1. Introduction

T

1. Overview

In humans, the gut microbiota human gastroias the largest numbers of bacteria and the greatest number of species compared to other areas of the body.^[3] In humans, testinal microbiota (GIM) is a complex and diverse ecosyhe 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.^[4][5] The relationship betem that consists ofween some gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship.^[2]:700 Some human gut micommunity of fungi, viruses,roorganisms 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 rotists and majorlle in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics.^[2][6] The systemic importance of the SCFAs bacteria.

Pand other compounds they produce are like hormones and the gut flora itself appears to function like an endocrine organ,^[6] and dysregulato its birth, it ision of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.^[3][7] The compresumed thaosition of human gut microbiota changes over time, when the diet changes, and as overall health changes.^[3][7] A systematic the unborn is free of mireview 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]

2. Classifications

The microbial composition oflora, and that at birt the gut microbiota varies across the digestive tract. In the stomach and small intestine, relatively few species of bacteria are generally present.^[9][10] The colon, the infantin contrast, contains the highest microbial density recorded in any habitat on Earth^[11] fwirst th up to 10¹² cells per gram omes in contf intestinal content.^[9] These bacteria withrepresent between 300 and 1000 different species.^[9][10] However, 99% of the bacteresiia come from about 30 or 40 species.^[12] As a consequence of their abundancent microbial flora of the mo in the intestine, bacteria also make up to 60% of the dry mass of feces.^[13] Fungi, protists, archers’ vagina iaea, and viruses are also present in the gut flora, but less is known about their activities.^[14] Over 99% of the birth wacteria in the gut are anaerobes, but in the cecum, aerobic bacteria reach high densities.^[2] It is estimated that thes through the ne gut flora have around a hundred times as many genes in total as there are in the human genome.^[15]

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

Many species in turalhe gut have not been studied outside of their hosts because most cannot be cultured.^[10][12][16] bWhirth canal, or tle there are a small number of core species of microbes shared by most individuals, populations of microbes can vary widely among different individuals.^[17] Withein an individual, microbial flora of the mothers’ skin if e populations stay fairly constant over time, even though some alterations may occur with changes in lifestyle, diet and age.^[9][18] The Human Microbiome Prth was through coject has set out to better describe the microflora of the human gut and other body locations. Thes four dominant barean sectiocterial phyla in the human gut are Firmicutes, Bacteroidetes, Actinobacteria, an^[1][2][3]d Proteobacteria.^[19] AMost bacteria belthoong to the genera Bacteroides, Clostridium, Faecalibacterium,^[9][12] Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, and Bifidobacterium.^[9][12] Other genera, sugch sas Escherichia and Lactobacillus, are present to a lesser extent.^[9] Species from the sgenus Bacteroides alone constitudiete about 30% of all bacteria in the gut, s^[4][5][6]uggesting thave st this genus is especially important in the functioning of the host.^[10] Funggeal genera that have been detected in the gut include Candida, Saccharomyces, Aspergillus, Penicillium, Rhodotorula, Trametes, Pleospora, Sclerotinia, Bullera, and Galactomyces, among others.^[20][21] Rhodotorula is most fred the eaquently found in individuals with inflammatory bowel disease while Candida is most frequently inocfound in individuals with hepatitis B cirrhosis and chronic hepatitis B.^[20] Archaea constitute another lation orge class of gut flora which are important in the metabolism of the fetbacterial products of fermentation. Industralization with bacteria anis 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.^[22]

Enterotype

An enterotype is a classification of living organisms based on its bacteria DNA through tological ecosystem in the human gut microbiome not dictated by age, gender, body weight, or national divisions.^[23] There placentaare indications that long-term diet influences enterotype.^[24] Thre se human enterotypes have been proposed,^[23][25] but their valudy by de has been questioned.^[26]

3. Composition

Anatomy

Stomach

Due to the Ghigh acidity offau et al the stomach, most microorganisms cannot survive there. The main bacterial inhabitants of the stomach include: Streptococcus, Staphylococcus, Lactobacillus, Peptostreptococcus, and types of yeast.^[7][2]:720 Helicobacter pylori is a greportedam-negative spiral bacterium that the human placentaestablishes on gastric mucosa causing chronic gastritis and peptic ulcer disease and is a carcinogen for gastric cancer.^[2]:904

