Gut microbiota

In humans, the gut microbiota has the highest numbers and species of bacteria compared to other areas of the body. The approximate number of bacteria composing the gut microbiota is about 1013–1014 (10 to 100 trillion). In humans, the gut flora is established at birth and gradually transitions towards a state resembling that of adults by the age of two, 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. The relationship between some gut microbiota and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship. 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. The composition of human gut microbiota changes over time, when the diet changes, and as overall health changes. == Classifications ==

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. Fungi, protists, archaea, and viruses are also present in the gut flora, but less is known about their activities. '', a yeast found in the gut Many species in the gut have not been studied outside of their hosts because they cannot be cultured. While there are a small number of core microbial species shared by most individuals, populations of microbes can vary widely. Within an individual, their microbial populations stay fairly constant over time, with some alterations occurring due to changes in lifestyle, diet and age. Most bacteria belong to the genera Bacteroides, Clostridium, Faecalibacterium, 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. Enterotype 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. There are indications that long-term diet influences enterotype. Three human enterotypes have been proposed, but their value has been questioned. == Composition ==

microbiota depicted in various regions Bacteria Stomach 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. The interaction between the pre-existing gastric microbiota with the introduction of H. pylori may influence disease progression. Intestines 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. In addition the large intestine contains the largest bacterial ecosystem in the human body. Factors that disrupt the microorganism population of the large intestine include antibiotics, stress, and parasites. and account for 60% of fecal nitrogen. Somewhere between 300 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. However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host. Due to the prevalence of fungi in the natural environment, determining which genera and species are permanent members of the gut mycobiome is difficult. while Candida albicans is likely a permanent member, and is believed to be acquired at birth through vertical transmission. Viruses The human virome includes all viruses associated with the human body, ranging from viruses that infect native cells to bacteriophages that infect bacteria in the microbiome. Among these, bacteriophages are by far the most numerous. ==Variation==

Age There are common patterns of microbiome composition evolution during life. 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. 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. Studies of hunter-gatherer populations have further demonstrated the impact of subsistence strategy on gut microbiome composition. Research on the Hadza, a hunter-gatherer community in Tanzania, found significantly greater microbial diversity compared to Italian controls, with enrichment in taxa such as Treponema, Prevotella, and unclassified Bacteroidetes associated with the fermentation of fibrous plant foods. Similarly, analysis of the gut microbiome of Yanomami Amerindians in Venezuela, a community with no prior documented contact with Western populations, revealed the highest level of bacterial diversity recorded in a human group. This suggests that industrialization and Western diets are associated with a progressive loss of ancestral microbial diversity. 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. Malnourished children also typically have more potentially pathogenic gut flora, and more yeast in their mouths and throats. Altering diet may lead to changes in gut microbiota composition and diversity. Antibiotic use 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. 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, it is gradual and long-term. == Functions ==

When the study of gut flora began in 1995, 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. The gut microbiota not only influences intestinal health but also plays a role in systemic immune regulation, including interactions with the pulmonary immune environment through what is known as the 'gut–lung axis'. Direct inhibition of pathogens 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. 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. Gut flora can also regulate the production of antibodies by the immune system. 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. These signaling molecules interact with B cells to induce class switching to IgA. Ultimately, IgA maintains a healthy environment between the host and gut bacteria. Metabolism 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. and may cause flatulence) and organic acids, such as lactic acid, are also produced by fermentation. 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. Gut microbiota also serve as a source of vitamins K and B12, which are not produced by the body or produced in little amount. Cellulose degradation 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. Pharmacomicrobiomics 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. Since the total number of microbial cells in the human body (over 100 trillion) greatly outnumbers Homo sapiens cells (tens of trillions), 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. 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. The microbial metabolism of drugs can sometimes inactivate the drug. Contribution to drug metabolism The gut microbiota is an enriched community that contains diverse genes with huge biochemical capabilities to modify drugs, especially those taken by mouth. Gut microbiota can affect drug metabolism via direct and indirect mechanisms. The direct mechanism is mediated by the microbial enzymes that can modify the chemical structure of the administered drugs. Conversely, the indirect pathway is mediated by the microbial metabolites which affect the expression of host metabolizing enzymes such as cytochrome P450. These effects can be varied; it could activate the inactive drugs such as lovastatin, inactivate the active drug such as digoxin or induce drug toxicity as in irinotecan. Since then, the impacts of the gut microbiota on the pharmacokinetics of many drugs were heavily studied. Eggerthella lanta has a cytochrome-encoding operon up-regulated by digoxin and associated with digoxin-inactivation. This effect is derived from the microbiome-encoded β-glucuronidase enzymes which recover the active form of the irinotecan causing gastrointestinal toxicity. Secondary metabolites 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. Microbial metabolites especially short chain fatty acids (SCFAs) and secondary bile acids (BAs) play important roles for the human in health and disease states. 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. Dysbiosis 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). The secondary bile acid deoxycholic acid is associated with alterations of the microbial community that lead to increased intestinal carcinogenesis. The high density of bacteria in the colon (about 1012 per ml.) that are subject to dysbiosis compared to the relatively low density in the small intestine (about 102 per ml.) may account for the greater than 10-fold higher incidence of cancer in the colon compared to the small intestine. 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. == Alterations in microbiota balance ==

