similarly sized foregut fermenter. The main food in that category is grass, and grassland grazers move over long distances to take advantage of the growth phases of grass in different regions. [ 9 ]


The ability to process food more rapidly than foregut fermenters gives hindgut fermenters an advantage at very large body size, as they are able to accommodate significantly larger food intakes. The largest extant and prehistoric  megaherbivores , elephants and  indricotheres  (a type of rhino), respectively, have been hindgut fermenters. [ 10 ]  Study of the rates of evolution of larger maximum body mass in different terrestrial mammalian groups has shown that the fastest growth in body mass over time occurred in hindgut fermenters ( perissodactyls ,  rodents   and  proboscids ). [ 11 ]


Hindgut fermenters are subdivided into two groups based on the relative size of various digestive organs in relationship to the rest of the system:  colonic  fermenters tend to be larger species such as horses, and cecal fermenters are smaller animals such as rabbits and rodents. [ 2 ]  However, in spite of the terminology, colonic fermenters such as horses make extensive use of the cecum to break down cellulose. [ 12 ] [ 13 ]  Also, colonic fermenters typically have a proportionally longer large intestine than small intestine, whereas cecal fermenters have a considerably enlarged cecum compared to the rest of the digestive tract.


In addition to mammals, several insects are also hindgut fermenters, the best studied of which are the  termites , which are characterised by an enlarged "paunch" of the hindgut that also houses the bulk of the gut microbiota. [ 14 ]  Digestion of wood particles in lower termites is accomplished inside the phagosomes of gut flagellates, but in the flagellate-free higher termites, this appears to be accomplished by fibre-associated bacteria. [ 15 ]


In  humans , the  anus  ( pl. :  anuses  or  ani ; from  Latin   ānus , "ring", "circle") [ 1 ] [ 2 ]  is the external opening of the  rectum  located inside the  intergluteal cleft . Two  sphincters  control the exit of  feces  from the body during an act of  defecation , which is the primary function of the anus. These are the  internal anal sphincter  and the  external anal sphincter , which are circular  muscles  that normally maintain constriction of the orifice and which relax as required by normal physiological functioning. The inner sphincter is involuntary and the outer is voluntary. Above the anus is the  perineum , which is also located beneath the  vulva  or  scrotum .


In part owing to its exposure to feces, a number of medical conditions may affect the anus, such as  hemorrhoids . [ 3 ]  The anus is the site of potential  infections  and other conditions, including  cancer  (see  anal cancer ). [ 4 ]


With  anal sex , the anus can play a role in  sexuality . Attitudes toward anal sex vary, and it is illegal in some countries. [ 5 ]  The anus is often considered a  taboo  part of the body, [ 5 ]  and is known by many, usually vulgar,  slang  terms. Some  sexually transmitted infections  including  HIV/AIDS  and  anal warts  can be spread via anal sex.


The anus is the final part of the  gastrointestinal tract , and directly continues from the  rectum , passing through the  pelvic floor . The top and bottom of the anus are surrounded by the  internal  and  external anal sphincters , two muscular rings which control defecation. [ 6 ] : 397
The anus is surrounded in its length by folds called  anal valves , which converge at a line known as the  pectinate line . This represents the point of transition between the  hindgut  and the  ectoderm  in the embryo. Below this point, the mucosa of the internal anus becomes skin. [ 6 ]   : 397   The pectinate line is also the division between the internal and external anus.


The anus receives blood from the  inferior rectal artery  and innervation from the  inferior rectal nerves , which branch from the  pudendal nerve . [ 7 ]


The pseudostratified columnar  epithelium  of the gastrointestinal tract transitions to stratified squamous epithelium at the pectinate line. The stratified squamous epithelium gradually accumulates  sebaceous  and  apocrine glands . [ 8 ] : 285


During  puberty , as testosterone triggers  androgenic hair  growth on the body,  pubic hair  begins to appear around the anus. Although initially sparse, it fills out by the end of puberty, if not earlier. In some genetic populations, androgenic hair is less common.


Intra-rectal pressure builds as the rectum fills with feces, pushing the feces against the walls of the  anal canal . Contractions of abdominal and pelvic floor muscles can create intra-abdominal pressure, which further increases intra-rectal pressure. The internal anal sphincter (an involuntary muscle) responds to the pressure by relaxing, thus allowing the feces to enter the canal. The rectum shortens as feces are pushed into the anal canal and  peristaltic waves  push the feces out of the rectum. Relaxation of the internal and external anal sphincters allows the feces to exit from the anus, finally, as the  levator ani  muscles pull the anus up over the exiting feces.


Anal fissures  are tears in the external lining of the lining (mucosa) of the anus. These are exquisitely painful, with pain occurring after a motion is passed; other symptoms may include minor bleeding, discharge, or itch. [ 9 ]  Generally, fissures are due to injury to the mucosa, or because of a poor local blood supply that prevents proper healing, with spasm of the external anal sphincter contributing. [ 9 ]  The external anal sphincter can be relaxed by the application of  glyceryl trinitrate  creams, and  constipation  is managed with  laxatives  and improving hydration. [ 9 ]  Some fissures may require  botulinum toxin  injection; worst cases may require surgical intervention, such as "lateral internal  anal sphincterotomy  or advancement anoplasty" [ clarification needed ] . [ 9 ]


Hemorrhoids  are visible blood vessels from the internal or external  venous plexuses  of the anus. Haemorrhoids may; cause bleeding after passing a motion; be painful; cause an itch; or  prolapse  out of the anus. [ 9 ]  Haemorrhoids are often associated with straining due to constipation, and  pregnancy . [ 9 ]  Usually, haemorrhoids are managed with medications to  make motions more soft  and prevent straining during constipation. Some haemorrhoids require surgery to manage, which may involve  placing a band around the haemorrhoid , in order for it to lose blood supply; or surgical excision. [ 9 ]


