1. Overview

In

1. Introduction

Thumans, the gut microbiota has the largest numbers of bacteria and the greatest number of species compared to other areas of the body.^[3] Ihuman gastroin 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.^[4][5] The relaestinal microbiota (GIM) is a complex and diverse ecosystionship between some gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship.^[2]:700m that consists of Scome 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]munity of fungi, viruses, Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobioticsrotists and majorly bacteria.^[2][6] The systemic impo

Prtance 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 or to its birthe gut flora, has been correlated with a host of inflammatory and autoimmune conditions.^[3][7]it is The composition of human gut microbiota changes over time, when the diet changes, and as overall health changes.^[3][7] A sysresumed thatematic 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]

2. Classifications

Tthe unborn is free of microbial flora, and the microbial composition of the gut microbiota varies across the digestive tract. In the stomach and small intestine, relatively few species of bacteria are generally present.^[9][10]t at birth, the infant The colon, fin contrast, contains the highest microbial density recorded in any habitat on Earth^[11] rst comes in contact with up to 10¹² chells per gram of intestinal content.^[9]resident These bactermia represent between 300 and 1000 different species.^[9][10] Howevecr, 99% of the bacteria come from about 30 or 40 species.^[12] As bial flora consequence of their abundance in the intestine, bacteria also make up to 60% of the dry mass of feces.^[13] Fungi, protists, archaea, and f the mothers’ viruses are also present in the gut flora, but less is known about their activities.^[14] Over 99% ogina if the bacteria in the gut are anaerobes, but in the cecum, aerobic bacteria reach high densities.^[2]irth was It is estimated that these 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

Mhrough the nany species in the gut have not been studied outside of their hosts because most cannot be cultured.^[10][12][16] While there are a smural birth canall, number of core species of microbes shared by most individuals, populations of microbes can vary widely among different individuals.^[17] Wior the microbial flora of thin ane individual, microbe populations stay fairly constant over time, even though some alterations may occur with changes in lifestyle, diet and age.^[9][18] The Human Micromothers’ skin if biome Project has set out to better describe the microflora of the human gut and other body locations. The four dominth was through cesant bacterial phyla in the human gut are Firmicutes, Bacteroidetes, Actinobacteria, aean sectiond Proteobacteria^[1][2][3].^[19] Most bacteria beAlong to the genera Bacteroides, Clostridium, Faecalibacterium,^[9][12] Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, and Bifidobacterium.^[9][12] Otthougher genera, such as Escherichia and Lactobacillus, are present to a lesser extent.^[9] Species from the genus Bacteroides alone consstitute about 30% of all bacteria in the gut, diesuggesting^[4][5][6] that this genus is especially important in the functioning of the host.^[10] Fungal ve suggenera 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 frequently found in individuals with inflammatory bowel disease while Candida is most fd the earequently found in individuals with hepatitis B cirrhosis and chronic hepatitis B.^[20] Archaea constitinocute another large class of gut flora which are important in the metabolism otion of the bacterial products of fermentation. Indfetustralization 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.^[22]

Enterotype

An enterotype is a classification of living organisms basewith bacteria and on its bacteriological ecosystem in the human gut microbiome not dictated by age, gender, body weight, or national divisions.^[23] Ta DNA through there are indications that long-term diet influences enterotypeplacenta.^[24] Three human enterotypes have been proposed,^[23][25] but stheir value has been questioned.^[26]

3. Composition

Anatomy

Stomach

Dudy by de tGo 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 yeastffau et al.^[2]:720[7] Helicobacter pylori is a gram-negative spiral bacteriumported that establishes on gastric mucosa causing chronic gastritis and peptic ulcer disease and is a carcinogen for gastric cancer.^[2]:904the human placenta