Intestines

The smas no microbiome. Detectll intestine contains a trace amount of microorganisms due to the proximity and influence of the stomach. Gram-positive cocci and rod-shaped bacteria were acquiare the predominant microorganisms found in the small intestine.^[2] However, in thed during la distal portion of the small intestine alkaline conditions support gram-negative bacteria of the Enterobacteriaceae.^[2] The bacterial flor and delivery. After birth, accora 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.^[28] In additiong to the the large intestine contains the largest bacterial ecosystem in the human body.^[2] About 99% of the large indinntestine and feces flora are made up of obligate anaerobes such as Bacteroides and Bifidobacterium.^[29] Factors that disrupt the microorganis of Koenigm population of the large intestine include antibiotics, stress, and parasites.^[2] Bacteria maket al.^[8], up most of the flora in the colon^[30] and 60% of the drey mass of feces.^[9] wThis fact makes feces an idere apparent chaotic shifts of microbiome al 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. Somewhere between 300^[9] and 1000 different species live in the gut,^[10] with most estim tates at about 500.^[31][32] However, it is probable that 99% of thendowed bacteria come from about 30 or 40 species, with Faecalibacterium prausnitzii being thenes most common species in healthy adults.^[12][33] Fungi and protists also make up a part of the gut flora, but less is known about their acitivities.^[34] The virome is mostly bacteriophages.^[35] Research suggests thating lactate utilization the relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather is a mutualistic, symbiotic relationship.^[10] andThough plant polyeople can survive with no gut flora,^[31] the microorganisms perform accharide meta host of useful functions, such as fermenting unused energy substrates, training the immune system via end products of metabolism mediated by milk-based diet to increaslike 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 inmodification and Bacteroidetesimbalances of the gut minitiated bycrobiota and its microbiome or gene collection are associated with obesity.^[36] However, introdu certain conditions, some species are thought to be capable of causing disease by causing infection of solid foor increasing cancer risk for the host.^[9][30]

Age

It has been demonstrated that prepares tthere are common patterns of microbiome composition evolution during life.^[37] In general, the dinfant gut forversity of microbiota composition of fecal samples is significantly higher in adult diet. However, in the findingss than in children, although interpersonal differences are higher in children than in adults.^[38] Much of Differding et althe maturation of microbiota into an adult-like configuration happens during the three first years of life.^[9][38] As the microbiome composition changes, so does the early introduction of infants to complementary food wascomposition 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.^[38]

Diet

Studies and ssociated with alteredtatistical analyses have identified the different bacterial genera in gut microbiota composand their associations with nutrient intake. Gut microflora is mainly composed of three enterotypes: Prevotella, Bacteroides, and Ruminococcus. There is an association and butyrbetween the concentration of each microbial community and diet. For example, Prevotella is related to c aarbohydrates and simple sugars, while Bacteroides is associated concentration, with proteins, amino acids, and saturated fats. Specialist microbes that break down mucin survive on their host's carbohydrate excretions.^[39] One enterotype will dominate depending on thich he diet. Altering the diet will result in a corresponding change in the numbers of species.^[24]

Vegetarian and vegan diets

While plant-based diets have been previously identified as psome variation, vegetarian and vegan diets patterns are the most common. Vegetarian diets exclude meat products but still allow for eggs and dairy, while vegan diets exclude all forms of animal products. The diets of vegetarian and vegan individuals create a microbiome distinct from meat eaters, however there is not a significant distinction between the two.^[40] In diets that are cursors to oxidative stress, immune disentered around meat and animal products, there are high abundances of Alistipes, Bilophila and Bacteroides which are all bile tolerant and may promote inflammation in the gut. In this type of diet, the group Firmicutes, which is associated with the metabolism of dietary plant polysaccharides, is found in low concentrations.^[41] Converder and obesely, diets rich in plant-based materials are associated with greater diversity in chilthe gut microbiome overall, and have a greater abundance of Prevotella, responsible for the long-term processing of fibers, rather than the bile tolerant species.^[42] Diet can be used to alter thood.

