Gut Microbe

Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut microbiota. The gut is the main location of the human microbiome. 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.

The microbial composition of the gut microbiota varies across regions of the digestive tract. The colon contains the highest microbial density recorded in any habitat on Earth, representing between 300 and 1000 different species. Bacteria are the largest and to date, best studied component and 99% of gut bacteria come from about 30 or 40 species. Up to 60% of the dry mass of feces is bacteria. Over 99% of the bacteria in the gut are anaerobes, but in the cecum, aerobic bacteria reach high densities. It is estimated that the human gut microbiota have around a hundred times as many genes as there are in the human genome.

Overview

In humans, the gut microbiota has the largest numbers and species of bacteria compared to other areas of the body. In humans, the gut flora is established at one to two years after birth, by which 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.

The relationship between some gut microbiota and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship. 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. Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics. 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, and dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.

The composition of human gut microbiota changes over time, when the diet changes, and as overall health changes. 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.

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. The colon, in contrast, contains the highest microbial density recorded in any habitat on Earth with up to 10¹² cells per gram of intestinal content. These bacteria represent between 300 and 1000 different species. However, 99% of the bacteria come from about 30 or 40 species. As a consequence of their abundance in the intestine, bacteria also make up to 60% of the dry mass of feces. Fungi, protists, archaea, and viruses are also present in the gut flora, but less is known about their activities.

Over 99% of the bacteria in the gut are anaerobes, but in the cecum, aerobic bacteria reach high densities. It is estimated that these gut flora have around a hundred times as many genes in total as there are in the human genome.

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. The Human Microbiome Project has set out to better describe the microbiota of the human gut and other body locations.

The four dominant bacterial phyla in the human gut are Bacillota (Firmicutes), Bacteroidota, Actinomycetota, and Pseudomonadota. Most bacteria belong to the genera '' Bacteroides'', ''Clostridium'', '' Faecalibacterium'', ''Eubacterium'', ''Ruminococcus'', ''Peptococcus'', '' Peptostreptococcus'', and '' Bifidobacterium''. Other genera, such as '' Escherichia'' and '' Lactobacillus'', are present to a lesser extent. 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.

Fungal genera that have been detected in the gut include '' Candida'', '' Saccharomyces'', '' Aspergillus'', '' Penicillium'', '' Rhodotorula'', '' Trametes'', ''Pleospora'', '' Sclerotinia'', ''Bullera'', and ''Galactomyces'', among others. ''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.

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

Industralization 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.

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

Bacteriome

Stomach

Due to the high acidity of the stomach, most microorganisms cannot survive there. The main bacterial inhabitants of the stomach include: '' Streptococcus'', ''Staphylococcus'', ''Lactobacillus'', ''Peptostreptococcus''. '' Helicobacter pylori'' is a gram-negative spiral bacterium that establishes on gastric mucosa causing chronic gastritis, and peptic ulcer disease, and is a carcinogen for gastric cancer.

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. However, in the distal portion of the small intestine alkaline conditions support gram-negative bacteria of the ''Enterobacteriaceae''. 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. In addition the large intestine contains the largest bacterial ecosystem in the human body. About 99% of the large intestine and feces flora are made up of obligate anaerobes such as ''Bacteroides'' and ''Bifidobacterium.'' Factors that disrupt the microorganism population of the large intestine include antibiotics, stress, and parasites.

Bacteria make up most of the flora in the colonUniversity of Glasgow. 2005
The normal gut flora.
Available through web archive. Accessed May 22, 2008 and 60% of the dry mass of feces. 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. Somewhere between 300 and 1000 different species live in the gut, with most estimates at about 500. 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.

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. Though people can survive with no gut flora, 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. Extensive modification and imbalances of the gut microbiota and its microbiome or gene collection are associated with obesity. However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host.

Mycobiome

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

Virome

The human virome is mostly bacteriophages.

Variation

Age

It has been demonstrated that 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. Much of the maturation of microbiota into an adult-like configuration happens during the three first years of life.

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.

Geography

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.

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.

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.

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.

Malnourishment

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. 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.

Race and ethnicity

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. 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.

Socioeconomic status

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.

Acquisition in human infants

The establishment of a gut flora is crucial to the health of an adult, as well as the functioning of the gastrointestinal tract. 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.

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. 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 with one study showing ''Lactobacillus'' and ''Bifidobacterium'' species were present in placental biopsies. 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. In another study, researchers administered a culture of bacteria orally to a pregnant dam, and detected the bacteria in the offspring, likely resulting from transmission between the digestive tract and amniotic fluid via the blood stream. However, researchers caution that the source of these intrauterine bacteria, whether they are alive, and their role, is not yet understood.

During birth and rapidly thereafter, bacteria from the mother and the surrounding environment colonize the infant's gut. The exact sources of bacteria is 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. Research has shown that the microbiome of babies born vaginally differ significantly from those of babies delivered by caesarean section and that vaginally born babies got most of their gut bacteria from their mother, while the microbiota of caesarean babies had more bacteria associated with hospital environments.

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. 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. 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. In contrast, the microbiota of formula-fed infants is more diverse, with high numbers of ''Enterobacteriaceae'', enterococci, bifidobacteria, ''Bacteroides'', and clostridia.

Caesarean section, antibiotics, and formula feeding may alter the gut microbiome composition. Children treated with antibiotics have less stable, and less diverse floral communities. 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 celiacs, asthma, and type 1 diabetes. 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.

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.

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 that kill or inhibit unwelcome organisms that would compete for nutrients with it, these compounds are known as cytokines. 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 ''Clostridium difficile'' to become established that otherwise are kept in abeyance.

Development of enteric protection and immune system

In humans, a gut flora similar to an adult's is formed within one to two years of birth. 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. 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. 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. The GALT that develops is tolerant to gut flora species, but not to other microorganisms. 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.

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. 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. 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. 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. Ultimately, IgA maintains a healthy environment between the host and gut bacteria. These cytokines and antibodies can have effects outside the gut, in the lungs and other tissues.

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. SCFAs stimulate a rapid increase in the production of innate immune cells like neutrophils, basophils and eosinophils. These cells are part of the innate immune system that try to limit the spread of infection.

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. 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. 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.

Bacteria turn carbohydrates they ferment into short-chain fatty acids by a form of fermentation called saccharolytic fermentation

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