Intestines

The small intestine contains a trace amount of microorganisms due to the proximity and influence of the stomach. Gram-positive cocci and rod-shapes no microbiome. Detected bacteria are the predominant microorganisms found in the small intestine.^[2] Howevewere acquir, in the distal portion of the small intestine alkaline conditions support gram-negative bacteria of the Enterobacteriaceae.^[2] The d during labacterial 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.^[28] In ad and delivery. After birth, accordition the large intestine contains the largest bacterial ecosystem in the human body.^[2] About 99% og to the f the large intestine and feces flora are made up of obligate anaerobes such as Bacteroides and Bifidobacterium.^[29] Factors that disrupt the microorndinganism population of the large intestine include antibiotics, stress, and parasites.^[2] of Koenig Bacteria make up most of the flora in the colon^[30] and 60% oft al.^[8], the dry mass of feces.^[9]e This fact makwes 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. Somewhere between 300^[9] and 1000 difre apparent chaotic shifts of microbiome ferent species live in the gut,^[10] with most estimates at about 500.^[31][32] However, it is probable t that 99% of the bacteria come from about 30 or 40 species, ndowed with Faecalibacterium prausnitzii being the most common species in healthy adults.^[12][33] Fungi and protists also make up a part of the gut nes flora, but less is known about their activities.^[34] The virome is mostily bacteriophages.^[35] 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]ing lactate utilization and Though people can survive with no gut flora,^[31] the microorganilant polysms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system via end products of metaccharide 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] Extmediated by milk-based diet to increasensive modificatioin andBacteroidetes imbalances of the gut microbiota and its microbiome or gene collection are associated with obesity.^[36]itiated by 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][30]

Age

It has been troduction of solid foodemonstrated that there are common patterns of microbiome composition evolution during life.^[37] Iprepares the infant 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.^[38]ut for adult diet. However, in the findings Much of the maturation of microbiota into an adult-like configuration happens during the three first years of lifeDifferding et al.^[38] As^[9], 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.^[38]arly introduction of infants to complementary food was

Diet

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

Vegetarian and vegan diets

While plant-bhich hased diets have some 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 dbeen previously identified as precursors to oxiets that are centered 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] Converselative stress, immune disorder and obesity, diets rich in plant-based materials are associated witin childhood.

Th greater diversity in the 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 f the adused to alter the composition of the gut microbiome in 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

M gut accommodates valnourished 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.^[43][44] Malnourisous communities of phed children also typically have more potentially pathogenic gut flora, and more yeast in their mouths and throats.^[45] Alotypes beltering diet may lead to changes in gut microbiota composition and diversity.^[39]

Geography

Gut microbiome composition depends on tnging to the geographic origin of populations.yla VariationsActinobacteria, inProteobacteria, a trade-off of PrevotellaBacteroidetes, the representation of the urease geneFusobacteria, andFirmicutes the representation of genes encodingnd glutamateVerrucomicrobia^[10]. synthase/degradatiMon or other enzymes involved in amino acids degradation or vitamin biosynthesis show significant differences between populations from the US, Malawi or Amerindian origin.^[38] Thst of these phyla are 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 resent in the stomach, small intestine and colon. However, the colon is more populations which have a corn-rich diet, the diet is probably the main determinant of the gut bacterial composition.^[38] Further studies have ed with several genera belongindicated 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 fat to the afore mentioned phyla, including the genus andAkkemansia animal proteins and rich in polysaccharides and plant proteins. The fecal bacteria of European children were dominated by Firmicutes and hat belongshowed 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 fto the phylora in African populations maym aidVerrucomicrobia, in twhe digestion of normally indigestible plant polysaccharides and also may result in a reduced incidence of non-infectious colonic diseases.^[46] On aich has been found 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.^[38]