Effects of antibiotic use Altering the numbers of gut bacteria, for example by taking broad-spectrum antibiotics, may affect the host's health and ability to digest food. Antibiotics can cause antibiotic-associated diarrhea by irritating the bowel directly, changing the levels of microbiota, or allowing pathogenic bacteria to grow. 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. 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. 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. Pregnancy 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. Probiotics, prebiotics, synbiotics, and pharmabiotics Probiotics contain live microorganisms. When consumed, they are believed to provide health benefits by altering the microbiome composition. 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. Synbiotics refers to food ingredients or dietary supplements combining probiotics and prebiotics in a form of synergism. 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; probiotics that have been genetically engineered or otherwise optimized for best performance (shelf life, survival in the digestive tract, etc.); and the natural products of gut flora metabolism (vitamins, etc.). There is some evidence that treatment with some probiotic strains of bacteria may be effective in treatment of irritable bowel syndrome, inflammatory bowel disease, and abdominal bloating. Those organisms most likely to result in a decrease of symptoms have included: • Bifidobacterium breve • Bifidobacterium infantis • Enterococcus faecium • Lactobacillus plantarum • Lactobacillus reuteri • Lactobacillus rhamnosus • Lactobacillus salivarius • Propionibacterium freudenreichii • Saccharomyces boulardii • Escherichia coli Nissle 1917 • Streptococcus thermophilus Research 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. == Role in disease ==

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. In turn, the inflammation damages parietal cells which release excessive hydrochloric acid into the stomach and produce less of the protective mucus. 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. 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. The second hypothesis focuses on the Western pattern diet, which lacks whole grains and fiber and has an overabundance of simple sugars. Lacking protective genera such as Lachnospira, Veillonella, Rothia and Faecalibacterium has been linked to reduced SCFA levels. Diabetes mellitus type 1 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 Treg expression. Treg cells downregulate effector T cells, which in turn reduces the inflammatory response in the gut. 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. 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. Butyrate-yielding diets may also have potential colorectal cancer suppression effects. Several studies showed that the gut bacterial composition in diabetic patients became altered with increased levels of Lactobacillus gasseri, Streptococcus mutans and Clostridiales members, with decrease in butyrate-producing bacteria such as Roseburia intestinalis and Faecalibacterium prausnitzii. This alteration is due to many factors such as antibiotic abuse, diet, and age. The decrease in butyrate production is associated with defects in intestinal permeability, which could lead to endotoxemia, which is the increased level of circulating Lipopolysaccharides from gram negative bacterial cells wall. It is found that endotoxemia has association with development of insulin resistance. There appears to be a metabolic link between cancer associated gut microbes and a fat- and meat rich diet. In rodents, elevated levels of bile acids produced by the gut microbiota in response to a high fat diet are associated with an increased the risk of colorectal cancer. There are multiple factors in the environment that affects the development of the microbiota with birthmode being one of the most impactful. Another factor that has been observed to cause huge changes in the gut microbiota, particularly in children, is the use of antibiotics, associating with health issues such as higher BMI, and further an increased risk towards metabolic diseases such as obesity. In infants it was observed that amoxicillin and macrolides cause significant shifts in the gut microbiota characterized by a change in the bacterial classes Bifidobacteria, Enterobacteria and Clostridia. A single course of antibiotics in adults causes changes in both the bacterial and fungal microbiota, with even more persistent changes in the fungal communities. The bacteria and fungi live together in the gut and there is most likely a competition for nutrient sources present. Seelbinder et al. found that commensal bacteria in the gut regulate the growth and pathogenicity of Candida albicans by their metabolites, particularly by propionate, acetic acid and 5-dodecenoate. and further it has been observed to be increased in non-responders to a biological drug, infliximab, given to IBD patients with severe IBD. Propionate and acetic acid are both short-chain fatty acids (SCFAs) that have been observed to be beneficial to gut microbiota health. When antibiotics affect the growth of bacteria in the gut, there might be an overgrowth of certain fungi, which might be pathogenic when not regulated. The BBB is a selectively permeable membrane that tightly regulates the transfer of substances between the circulation and the brain parenchyma. During development, germ-free mice exhibit increased BBB permeability from embryonic stages through adulthood with reduced tight junction proteins, while colonization with mature microbiota restores barrier function through SCFAs like butyrate. This developmental impact persists, as mice with gut microbiota associated with preterm birth show early-life BBB hyperpermeability and cognitive deficits, whereas those with microbiota associated with full-term birth maintain an intact BBB. During aging, altered microbiota composition with increased Firmicutes/Bacteroidetes ratio correlates with compromised BBB function, reduced P-glycoprotein activity, and cognitive impairment. These effects may be mediated by microbial metabolites including SCFAs that enhance barrier integrity and methylamines, where trimethylamine N-oxide protects BBB function while its precursor trimethylamine disrupts it. Obesity and metabolic syndrome 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. 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. 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. 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. == Other animals ==

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. 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. 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. It is known that the disruption of gut microbiota of termites using agents like antibiotics or boric acid (a common agent used in preventative treatment) causes severe damage to digestive function and leads to the rise of opportunistic pathogens. In cockroaches, gut microbiota have been shown to assemble in a deterministic fashion, irrespective of the inoculum; 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. 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. == See also ==