Gut flora

Escherichia coli, one of the many species of bacteria present in the human gut

Gut flora (gut microbiota, or gastrointestinal microbiota) is the complex community of microorganisms that live in the digestive tracts of humans and other animals, including insects. The gut metagenome is the aggregate of all the genomes of gut microbiota.[1] The gut is one niche that human microbiota inhabit.[2]

In humans, the gut microbiota has the largest numbers of bacteria and the greatest number of species compared to other areas of the body.[3] In humans the gut flora is established at one to two years after birth, and 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.[4][5]

The relationship between some gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship.[2]: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.[3][6] Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics.[2][6] 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,[6] and dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.[3][7]

The composition of human gut flora changes over time, when the diet changes, and as overall health changes.[3][7] 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.[8]

Classifications

The microbial composition of the gut flora varies across the digestive tract. In the stomach and small intestine, relatively few species of bacteria are generally present.[9][10] The colon, in contrast, contains a densely-populated microbial ecosystem with up to 1012 cells per gram of intestinal content.[9] These bacteria represent between 300 and 1000 different species.[9][10] However, 99% of the bacteria come from about 30 or 40 species.[11] As a consequence of their abundance in the intestine, bacteria also make up to 60% of the dry mass of feces.[12] Fungi, archaea, and viruses are also present in the gut flora, but less is known about their activities.[13]

Over 99% of the bacteria in the gut are anaerobes, but in the cecum, aerobic bacteria reach high densities.[2] It is estimated that these gut flora have around a hundred times as many genes in total as there are in the human genome.[14]

Candida albicans, a dimorphic fungus that grows as a yeast in the gut

Many species in the gut have not been studied outside of their hosts because most cannot be cultured.[10][11][15] While there are a small number of core species of microbes shared by most individuals, populations of microbes can vary widely among different individuals.[16] Within an individual, microbe populations stay fairly constant over time, even though some alterations may occur with changes in lifestyle, diet and age.[9][17] The Human Microbiome Project has set out to better describe the microflora of the human gut and other body locations.

The four dominant bacterial phyla in the human gut are Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria.[18] Most bacteria belong to the genera Bacteroides, Clostridium, Faecalibacterium,[9][11] Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, and Bifidobacterium.[9][11] Other genera, such as Escherichia and Lactobacillus, are present to a lesser extent.[9] 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.[10]

Fungal genera that have been detected in the gut include Candida, Saccharomyces, Aspergillus, Penicillium, Rhodotorula, Trametes, Pleospora, Sclerotinia, Bullera, and Galactomyces, among others.[19][20] 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.[19]

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

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.[21] There are indications that long-term diet influences enterotype.[22] Three human enterotypes have been proposed,[21][23] but their value has been questioned.[24]

Flora composition

Anatomy

Stomach flora

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, and types of yeast.[2]:720 Helicobacter pylori is a Gram-negative spiral organism that establishes on gastric mucosa causing chronic gastritis and peptic ulcer disease and is a carcinogen for gastric cancer.[2]:904

Intestinal flora

Bacteria commonly found in the human colon[25]
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 enteritidis 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.[2] However, in the distal portion of the small intestine alkaline conditions support gram-negative bacteria of the Enterobacteriaceae.[2] 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.[26] In addition the large intestine contains the largest bacterial ecosystem in the human body.[2] About 99% of the large intestine and feces flora are made up of obligate anaerobes such as Bacteroides and Bifidobacterium.[27] Factors that disrupt the microorganism population of the large intestine include antibiotics, stress, and parasites.[2]

Bacteria make up most of the flora in the colon[28] and 60% of the dry mass of feces.[9] This fact makes feces an ideal source to test for 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. Somewhere between 300[9] and 1000 different species live in the gut,[10] with most estimates at about 500.[29][30] However, it is probable that 99% of the bacteria come from about 30 or 40 species, with Faecalibacterium prausnitzii being the most common species in healthy adults.[11][31] Fungi and protozoa also make up a part of the gut flora, but little is known about their activities. The virome is mostly bacteriophages.[32]