Other


Anal abscesses  usually result from infection of the normal glands of the anus, or sometimes because of  Crohn's disease . [ 9 ]  They usually occur to the sides of the sphincters, and between the internal and external sphincters, either on the surface, or deeper. They may get bigger, enlarging in the direction of the rectum, and resulting in an abnormal connection called an  anorectal fistula . They are usually managed with surgical drainage [ 9 ]  and antibiotics. [ 10 ] [ 11 ]


Additional


Anal cancer , also called "anal carcinoma", and  anal intraepithelial neoplasia . [ 12 ]


Itchiness, called  pruritus ani , can affect the anus area. It is most often due to long-term exposure of the anus to faeces, with reasons including diseases of the anus such as haemorrhoids, fistulas and fissures; poor hygiene or chronic diarrhoea; local infections such as  tapeworm  and  thrush ; or skin conditions such as  psoriasis  and  contact dermatitis . If there is a specific cause identified, the cause may be treated to relieve the itch. Otherwise, treatment includes keeping the area clean and dry, ceasing topical creams and ointments, and potentially bulk-forming laxatives to reduce the chance of faecal contamination. [ 9 ]


Damage or injury to the anal sphincter ( patulous anus  in more severe cases) as a result of damage during surgery, such as to the  perineal  region, or resulting from  anal sex ; can lead to  flatus  and/or  fecal incontinence , chronic constipation and  megacolon . [ 13 ]


The anus has a relatively high concentration of  nerve endings  and can be an  erogenous zone , which can make anal intercourse pleasurable if performed properly. The pudendal nerve that branches to supply the external anal sphincter also branches to the  dorsal nerve of the clitoris  and the  dorsal nerve of the penis . [ 14 ]


In addition to nerve endings, pleasure from anal intercourse may be aided by the close proximity between the anus and the  prostate  for males, and  vagina ,  clitoral   legs  and anal area for females. This is because of indirect stimulation of the prostate and vagina or clitoral legs. [ 14 ] [ 15 ] [ 16 ]  For a male insertive partner, the tightness of the anus can be a source of pleasure via the tactile pressure on the penis. [ 17 ] [ 18 ]  Pleasure from the anus can also be achieved through  anal masturbation ,  anal fingering , [ 5 ]   facesitting ,  anilingus , and other penetrative and  non-penetrative acts . Anal stretching or  fisting  is pleasurable for some, but it poses a more serious threat of damage due to the deliberate stretching of the anal and rectal tissues; its injuries include anal sphincter lacerations and rectal and  sigmoid colon  (rectosigmoid) perforation, which might result in death. [ 19 ]  Lubricant and  condoms  are widely regarded as a necessity while performing anal sex, as well as a slow and cautious penetration. [ 20 ]


Anal intercourse is sometimes referred to as  sodomy  or buggery, and is considered  taboo  in a number of legal systems. It has been, and in some  jurisdictions  continues to be, a crime carrying severe punishment. [ 5 ]


To prevent diseases of the anus [ citation needed ]  and to promote general hygiene, humans often clean the exterior of the anus after emptying the bowels. A rinse with water from a  bidet  or a wipe with  toilet paper  is often used for this purpose, though anal cleansing practices vary greatly between cultures.


Shaving, trimming,  depilatory  (hair removal), or  Brazilian waxing  can clear the  perineum  of hair.


Anal bleaching  is a process in which the anus and perineum is lightened.  Perineum sunning  is a process in which the anus is  sun tanned  by deliberate exposure to sunlight, resulting in a darkening of the area. [ 21 ]


A true  anal piercing  is rare because it may interfere with the function of the anus and cause infections. Surface piercings of the perineum are easier to care for and much more common.


Some people have their anuses  tattooed .


The anus has many slang terms including  asshole ,  butthole  (and their respective British equivalents  arsehole ,  bumhole ),  cornhole , and  bunghole .


In  human anatomy , the  mouth  is the first portion of the  alimentary canal  that receives  food  and produces  saliva . [ 2 ]  The  oral mucosa  is the mucous membrane  epithelium  lining the inside of the mouth.


In addition to its primary role as the beginning of the  digestive system , the mouth also plays a significant role in  communication . While primary aspects of the  voice  are produced in the  throat , the  tongue ,  lips , and  jaw  are also needed to produce the range of sounds included in  speech .


The mouth consists of two regions, the  vestibule  and the  oral cavity proper . The mouth, normally moist, is lined with a  mucous membrane , and contains the  teeth .  The lips mark the transition from mucous membrane to  skin , which covers most of the  body .


The mouth consists of two regions: the vestibule and the oral cavity proper. The vestibule is the area between the teeth, lips and cheeks. [ 3 ]  The oral cavity is bounded at the sides and in front by the  alveolar process  (containing the  teeth ) and at the back by the  isthmus of the fauces . Its roof is formed by the  hard palate . The floor is formed by the  mylohyoid muscles  and is occupied mainly by the anterior two-thirds of the  tongue . A  mucous membrane  – the  oral mucosa , lines the sides and under surface of the tongue to the  gums , and lines the inner aspect of the jaw ( mandible ). It receives secretions from the  submandibular  and  sublingual   salivary glands . The posterior border of the oral cavity (ie, junction between the oral cavity and the  oropharynx ) includes the junction of the  hard palate  and the  soft palate  superiorly, the  circumvallate papillae  of the  tongue  inferiorly, and the  retromolar trigone .