Gut microbiota
Gut microbiota, gut microbiome, or gut flora are the
The microbial composition of the gut microbiota varies across regions of the digestive tract. The
Overview
In humans, the gut microbiota has the largest numbers and species of bacteria compared to other areas of the body.[9] The approximate number of bacteria composing the gut microbiota is about 1013–1014.[10] 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.[11][12]
The relationship between some gut microbiota and humans is not merely
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
Over 99% of the bacteria in the gut are
Many species in the gut have not been studied outside of their hosts because they cannot be cultured.[16][7][21] While there are a small number of core microbial species shared by most individuals, populations of microbes can vary widely.[22] Within an individual, their microbial populations stay fairly constant over time, with some alterations occurring due to changes in lifestyle, diet and age.[6][23] 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.[24] 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.[16]
Fungal genera that have been detected in the gut include
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.[27]
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.[28] There are indications that long-term diet influences enterotype.[29] Three human enterotypes have been proposed,[28][30] but their value has been questioned.[31]
Composition
Bacteriome
Stomach
Due to the high acidity of the
Intestines
Bacteria commonly found in the human colon[34] | |
Bacterium | Incidence (%) |
---|---|
Bacteroides fragilis | 100 |
Bacteroides melaninogenicus
|
100 |
Bacteroides oralis | 100 |
Enterococcus faecalis | 100 |
Escherichia coli | 100 |
Enterobacter sp. | 40–80 |
Klebsiella sp. | 40–80 |
Bifidobacterium bifidum | 30–70 |
Staphylococcus aureus | 30–50 |
Lactobacillus | 20–60 |
Clostridium perfringens | 25–35 |
Proteus mirabilis | 5–55 |
Clostridium tetani | 1–35 |
Clostridium septicum | 5–25 |
Pseudomonas aeruginosa | 3–11 |
Salmonella enterica | 3–7 |
Faecalibacterium prausnitzii
|
?common |
Peptostreptococcus sp. | ?common |
Peptococcus sp. | ?common |
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.[35] 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.[36] 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
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
Research suggests that the relationship between gut
Mycobiome
Fungi and protists also make up a part of the gut flora, but less is known about their activities.[43]
Virome
The human virome is mostly bacteriophages.[44]
Variation
Age
There are common patterns of microbiome composition evolution during life.[45] 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.[46] Much of the maturation of microbiota into an adult-like configuration happens during the first three years of life.[46]
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.[46]
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.[46]
The US population has a high representation of enzymes encoding the degradation of
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.[47]
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.[46]
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.[48][49] Malnourished children also typically have more potentially pathogenic gut flora, and more yeast in their mouths and throats.[50] Altering diet may lead to changes in gut microbiota composition and diversity.[51]
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.[52] 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.[52]
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.[52]
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.[53] 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.[54][11]
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?][55] 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[56] with one study showing Lactobacillus and Bifidobacterium species were present in placental biopsies.[57] 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.[58][59] 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.[60] However, researchers caution that the source of these intrauterine bacteria, whether they are alive, and their role, is not yet understood.[61][57]
During birth and rapidly thereafter, bacteria from the mother and the surrounding environment colonize the infant's gut.[11] 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.[62] 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.[63]
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.
Caesarean section,
Functions
When the study of gut flora began in 1995,[68] 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.[69]
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
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.
The human
The immune system can also be altered due to the gut bacteria's ability to produce
Metabolism
Tryptophan metabolism by
human gastrointestinal microbiota ( ) |
Without gut flora, the human body would be unable to utilize some of the undigested
Bacteria turn carbohydrates they ferment into short-chain fatty acids by a form of fermentation called saccharolytic fermentation.[40] Products include acetic acid, propionic acid and butyric acid.[7][40] These materials can be used by host cells, providing a major source of energy and nutrients.[40] Gases (which are involved in signaling[80] 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.[40]
Gut flora also synthesize vitamins like
Gut microbiota also serve as a source of vitamins K and B12, which are not produced by the body or produced in little amount.[82][83]
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.[84]
Pharmacomicrobiomics
The human
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.[89] The microbial metabolism of drugs can sometimes inactivate the drug.[90]
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.[91] Gut microbiota can affect drug metabolism via direct and indirect mechanisms.[92] The direct mechanism is mediated by the microbial enzymes that can modify the chemical structure of the administered drugs.[93] Conversely, the indirect pathway is mediated by the microbial metabolites which affect the expression of host metabolizing enzymes such as cytochrome P450.[94][92] The effects of the gut microbiota on the pharmacokinetics and bioavailability of the drug have been investigated a few decades ago.[95][96][97] These effects can be varied; it could activate the inactive drugs such as lovastatin,[98] inactivate the active drug such as digoxin[99] or induce drug toxicity as in irinotecan.[100] Since then, the impacts of the gut microbiota on the pharmacokinetics of many drugs were heavily studied.[101][91]