4. Acquisition in Human Infants

The establishment of a gut flora is crucial to the health of an adulto be limited in patients with obesity, as well the functioning of the gastrointestinal tract.^[47] In huinflamans, 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, aatory bowel disease and other environmental sources.^[48][4] The traditionametabol view of the gastrointestinal tract of a normal fetus is that it is sterile, although this view has been challengedc syndromes, while it is in abundance in the past few years.^[49] Multbiopsiple lines of evidence have begun to emerge that suggest there may be bacteria in the intrauterine environment. In humanhealthy individuals,^[10][11]. reAsearch has shown that microbial colonization may occur in the fetus^[50] with o has beene study showing Lactobacillus and Bifidobacterium species were present in placental biopsies.^[51] Seorted in 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.^[52][53], dietary types and pattern shapes In another study, researchers administered a culture of bacteria orally to a pregnant dam, and detected the bacteria in the offspring, likely resulting from transmission between the digestive tract and amniotic fluid via the blood stream.^[54] However, researchers cautd determines the diversion that the source of these intrauterine bacteria, whether they are alive, and their role, is not yet understood.^{[51] [55]} During y of the gut microbirth and rapidly thereafter, bacteria from the mother ande. In the surrounding environment colonize the infant's gut.^[4] The exact bmissiources of bacteria is not fully understood, but may include the birth canal, other people (parents, siblings, hospital workers), breastmilk, food, and the general environment with which the infant interactsn of Amabebe et al.^[56] However^[12], as of 2013, it remains unclear whether most colonizing arises from the mother or not.^[4] Inigh fants 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.^[50] During the first and carbohyear 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.^[4] The inirate dietial bacterial population are generally facultative anaerobic organisms; investigators believe that these initial colonizers decrease the oxygen concentration in the gut, which in turn allows obligately anaerobic bacteria like Bacteroides, Actinobacteria, and Firmicutes uilds a gut microbiota to become established and thrive.^[4]at Breast-fed babies become s predominated by bifidobacteriaMethanobrevibacter, possiblyFirmicutes due(Clostridium) to the coantents of bifidobacteriald growthPrevotella factors in breast milk, and by the fact that breast milk carries prebiotic components, allowing for healthy nd deficient in bacterial growth.^[51][57] In sucontrast, the microbiota of formula-fed infant as is more diverseBacteroides, with high numbers of EnterobacteriaceaeLactobacillus, enterococci,Akkermansia bifidobacteria, Bacteroides, and clostridiaBifidobacterium.^[58] CBaesarean section, antibioticsrone et al.^[13], and formula feeding may alter the gut microbiome composition.^[51] Chil their studreny treated with antibiotics have less stable, and less diverse floral communities.^[59] Caesarean sections broughave been shown to be disruptive to mother-offspring transmission of bacteria, which impacts the overall health of the offspring by raising risks of disease such as celiacs, asthma, and type 1 diabetes.^[51] This further eviden to the fore the impaces the importance of a healthy gut microbiome. Various methods of microbiome restoration are being explored, typically involving exposing the infant to maternal vaginal contents, and oral probiotics.^[51]

5. Functions

Wh of modern Paleolithic dien 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.^[60] (MPD) that consist of vegetables, seeds, lean meat, fruits, eggs, nuts

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 itd fish on the gut microbiome.^[61] Disruption of tThe gut flora allows competing organisms like Clostridium difficile to become establishey observed that otherwise 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 e gut flora similar to an adult's is formed within one to two years of birth.^[4] As the gcrobiome of ut flora gets established, the lining of the intestines – the intestinal epithelium and the intestinal mucosal barrier that it secretes – develop as well, in a way that is tolerant to, and even supportive of, commensalistic microorganisms to a certain extent and also provides a barrier to pathogenic ones.^[4] Specificban Italians adhering to MPD showed an ally, 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] Addple degree of biodiversitionally, 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 with high relative abundance of fat-loving and bile 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 (molecules formed from metabolism) produced from food.^[4] The human immune system creates cytokines s have been mentioned earlier, perthat 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 brbations or dysbiosis in combinacterial 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 anion with altered some Clostridia species appear to drive an anti-inflammatory response, while some segmented filamentous bacteria drive the production of inflammatory cytokines.^[4][62] Gut florameability are can also regulate the production of antibodies by the immune system.^[4][63] One funucial mection 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 beianisms that mediate disease manifestationg secreted^[14].^[64] ThFese signaling molecules interact with B cells to induce class switching to IgA.^[64] IgA is an ical mportant type of antibody that is used in mucosal environments like the gut. It has been shown that IgA can help diversify the gut community and helps in getting rid of bacteria that cause inflammatory responses.^[65] Ucrobiota transpltimately, IgA maintains a healthy environment between the host and gut bacteria.^[65] These cytokintation (FMT) has gaines and antibodies can have effects outside the gut, in the lungs and other tissues.^[4] Threlevance in rece immune system can also be altered due to the gut bacteria's ability to produce metabolites that can affect cells t times in the immune system. For example short-chain fatty acids (SCFA) can be produced by some gut bacteria through fermentation.^[66] SCFAs stimulate a treatment and corrapid increase in the production of innate immune cells like neutrophils, basophils and eosinophils.^[66] These cells agut infections or disorde part of the innate immune systemrs that try to limit the spread of infection.