Te composition of the gut microbiome of the adult gut accin relatively short timescales. However, if wanting to change the microbiome to combat a disease or illness, long-term changes in diet have proven to be most successful.^[41]

Malnourishment

Malnourished hummodates various communities of pan 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.^[43][44] Malnourished children also tylotypes bpically have more potentially pathogenic gut flora, and more yeast in their mouths and throats.^[45] Altering diet may longing to tead to changes in gut microbiota composition and diversity.^[39]

Geography

Gut microbiome composition depends on the geographylaic origin of populations. ActinobacteriaVariations in a trade-off of Prevotella, Proteobacteriathe representation of the urease gene, Bacteroidetes,and the representation of Fusobacteria,genes Firmicutesencoding glutamandte synthase/degradation Verrucomicrobia^[10].or Most of these phyla arther enzymes involved in amino acids degradation or vitamin biosynthesis show significant differences between populations from the US, Malawi or Amerindian origin.^[38] The US popresent in the stomach, small intestine and colon. However, the colon is moreulation 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 populated with several genera belonions which have a corn-rich diet, the diet is probably the main determinant of the gut bacterial composition.^[38] Further studies have indicated a large ding to the afore mentioned phyla, including the genfference 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, Akkemansiawhile the fecal bat bcteria of the Boulpon children was dominated by Bacteroidetes. The increased biodiversity and different composition of gut flongs to the phylura 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.^[46] On a smaller Verrucomicrobiascale, it has been showhich has been found to be limited in patin 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.^[38]

4. Acquisition in Human Infants

The establishments with obesityt of a gut flora is crucial to the health of an adult, as well the functioning of the gastrointestinal tract.^[47] In humans, ina gut flammatory bowel diseaseora 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 metabenvironmental sources.^[48][4] The traditionalic syndromes, while it is in abundance 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.^[49] bMultiopsiple lines of healthy individualevidence have begun to emerge that suggest there may be bacteria in the intrauterine environment. In humans^[10][11]., Ares has beeearch has shown that microbial colonization may occur in the fetus^[50] with one study showing Lactobacillus and Bifidobacterium species were ported in seresent in placental biopsies.^[51] Several rodent studies, dietary t 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.^[52][53] In another studyp, researches and pattern shapes and deters 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.^[54] However, researmchers cautines the diverson that the source of these intrauterine bacteria, whether they are alive, and their role, is not yet understood.^{[51] [55]} During birty of th and rapidly thereafter, bacteria from the mother and the surrounding environment colonize the infant's gut.^[4] The gexact sources of bacteria is not fully understood, but microbiome. In the say include the birth canal, other people (parents, siblings, hospital workers), breastmilk, food, and the general environment with which the infant interacts.^[56] However, as of 2013, it remains ubnclear whether missost colonizing arises from the mother or not.^[4] Infants born by caesarean section may alsof Amabebe et al.^[12], be exposed to their mothers' microflora, but the initial exposure is most likely to be from the surrounding environment such as thigh fat and carbe air, other infants, and the nursing staff, which serve as vectors for transfer.^[50] During the first year of life, the composition of thydrate diee gut flora is generally simple and changes a great deal with time and is not the same across individuals.^[4] The initial builds a gut microbiota acterial 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 Bacteroides, Actinobacteria, and Firmicutes to become establishated and thrive.^[4] Breast-fed babis prees become dominated by Methanobrevibacterbifidobacteria, Firmicutespossibly due to the contents of bifidobacterial (Clostridium)growth fandctors in breast Prevotellamilk, and by deficient in the fact that breast milk carries prebiotic components, allowing for healthy bacterial growth.^[51][57] In contrasuch at, the microbiota of formula-fed infants is more diverse, with high numbers Bacteroidesof Enterobacteriaceae, enterococci, Lactobacillusbifidobacteria, AkkermansiaBacteroides, and Bifidobacteriumclostridia.^[58] BCaesarone et al.^[13],ean section, antibiotics, and formula feedin their stug may alter the gut microbiome composition.^[51] Children treatedy with antibiotics have less broustable, and less diverse floral communities.^[59] Caesarean sections have been shown to be disruptive to mother-offspring transmission of bacteria, wht to the foich impacts the overall health of the offspring by raising risks of disease such as celiacs, asthma, and type 1 diabetes.^[51] This furthe r evidences the impact of modern Paleolitortance 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.^[51]