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.[10] Though people can survive with no gut flora,[29] 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.[2] Extensive modification and imbalances of the gut microbiota and its microbiome or gene collection are associated with obesity.[33] However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host.[9][28]

Age

It has been demonstrated that there are common patterns of microbiome composition evolution during life.[34] 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.[35] Much of the maturation of microbiota into an adult-like configuration happens during the three first years of life.[35]

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.[35]

Diet

Studies and statistical analyses have identified the different bacterial genera in gut microbiota and their associations with nutrient intake. Gut microflora is mainly composed of three enterotypes: Prevotella, Bacteroides, and Ruminococcus. There is an association between the concentration of each microbial community and diet. For example, Prevotella is related to carbohydrates and simple sugars, while Bacteroides is associated with proteins, amino acids, and saturated fats. Specialist microbes that break down mucin, survive on their host's carbohydrate excretions.[36] One enterotype will dominate depending on the diet. Altering the diet will result in a corresponding change in the numbers of species.[22]

Malnourished human 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.[37][38] Malnourished children also typically have more potentially pathogenic gut flora, and more yeast in their mouths and throats.[39] Altering diet may lead to changes in gut microbiota composition and diversity.[36]

Geography

Gut microbiome composition depends on the geographic origin of populations. Variations in 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 USA, Malawi or Amerindian origin.[35]

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 a main determinant of gut bacterial composition.[35]

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 was 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 gut flora 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.[40]

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.[35]

Acquisition of gut flora in human infants

In humans, a gut flora similar to an adult's is formed within one to two years of birth.[4] The gastrointestinal tract of a normal fetus is considered sterile, but microbial colonisation may occur in the fetus[41] and Lactobacillus and Bifidobacterium species were present in placental biopsies in one study.[42] During birth and rapidly thereafter, bacteria from the mother and the surrounding environment colonize the infant's gut.[4] As of 2013, it was unclear whether most of colonizing arise from the mother or not.[4] Infants born by caesarean section may also be exposed to their mothers' microflora, but the initial exposure is most likely to be from the surrounding environment such as the air, other infants, and the nursing staff, which serve as vectors for transfer.[41] During the first year of life, the composition of the gut flora is generally simple and it changes a great deal with time and is not the same across individuals.[4]

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 purely anaerobic bacteria like Bacteroides, Actinobacteria, and Firmicutes to become established and thrive.[4] 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.[42][43][44] In contrast, the microbiota of formula-fed infants is more diverse, with high numbers of Enterobacteriaceae, enterococci, bifidobacteria, Bacteroides, and clostridia.[45]

Functions

When the gut flora first started to be studied, it was thought to have three key roles: directly defending against pathogens, fortifying 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.[46]

Direct inhibition of pathogens

The gut flora community plays a direct role in defending against pathogens by fully colonizing 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.[47] Disruption of the gut flora allows competing organisms like Clostridium difficile to become established that otherwise are kept in abeyance.[47]

Development of enteric protection and immune system

Microfold cells transfer antigens (Ag) from the lumen of the gut to gut-associated lymphoid tissue (GALT) via transcytosis and present them to different innate and adaptive immune cells.

In humans, a gut flora similar to an adult's is formed within one to two years of birth.[4] 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, commensurate microorganisms to a certain extent and also provides a barrier to pathogenic ones.[4] 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.[4][5] 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.[4] The GALT that develops is tolerant to gut flora species, but not to other microorganisms.[4] 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 produced from food.[4]

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.[4] 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.[4][48] Gut flora can also regulate the production of antibodies by the immune system.[4][49] These cytokines and antibodies can have effects outside the gut, in the lungs and other tissues.[4]

Metabolism

Tryptophan metabolism by human gastrointestinal microbiota ()
Tryptophan metabolism diagram