Metabolism

{{Annotated image 4 | image = Microbiota-derimight haved 3-Indolepropionic acid-notext.svg | link = Commons:File:Microbiota-derived 3-Indolepropionic acid.svg | header = Tryptophan metabolism by human gastrointestinalresulted from the depletion of resident microbiota (v · d · e ) | header_align = 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 bd infection by pathogenic bacteria in the gut.^[67] Indol. Huge is produced from tryptophan by bacteria that express tryptophanase.^[67] Clostridium sporogenes metabolizeuccesses tryptophan into indole and subsequently 3-indolepropionic acid (IPA),^[68]ve been a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals.^[67][69][70] IPA biecorded inds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.^[67] Following absorption from the intestine and distribFMT therapy, with aboution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease.^[67] Lactobacillus s92% efficacy repecies metabolize tryptophan into {{when pagename is|Indole-3-carboxaldehyde=indole-3-carboxaldehyde|other=indole-3-aldehyde}} (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinalrted in the treatment of recurrent immuneClostridium difficile cells, in turn increasing interleukin-22 (IL-22) produfection^[15].^[67] Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR.^[67] Indole can alsoa recent study be metabolized by the liver into ]], a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunctionZou et al.^[67] AST-120 (activated charcoal)^[16], an intestinal sorbent that is [[Oral administrat[[Physics:taken by mouth,Chemistry:Adsorption|adsorbs i]]ndole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.^[67] }}} | annot-font was shown that pat-size = 14 | annot-text-align = left | annotations =

}} Wents 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] RodenCrohn’s disease and ulcerats 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] Carbohyve colitis that hadrates 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] BactFMT were in remission after threeria turn carbohydrates they ferment into short-chain fatty acids by a form of fermentation called saccharolytic fermentation.^[32] Producdays of transplants include acetic acid, propionic acid and butyric acid.^[12][32] These materiawith notabls can be used by host cells, providing a major source of energy and nutrients.^[32] Gases (which cause flatulence) and obacterganic acids, such as lactic acid, are also produced by fermentation.^[12] Acetic acid is used by muscal cole, propionic acid facilitates liver production of ATP, and butyric acid provides energy to gut cellszation of the gut.^[32] GutFMT flora also synthesize vitamins like biotin and folate, and facilitate absorption of dietary minerals, including magnesium, calcium, and iron.^[9][18] Methanobrevibacter smithii is unique therapy has because it is not a species of bacteria, but rather a member of domain Archeae, ann extend is the most abundant methane-producing archaeal species in the human gastrointestinal microbiota.^[71]

Pharmacomicrobiomics

The hud to the treatman metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals.^[72][73]nt of lifestyle and Since othe total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers Homo sapiens cer diseasells (tens of trillions),^{[note 1][72][74]} there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the human microbiome, drug uch as diabetes, metabolism by microbial enzymes modifying the drug's pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical efficacy and toxicity profile.^[72][73][75] Apart from carbohydratec syndrome, Parkinson’s dis, 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 metabolism of ase, obesity andrugs can sometimes inactivate the drugcer.^[77]

Gut-brain axis

FMTh e gut-brain axis is the biochemical signaling that takes place between the gastrointestinal tract and the central nervous system.^[60] That tentails transferm has been expanded to include the role of the gut flora in the interplay; the term "mof gut microbiome-gut-brain axis" is sometimes used to describe paradigms explicitly including the gut flora.^[60][78][79] Broadly deta in feces ofined, 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.^[60][79] A systemata healthy donor to recipic 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 genent patient to correct/tra (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 t a disorders.^[8]

6. 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.^[80] Antibiotics can caus gastrointestinal dise antibiotic-associatsed^[17][18][19]. diarrhea (AAD) by irritating the bowel directly, changinglthough the levels of gut flora, or allowing pathogenic bacteria to grow.^[12] Another harm of success oful 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 ththis procedure, is yet to be wide 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 diarrhea.^[12] A repread due to some constraints iduction 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 ntified by Cammarothese species can get out of hand et al.^[20], though their overgrowth may be incidental and not be the true cause of diarrhea.^[9][12][80] Emergincluding treatment protocols for C. difficile infections involve fecal microbiota transplantation of ulties with 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 bacteroiderecruitment, lack of dedicated centers and firmicutes classes of bacteria.^[81] Guissues pert 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.^[82] Antibiotics alteining to safety monitoring and regulation, hence, the proposal for the propulatvision 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.^[83]stool banks to bridge the gap of FMThere is reasonable evidence that taking probiotics containing Lactobacillus species may he in clinicalp prevent antibiotic-associated diarrhea and that taking probiotics with Saccharomyces (actice.g., Saccharomyces boulardii) may