5. Functions

When the gut flora fic diet (MPD) that consist of vegetables, seeds, lean meat, fruits, egrst 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.^[60]

Direct inhibition of pathogens

The gs,ut flora nuts and fish on the gut microbiomecommunity 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.^[61] TDisruption of they observ gut flora allows competing organisms like Clostridium difficile to become established that othe erwise are kept in abeyance.^[61]

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 simicrobiome of lar to an adult's is formed within one to two years of birth.^[4] As the gut florban Italians adhering to MPD showeda 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.^[4] Specifican ample degree of biodiverslly, 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 with high relative abundance of fat-loving and bi, 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 tole tolerant rant to gut flora species, but not to other microorganisms.^[4] GAs have been mentioned earlier, perLT 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.^[4] The human immune system creates cytokines that can drive the immurbations or dysbiosis in combne 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] Differenation with alteret 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 appearmeabili to drive an anti-inflammatory response, while some segmented filamentous bacteria drive the production of inflammatory cytokines.^[4][62] Guty flora can are crucial mlso regulate the production of antibodies by the immune system.^[4][63] One funchanisms that mediate disease manifestatiotion 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 bein^[14]g secreted.^[64] FThese signaling molecal ules interact with B cells to induce class switching to IgA.^[64] IgA is an important type of antibody that icrobiota transps 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.^[65] Ultimantation (FMT) has gaitely, IgA maintains a healthy environment between the host and gut bacteria.^[65] These cytokines and relevance in reantibodies can have effects outside the gut, in the lungs and other tissues.^[4] The immune system can also bent times altered due to the gut bacteria's ability to produce metabolites that can affect cells in the treatment and corimmune system. For example short-chain fatty acids (SCFA) can be produced by some gut bacteria through fermentation.^[66] SCFAs stimulate a rapid increase in the production of gut infections or diinnate immune cells like neutrophils, basophils and eosinophils.^[66] Thesoe cells arderse part of the innate immune system that mighttry to limit the spread of infection.

Metabolism

{{Annotated image 4 h| image = Microbiotave resulted from the depletion of resident-derived 3-Indolepropionic acid-notext.svg | link = Commons:File:Microbiota-derived 3-Indolepropionic acid.svg | header = Tryptophan metabolism by human gastrointestinal microbiota (v · d · e ) | header_alignd infection by pathogenic b = center | header_background = #F0F8FF | align = right | image-width = 600 | image-left = 0 | image-top = 10 | width = 580 | height = 470 | alt = Tryptophan metabolism diagram | caption = {{{caption|This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from by bacteria in the gut.^[67] HugIndole successeis produced from tryptophan by bacteria that express tryptophanase.^[67] Clostridium sporogenes metabolizes tryptophave beenn into indole and subsequently 3-indolepropionic acid (IPA),^[68] a highly potent neurecorded ioprotective antioxidant that scavenges hydroxyl radicals.^[67][69][70] IPA binds FMT therapy,to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.^[67] Followith about 92% efficacng absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease.^[67] Lactobacillus species metabolize tryptophan reported iinto {{when pagename is|Indole-3-carboxaldehyde=indole-3-carboxaldehyde|other=indole-3-aldehyde}} (I3A) which acts on the treatment oaryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production.^[67] Indole itself trecurrentiggers the secretion of glucagon-like peptide-1 Clostridium difficile(GLP-1) in inftection^[15]stinal L cells and acts as a ligand for AhR.^[67] Indole a recentcan also be metabolized by the liver into ]], a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction.^[67] AST-120 (activated charcoal), an intestudy by Zou et al.^[16]inal sorbent that is [[Oral administrat[[Physics:taken by mouth,Chemistry:Adsorption|adsorbs i]]ndole, in t was shown thurn decreasing the concentration of indoxyl sulfate in blood plasma.^[67] }}} | annot patients w-font-size = 14 | annot-text-align = left | annotations =