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.[93] 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.[94]
A large number of studies have demonstrated the metabolism of over 50 drugs by the gut microbiota.[101][92] 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.[98] Conversely, digoxin (a drug used to treat Congestive Heart Failure) is inactivated by a member of the gut microbiota (i.e. Eggerthella lanta).[102] Eggerthella lanta has a cytochrome-encoding operon up-regulated by digoxin and associated with digoxin-inactivation.[102] Gut microbiota can also modulate the efficacy and toxicity of chemotherapeutic agents such as irinotecan.[103] This effect is derived from the microbiome-encoded β-glucuronidase enzymes which recover the active form of the irinotecan causing gastrointestinal toxicity.[104]
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.[105][106][107] Microbial metabolites especially short chain fatty acids (SCFAs) and secondary bile acids (BAs) play important roles for the human in health and disease states.[108][109][110]
One of the most important bacterial metabolites produced by the gut microbiota is secondary bile acids (BAs).[107] 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.[111] 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.[111] 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.[111] Secondary bile acids (BAs) such as DCA and LCA have been demonstrated to inhibit both Clostridium difficile germination and outgrowth.[110]
Dysbiosis
The gut microbiota is important for maintaining homeostasis in the intestine. Development of
Gut–brain axis
The gut–brain axis is the biochemical signaling that takes place between the
A
Alterations in microbiota balance
Effects of antibiotic use
Altering the numbers of gut bacteria, for example by taking
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
The composition of the gut microbiome also changes in severe illnesses, due not only to antibiotic use but also to such factors as
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 affects host metabolic, hormonal and immune homeostasis.[120]
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 Clostridium difficile infection following systemic antibiotic treatment.[121]
Pregnancy
The gut microbiota of a woman changes as
Probiotics, prebiotics, synbiotics, and pharmabiotics
The term "pharmabiotics" is used in various ways, to mean:
There is some evidence that treatment with some probiotic strains of bacteria may be effective in
- Bifidobacterium breve
- Bifidobacterium infantis
- Enterococcus faecium
- Lactobacillus plantarum
- Lactobacillus reuteri
- Lactobacillus rhamnosus
- Lactobacillus salivarius
- Propionibacterium freudenreichii
- Saccharomyces boulardii
- Escherichia coli Nissle 1917
- Streptococcus thermophilus[132][133][134]
Fecal floatation
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.[135] 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'.[136]
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.[137]
Effects of exercise
Gut microbiota and exercise have recently been shown to be interconnected. Both moderate and intense exercise are typically part of the training regimen of endurance athletes, but they exert different effects on health. The interconnection between gut microbiota and endurance sports depends upon exercise intensity and training status.[138]
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
Ulcers
Bowel perforation
Normally-
Inflammatory bowel diseases
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.[14][141][142][143] 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
Irritable bowel syndrome
Asthma
With asthma, two hypotheses have been posed to explain its rising prevalence in the developed world. The
Diabetes mellitus type 1
The connection between the gut microbiota and
Obesity and metabolic syndrome
The gut flora have been implicated in obesity and
Additionally, the liver plays a dominant role in
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.[143]
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.[153] 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.[153] 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.
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.[120]
In a study carried out on
See also
- Colonisation resistance
- List of human flora
- List of microbiota species of the lower reproductive tract of women
- Skin flora
- Verotoxin-producing Escherichia coli
Notes
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Lactobacillus spp. convert tryptophan to indole-3-aldehyde (I3A) through unidentified enzymes [125]. Clostridium sporogenes convert tryptophan to IPA [6], likely via a tryptophan deaminase. ... IPA also potently scavenges hydroxyl radicals
Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
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Further reading
- Review articles
- De Preter, Vicky; Hamer, Henrike M; Windey, Karen; Verbeke, Kristin (2011). "The impact of pre- and/or probiotics on human colonic metabolism: Does it affect human health?". Molecular Nutrition & Food Research. 55 (1): 46–57. PMID 21207512.
- Maranduba, Carlos Magno da Costa; De Castro, Sandra Bertelli Ribeiro; Souza, Gustavo Torres de; Rossato, Cristiano; Da Guia, Francisco Carlos; Valente, Maria Anete Santana; Rettore, João Vitor Paes; Maranduba, Claudinéia Pereira; Souza, Camila Maurmann de; Carmo, Antônio Márcio Resende do; MacEdo, Gilson Costa; Silva, Fernando de Sá (2015). "Intestinal Microbiota as Modulators of the Immune System and Neuroimmune System: Impact on the Host Health and Homeostasis". Journal of Immunology Research. 2015: 931574. PMID 25759850.
- Prakash, Satya; Rodes, Laetitia; Coussa-Charley, Michael; Tomaro-Duchesneau, Catherine; Tomaro-Duchesneau, Catherine; Coussa-Charley; Rodes (2011). "Gut microbiota: Next frontier in understanding human health and development of biotherapeutics". Biologics: Targets and Therapy. 5: 71–86. PMID 21847343.
- Wu, G. D.; Chen, J.; Hoffmann, C.; Bittinger, K.; Chen, Y.-Y.; Keilbaugh, S. A.; Bewtra, M.; Knights, D.; Walters, W. A.; Knight, R.; Sinha, R.; Gilroy, E.; Gupta, K.; Baldassano, R.; Nessel, L.; Li, H.; Bushman, F. D.; Lewis, J.D. (2011). "Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes". Science. 334 (6052): 105–108. PMID 21885731.