Thelp to prevent Clostridium difficile infection afollowing systemic antibiotic treatment.^[84]

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.^[51][85]

Probiotics, prebiotics, synbiotics, and pharmabiotics

Probioioned technique offers a natural optics are microorganisms that are believed to provide health benefits when consumed.^[86][87] Wn to routine medith regcard 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] Synbl treatments of chronic ailments by proviotics refers to food ingredients or dietary supplements combining probiotics and prebiotics in a form of synergism.^[89] Thing direct and effective trerm "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]medy preventing dysbiosis in probiotics that have been genetically engineered or otherwise optimized for best performance (shelf life, survival in the digestive tract, etc.);^[91] ahe host, thereby improving health cond the natural products of gut flora metabolism (vitamiions, etc^[21][22].).^[92] There

2. Technologies in Gastrointestinal Microbiome Study

Sis 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:

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

Research

Tests for we structure, composition and diversity of the hether non-antibiotic drugs may impact human gut-associated bacteria were performed by in vitro analysman gut microbis 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.^[96]

7. Role in Disease

Bacteria in tta has been correlated with the healthe 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] Adstatus of humans, it could be presumeditionally, metabolites from certain members of the gut flora may influence host signalling pathways, contributing to disorders such as obesity and colon cancer.^[9] Althat the future of combating certernatively, 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 cain ailments is throuse 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⁺) h exploring individualized gastrointo 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.^[37]

Bowel perforation

Nstinal microbiome as the gastrormally-commensal bacteria can harm the host if they extrude from the intestinal tract.^[4][5] Tntestinal micranslocation, which occurs when bacteria leave the gut through its mucosal lining, can occur in a number of different diseasesbiome era heralds.^[5] Ifn the gut is perforated, bacteria invade the interstitium, causing a potentially fatal infection.^[2]:715

Inflammatory bowel diseases

The two main typepast, scientis 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, it apps have used culture independent techniquears 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]such as electrophoresis based methods, including denaturing gradient gel 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 sevlectrophoresis (DGGE), temperature gradient gel eral Proteobacteria appear to be over-represented.^[1] Tectrophere is reasonable evidence that correcting gut flora imbalances by taking probiotics withresis (TGGE) Lactobacilli and BifidobacteriaPCR cban reduce visceral pain and gut inflammation in IBD.^[84]

Irritable bowel syndrome

Irritable bowel synsed methodrome is a result of stress and chronic activation of the HPA axis; its symptoms include abdo, such as terminal 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, anrestriction fragment length polymorphism (T-RFLP) and rand increased ratios of Firmicutes: Bacteroidetes.^[79]

Other inflammatory or autoimmune conditions

Allergy, asthm ama, and diabetes mepllitus 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 ified polymorphic DNA (RAPD), to study the clear 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 hammunity structure, dive been porsed 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 ity and genetic relatedness of bacterial taxa that play protective roles.^[101] The se in commund hypothesis focuses on the Western pattern diet, which lacks whole grains and fiber and has an overabundance of simple sugars.^[7] Both hypothesities. Fluores 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 proence in situ hybridization (FISH) is a cytogenetic technique thatective genera such has Lachnospira, Veillonella, Rothia and Faecalibacterium has been linked to reduced SCFA levels.^[101] Furthser, SCFAs are the product of bacterial fermentation of fiber, which is low in the Western pattern diet.^[7][102] in the study SCFAs offer a link between gut flora and immune disorders, and as of 2016, this was an active area of research.^[7] Similar hypotheses have also f individual microbeen posited for the rise of food and other allergies.^[103]