}} Without gut Crohn’s disease and ulceraflora, 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 raive colitis thatsed 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] Carbohad FMT were in remission after threydrates 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 days of tranturn carbohydrates they ferment into short-chain fatty acids by a form of fermentation called saccharolytic fermentation.^[32] Products include acetic acid, propionic acid and butyric acid.^[12][32] These materials cant be used by host cells, providing a major source of energy and nutrients.^[32] Gases (whith noch cause flatulence) and organic acids, such as lactic acid, are also produced by fermentation.^[12] Acetic able bacterialcid is used by muscle, propionic acid facilitates liver production of ATP, and butyric acid provides energy to gut cells.^[32] cGut flolonization of the gura also synthesize vitamins like biotin and folate, and facilitate absorption of dietary minerals, including magnesium, calcium, and iron.^[9][18] Methanobrevibacter smithii is unique because it. is not a species of bacteria, but rather a member of domain Archeae, and is the most FMTabundant therapy has bmethane-producing archaeal species in the human gastrointestinal microbiota.^[71]

Pharmacomicrobiomics

The human men extended to the treatmentagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals.^[72][73] Since the of lifestyle atotal number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers Homo sapiens cells (tends otf trillions),^{[note 1][72][74]} there diseases, such as diabetes,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 metabolic syndrosm affecting a drug's clinical efficacy and toxicity profile.^[72][73][75] Apart from carbohydrate, Parkinson’s disease, obesitys, 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.^[76] The microbial metand cancerbolism of drugs can sometimes inactivate the drug.^[77] FM

Gut-brain axis

The gut-brain entails taxis is the biochemical signaling that takes place between the gastrointestinal tract and the central nervous system.^[60] That term hansfer of gut ms been expanded to include the role of the gut flora in the interplay; the term "microbiota in fme-gut-brain axis" is sometimes used to describe paradigms explicitly including the gut flora.^[60][78][79] Broadly defined, the gut-brain axis inces of a healthy donor to recipludes 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.^[60][79] A systematic review from 2016 examint patient to correct/ted 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 potentiat a l to be useful for certain central nervous system disorders.^[8]

6. Alterations in Flora Balance

Effects of antibiotic use

Altering the numbers of gut bacter gastrointestinal disia, for example by taking broad-spectrum antibiotics, may affect the host's health and ability to digest food.^[80] Antibiotics can cause asntibiotic-associate^[17][18][19].d diarrhea (AAlthough tD) by irritating the bowel directly, changing the levels of gut flora, or allowing pathogenic bacteria to grow.^[12] Another level of success of this procharmful 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.^[80] Changing the numbers andure, is yet to be wide spread due to some constraints i 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 diarrhea.^[12] A reduction in lentified by Cammvels 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 carn get ota et al.^[20],ut of hand, though their overgrowth may be incidentaludi and not be the true cause of diarrhea.^[9][12][80] Emerging treatment protocols for C. difficulties withile infections involve fecal microbiota transplantation of donor recruitment, lack of dedicated centerfeces. (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 issues perfirmicutes classes of bacteria.^[81] Gut floraining to safety monitoring and regulation, hence, the proposal fo 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.^[82] Antibiotics alter the provisipulation of stool banks to bridge the gap ofthe 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.^[83] FMT in clinihere is reasonable evidence that taking probiotics containing Lactobacillus species mal practicy help prevent antibiotic-associated diarrhea and that taking probiotics with Saccharomyces (e.

Tg., Saccharomyces boulardii) may help to prevent Clostridium difficile infection following systemic afntibioretic treatment.^[84]

Pregnancy

Women's gutioned technique offers a natural op 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.^[51][85]

Probiotics, prebiotics, synbiotics, and pharmabiotics

Probiotics are micron to routine medorganisms that are believed to provide health benefits when consumed.^[86][87] Wicth regal treatments of chronic ailments by provrd 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.^[32][88] Synbiotics refers to fooding direct and effectiv ingredients or dietary supplements combining probiotics and prebiotics in a form of synergism.^[89] The teremedy preventing dysbiosis im "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;^[90] probiotics that have been genethe host, thereby improvingically engineered or otherwise optimized for best performance (shelf life, survival in the digestive tract, etc.);^[91] and thealth conditio natural products of gut flora metabolism (vitamins^[21][22], etc.).