This diagram shows the biosynthesis of bioactive compounds (indole and certain derivatives) from tryptophan by bacteria in the gut.[50] Indole is produced from tryptophan by bacteria that express tryptophanase.[50] Clostridium sporogenes metabolizes indole into 3-indolepropionic acid (IPA),[51] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals.[50][52][53] In the intestine, IPA binds to pregnane X receptors (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.[50] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer’s disease.[50] Lactobacillus species metabolize tryptophan into indole-3-aldehyde (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production.[50] Indole itself acts as a glucagon-like peptide-1 (GLP-1) secretagogue in intestinal L cells and as a ligand for AhR.[50] Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction.[50] AST-120 (activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.[50]

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.[6] 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.[6] 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.[3][6]

Bacteria turn carbohydrates they ferment into short-chain fatty acids (SCFAs)[11][30] by a form of fermentation called saccharolytic fermentation.[30] Products include acetic acid, propionic acid and butyric acid.[11][30] These materials can be used by host cells, providing a major source of useful energy and nutrients for humans,[30] as well as helping the body to absorb essential dietary minerals such as calcium, magnesium and iron.[9] Gases and organic acids, such as lactic acid, are also produced by saccharolytic fermentation.[11] Acetic acid is used by muscle, propionic acid helps the liver produce ATP, and butyric acid provides energy to gut cells and may prevent cancer.[30] Evidence also indicates that bacteria enhance the absorption and storage of lipids[10] and produce and then facilitate the body to absorb needed vitamins like vitamin K.

Gut flora also synthesize vitamins like biotin and folate, and help with absorption of dietary elements including magnesium, calcium and iron.[17] Methanogenic archaea such as Methanobrevibacter smithii are involved in the removal of end products of bacterial fermentation such as hydrogen.[2]

Host-gut microbiota-xenobiotic interaction

Apart from carbohydrates, gut microbiota can also metabolize other xenobiotic such as drugs, phytochemicals, and food toxicants. More than 30 drugs have been shown to be metabolized by gut microbiota.[54] The microbial metabolism of drugs can sometimes inactivate the drug.[55]

Gut-brain axis

The gut-brain axis is the biochemical signaling that takes place between the gastrointestinal tract and the central nervous system.[46] That term has been expanded to include the role of the gut flora in the interplay; the term "microbiome-gut-brain axis" is sometimes used to describe paradigms explicitly including the gut flora.[46][56][57] 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.[46][57]

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.[8]

Alterations in flora 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.[58] Antibiotics can cause antibiotic-associated diarrhea (AAD) by irritating the bowel directly, changing the levels of gut flora, or allowing pathogenic bacteria to grow.[11] 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.[58]

Changing the numbers and species of gut flora 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 flora could cause the diarrhea.[11]

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.[9][11][58] Emerging treatment protocols for C. difficile infections involve fecal microbiota transplantation of donor feces. (see Fecal transplant). 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.[59]

Gut flora composition 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 (SDD), a treatment to kill only pathogenic bacteria and allow the re-establishment of healthy ones.[60]

Antibiotics alter the population of the gastrointestinal (GI) tract microbiota, may change the intra-community metabolic interactions, modify caloric intake by using carbohydrates, and globally affects host metabolic, hormonal and immune homeostasis.[61]

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.[62]

Pregnancy

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

Probiotics, prebiotics, synbiotics, and pharmabiotics

Probiotics are microorganisms that are believed to provide health benefits when consumed.[64][65] With regard to gut flora, 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.[30][66]

Synbiotics refers to food ingredients or dietary supplements combining probiotics and prebiotics in a form of synergism.[67]

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;[68] probiotics that have been genetically engineered or otherwise optimized for best performance (shelf life, survival in the digestive tract, etc.);[69] and the natural products of gut flora metabolism (vitamins, etc.).[70]

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

Gram positive bacteria present in the lumen may be associated with extending the duration of relapse for ulcerative colitis.[72]

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.[9] Additionally, metabolites from certain members of the gut flora may influence host signaling pathways, contributing to disorders such as obesity and colon cancer.[9] Alternatively, in the event of a breakdown of the gut epithelium, the intrusion of gut flora components into other host compartments can lead to sepsis.[9]