Diabetes mellitus type 1

The cons withinection between the gut microbiota and diabetes mellitus type 1 has also been linked to SCFAs, such as butyrateListeria monocytogenes, and acetate. DietSalmonella s yipelding butyrate and acetate from bacterial fermentation cieshow, Helicobacter pylori increased T_reg expression.^[104] T_reg cells downregulate effector T cells Yersinia enterocoliticai, which in turn reduces the inflammatory response in the gut.^[105]are gut Butyrpate is an energy source for colon cellhogens^{[23][24][25][26]}. bRutyrate-yielding diets thus decrease gut permeability by providing sufficient energy for the formation of tight junctionsssmann et al.^[106][27] Additionally, butyrate has also been shown to decrease insulin resistance, suggesting gut communities low in butyrate-producing microbes may increase chances sed FISH in the diagnosis of aHelicobacter pylori cquiring diabetes mellitus type 2.^[107]Butylturate-yielding diets may also have potential colorectal cancer suppression effects.^[106]

Obesity and metabolic syndrome

Thd isolate 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 i, and the same technique was used.^[99][108] One aspect of a healthy diet that is often lacking in the Western-pattern diet is fiber and other complex carbohydrates that a healthy gut flora require flourishing; changes to gut flora in response to a Western-pattern diet appear to increase the amount of energy generated by the gut flora which may contribute to obesity and metabolic syndromeo proffer antibiotic treatment options.^[84] There is 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 manipulatie methods had a lot of drawbacks, including the 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 need for splays a dominant role in blood glucose homeostasis by maintaining a balance between the uptake and storage of glucose through the metabolic pathways of glycogenesis and gluconeogenesis. Intestinal lipids regulate glucose homeostasis involving a gut-brain-liver axis. The direct administration of lipids into the upper intestine increases the long chain fatty acyl-coenzyme A (LCFA-CoA) levels in the upper intestines and suppresses glucose production even under subdiaphragmatic vagotomy or gut vagal deafferentation. This interrupts the neural connection between the brain and the gut and blocks the upper intestinal lipids' ability to inhibit glucose production. The gut-brain-liver axis and gut microbiota composition can regulate the glucose homeostasis in the liver and provide potential therapeutic methods to treat obesity and diabetes.^[109] Just as gucific probes, low resolution, specificity and sensitivity. However, advances in sequencing and culture technologies have paved the way t 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 composi analyzing big data arising from exploration of the gut flora.^[99]

Liver disease

As the lriver 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.^[110] Dysbih microbiome ecosystem osisf in the gut flora has been linked with the development of cirrhosis and non-alcoholic fatty liver disease.^[110], which is

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, ardent in se known to prevent tumor formation.^[9]ral As of December 2017 there was preliminary and indirect evidence that gut microbiota might mediate response to PD-1 inhibitors; the mechanism was unknown.^[111]tudies, as shown

Neuropsychiatric

Interest in the relTationship 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.^[60] Able 1. Such technologies 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.^[60][84] A systematre high-throughput sequencing, microfluidics, high-throughput metabolomics, assays engineered organoids deric reviewed 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, the genera Bifidobacterium and Lactobacillus (B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei) human stem cells and high-throughad the most potential to be useful for certain central nervous system disorders.^[8]

8. Other Animals

The compositut culturion of the human gut microbiome is similar to that of the other great apes^[28]. However, Thumans’ gut biota has decreased in diversity and changed in composition since our evolutionary split from Pan.^[112] Humey have fans 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.^[113] Thes reaching advantages over the olde changes are the result of the combined dietary, genetic, and cultural changes humans have undergone since evolutionary divergence from Pan. In addition to or traditional techumans and vertebrates, some insects also possess complex and diverse gut microbiota that play key nutritional roles.^[114] Microbiology alrealdy 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.^[115] Thementioned, but with some limitationse communities are host-specific, and closely related insect species share comparable similarities in gut microbiota compositionas well (summary in Table 2).^[116][117] In cockroacThes, gut microbiota have been shown to assemble in a deterministic fashion, irrespective of the inoculum;^[118] the rea pros and conson 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.^[116][117] Foof these technologies are descr more than 51 years it has been known that the administration of low doses of antibacterial agents promotes the growth of farbed below.

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

Table 2. Sum animals to increase weight gain.^[83] In a studry peroformed on mice by Ilseung Cho,^[83] the ratiPo 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 concentratntial Clinical Application 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 SCFAsVarious Technologies and Their Advantages and Disadvantages.^[83]