2. Technologies in Gastrointestinal Microbiome Study

S^[92] There is some evidence the structure, composition and diversityat 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:

• Enterococcus faecium
• Lactobacillus plantarum
• Lactobacillus rhamnosus
• Propionibacterium freudenreichii
• Bifidobacterium breve
• Lactobacillus reuteri
• Lactobacillus salivarius
• Bifidobacterium infantis
• Streptococcus thermophilus^[93][94][95]

Research

Tests fof the r whether non-antibiotic drugs may impact human gut microb-associated bacteria were performed by in vitro analysis ota has been correlated with the healtn 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.^[96]

7. Role in Disease

Bacteria in the status of humans, it could be presumedigestive 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, that the future of combating cermetabolites from certain members of the gut flora may influence host signalling pathways, contributing to disorders such as obesity and colon cancer.^[9] Alternain ailments is ttively, 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 ulcerough exploring individuas 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⁺) iznto the stomach. However, the responsed gastrointestinal micr 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.^[37]

Bowel perforation

Normally-commensal biome as the gastroacteria can harm the host if they extrude from the intestinal mictract.^[4][5] Translobiome era heraldscation, which occurs when bacteria leave the gut through its mucosal lining, can occur in a number of different diseases.^[5] Inf the past, scigut is perforated, bacteria invade the interstitium, causing a potentially fatal infection.^[2]:715

Inflammatory bowel diseases

The two maintists have used culture independent techn 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.^{[7][97][98][99]} Additionally, iqut appes such as electrophoresis based methods, including denaturing graars 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 divent gel electrophoresis (DGGE), temperature gradient gel rsity 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 severalectrop Proteobacteria appear to be over-represented.^[1] There is reasoresis (TGGE)nable evidence that correcting gut flora imbalances by taking probiotics with Lactobacilli and PCRBifidobacteria bcased mn reduce visceral pain and gut inflammation in IBD.^[84]

Irritable bowel syndrome

Irritableth bods, such as terwel syndrome is a result of stress and chronic activation of the HPA axis; its symptoms include abdominal restriction fragment length polymorphism (T-RFLP) and ranpain, 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 ratiom as of Firmicutes: Bacteroidetes.^[79]

Other inflammatory or autoimmune conditions

Allergy, asthmpa, and diabetes mellified polymorphtus are autoimmune and inflammatory disorders of unknown cause, but have been linked to imbalances in the gut flora and its relationship with the host.^[7] As of 2016 it was not c DNA (RAPD), to study the community structurelear if changes to the gut flora cause these auto-immune and inflammatory disorders or are a product of or adaptation to them.^[7][100]

Asthma

With asthma, two hypotheses have been posediversity and genetic relatedness of to explain its rising prevalence in the developed world. The hygiene hypothesis posits that children in the developed world are not exposed to enough microbes and thus may contain lower prevalence of specific bacteria il taxa that play protective roles.^[101] The second hypothesis communities. Flufocuses on the Western pattern diet, which lacks whole grains and fiber and has an overabundance of simple sugars.^[7] Borth hypothesescence in situ hybridization (FISH) is a cytogeneti converge on the role of short-chain fatty acids (SCFAs) in immunomodulation. These bacterial fermentation metabolites are involved in immune signalling that prevents the triggering of asthma and lower SCFA levels are associated with the disease.^[101][102] Lacking technique thatprotective genera such as Lachnospira, Veillonella, Rothia and Faecalibacterium has been linked to redusced SCFA levels.^[101] Further, SCFAs are the prod in the studyuct of bacterial fermentation of fiber, which is low in the Western pattern diet.^[7][102] SCFAs off individualer a link between gut flora and immune disorders, and as of 2016, this was an active area of research.^[7] Simicrobes withilar hypotheses have also been posited for the rise of food and other allergies.^[103]