Ulcers

Helicobacter pylori can cause stomach ulcers by crossing the epithelial lining of the stomach. Here the body produces an immune response. During this response parietal cells are stimulated and release extra hydrochloric acid (HCl+) into the stomach. However, the response does not stimulate the mucus-secreting cells that protect and line the epithelium of the stomach. The extra acid sears holes into the epithelial lining of the stomach, resulting in stomach ulcers.[34]

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 disease are unknown and issues with the gut flora and its relationship with the host have been implicated in these conditions.[7][74][75][76] 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.[1]

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.[1]

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.[62]

Irritable bowel syndrome

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.[57]

Other inflammatory or autoimmune conditions

Allergy, asthma, and diabetes mellitus type 1 are autoimmune and inflammatory disorders' the causes of these disease are unknown and issues with the gut flora and its relationship with the host have been implicated in these conditions.[7]

Two hypotheses have been posed to explain the rising prevalence of these diseases in the developed world: the hygiene hypothesis, which posits that children in the developed world are not exposed to a wide enough range of pathogens and end up with an overreactive immune system, and the role of the Western pattern diet which lacks whole grains and fiber and has an overabundance of simple sugars.[7] Both hypotheses converge on the changes in the gut flora and its role in modulating the immune system, and as of 2016 this was an active area of research.[7]

Similar hypotheses have been posited for the rise of food and other allergies.[77]

As of 2016 it was not clear if changes to the gut flora cause these auto-immune and inflammatory disorders or are a product of them or adaptation to them.[7][78]

Obesity and metabolic syndrome

The gut flora has also been implicated in obesity and metabolic syndrome due to the key role it plays 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.[76][79] 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 to flourish; 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.[62] There is also evidence that microbiota influence eating behaviors 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.[80]

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. In recent studies, it is illustrated that 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 sub diaphragmatic 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.[81]

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.[76]

Liver disease

As the liver is fed directly by the portal vein, whatever crosses the intestinal epithelium and the intestinal mucosal barrier enters the liver, as do cytokines generated there.[82] Dysbiosis in the gut flora has been linked with the development of cirrhosis and non-alcoholic fatty liver disease.[82]

Systemic infections

Normally-commensal bacteria can be very harmful to the host if they get outside of the intestinal tract.[4][5] Translocation, which occurs when bacteria leave the gut through its mucosal lining, the border between the lumen of the gut and the inside of the body, can occur in a number of different diseases, and can be caused by too much growth of bacteria in the small intestine, reduced immunity of the host, or increased gut lining permeability.[5]

If the gut is perforated, bacteria can invade the body, causing a potentially fatal infection. Aerobic bacteria can make an infection worse by using up all available oxygen and creating an environment favorable to anaerobes.[2]:715

Cancer

Some genera of bacteria, such as Bacteroides and Clostridium, have been associated with an increase in tumor growth rate, while other genera, such as Lactobacillus and Bifidobacteria, are known to prevent tumor formation.[9]

Neuropsychiatric

Interest in the relationship between gut flora and neuropsychiatric issues was sparked by a 2004 study showing that germ-free mice showed an exaggerated HPA axis response to stress compared to non-GF laboratory mice.[46] As of January 2016, most of the work that has been done on the role of gut flora in the gut-brain axis had been conducted in animals, or characterizing the various neuroactive compounds that gut flora can produce, and studies with humans measuring differences between people with various psychiatric and neurological differences, or changes to gut flora in response to stress, or measuring effects of various probiotics (dubbed "psychobiotics in this context), had generally been small and could not be generalized; whether changes to gut flora are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut-brain axis, remained unclear.[46][62]

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.[8]

Other animals

Aside from mammals, some insects also possess complex and diverse gut microbiota that play key nutritional roles.[83] Microbial communities associated termites can constitute a majority of the weight of the individuals and perform important roles in the digestion of lignocellulose and nitrogen fixation.[84] These communities are host-specific, and closely related insect species share comparable similarities in gut microbiota composition.[85][86] In cockroaches, gut microbiota have been shown to assemble in a deterministic fashion, irrespective of the inoculum;[87] 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.[85][86]

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.[61]

In a study performed on mice by Ilseung Cho,[61] 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, they 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.[61]

See also

Sources and notes

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    Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
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