Diabetes mellitus type 1

The connection between the gut microbiota and diabetes mellitus type 1 has also been linked to SCFAs, such as Listeria monocytogenes,butyrate and acetate. Salmonella Dietsp yielding butyrate and acetatecie from bacterial fermentation s, Helicobacter pylorihow increased T_reg expression.^[104] T_reg cells d Yersinia enterocoliticaiownregulate effector T cells, which in are gutturn reduces the inflammatory response in the gut.^[105] pButyrathogene is an energy source for colon cells^{[23][24][25][26]}. Rbutyrate-yielding diets thussmann et a decrease gut permeability by providing sufficient energy for the formation of tight junctions.^[106] Additionall.^[27]y, bused FISH in the diagnosis tyrate has also been shown to decrease insulin resistance, suggesting gut communities low in butyrate-producing microbes may increase chances of Helicobacter pylori acqultuiring diabetes mellitus type 2.^[107]Butyrate-yied isolatlding diets may also have potential colorectal cancer suppression effects.^[106]

Obesity and metabolic syndrome

The gut flora has, and the same technique wa 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.^[99][108] One aspecto proffer antibiotic treatment options 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.^[84] There ise methods had a lot of drawbacks, includ also evidence that microbiota influence eating behaviours based on the preferences of the microbiota, which can lead to the host consuming more food eventually resulting in obesity. It has generally been observed that with higher gut microbiome diversity, the microbiota will spend energy and resources on competing with other microbiota and less on manipulating the need for host. The opposite is seen with lower gut microbiome diversity, and these microbiotas may work together to create host food cravings.^[39] Additionally, the liver playspecific probes, low resolution, specificity 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 sensitivity. However, advances in sequencing and cuppresses 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.^[109] Just as gut flture technologies haora 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.^[99]

Liver disease

As the liver is fed pavedirectly by the portal vein, whatever crosses the intestinal epithelium and the way to analyzing intestinal mucosal barrier enters the liver, as do cytokines generated there.^[110] Dysbiosis ig datan the gut flora has been linked with the development of cirrhosis and non-alcoholic fatty liver disease.^[110]

Cancer

Some genera of bacterisa, such as Bacteroides and Clostridium, have been associated with ang from increase in tumor growth rate, while other genera, such as Lactobacillus and Bifidobacteria, arexploration known to prevent tumor formation.^[9] As of the rich December 2017 there was preliminary and indirect evidence that gut microbiome ecosystem ofta might mediate response to PD-1 inhibitors; the mechanism was unknown.^[111]

Neuropsychiatric

Interest in the relationship between gut, which is ev 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.^[60] As of January 2016, most of the work that has been done on the role of gut flora in the gut-brain axis hadent in several been conducted in animals, or characterizing the various neuroactive compounds that gut flora can produce, and studies, as shown in Table 1. Such technologies are high-throughput sequencing, micr 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.^[60][84] A systematic review frofm 2016 examined the precluidics, high-throughput metabolomics, ainical and small human trials that have been conducted with certain commercially available strains of probiotic bacteria and found that among those tested, the genera Bifidobacterium and Lactobacillus (B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei) had the most potential to be usays eeful for certain central nervous system disorders.^[8]

8. Other Animals

The composition of the human gineered organoids derived ut 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 hPan.^[112] Humans stem cells and high-throudisplay 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.^[113] These changes are thput culturie result of the combined dietary, genetic, and cultural chang^[28].es Theyumans have far reundergone since evolutionary divergence from Pan. In acddition to hing advantages over the olumans and vertebrates, some insects also possess complex and diverse gut microbiota that play key nutritional roles.^[114] Microbial communities associated ter or traditional temites can constitute a majority of the weight of the individuals and perform important roles in the digestion of lignocellulose and nitrogen fixation.^[115] These communities are hnology already mentionost-specific, and closely related insect species share comparable similarities in gut microbiota composition.^[116][117] In cockroacheds, but with some limitationgut microbiota have been shown to assemble in a deterministic fashion, irrespective of the inoculum;^[118] the reason as well (summary in Table 2). The pros and cons of these technologies are descfor 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.^[116][117] For more than 51 years ibed belowt has been known that the administration of low doses of antibacterial agents promotes the growth of farm animals to increase weight gain.

Table 1. Studies on Microbiome, Outcomes and Methods Employed.

Table 2. S^[83] In a study performmary ofed on mice by Ilseung Cho,^[83] the Pratio of Firmicutes and Lachnospiraceae was significantly elential Clinical Applicatvated in animals treated with subtherapeutic doses of different antibiotics. By analyzing the caloric content of faeces and the concentration of Various Technologies and Their Advantages and Disadvantagessmall 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.

^[83]