MEDICINE

The Gut Microbiota: A Clinically Impactful Factor in PatientHealth and Disease

David Avelar Rodriguez1 & Rubén Peña Vélez1 & Erick Manuel Toro Monjaraz1 & Jaime Ramirez Mayans1 &

Paul MacDaragh Ryan2

Accepted: 5 December 2018# Springer Nature Switzerland AG 2018

AbstractThe gut microbiota, often referred to as the body’s virtual organ, is a complex ecosystem made up of trillions of microorganismsthat interact with host physiology in a myriad of ways. This lifelong interaction begins in the early stages of life, and it is subjectto alterations exerted by environmental factors, especially those that characterise modern societies such as ultra-processed foodsand pharmaceutical interventions, amongst others. These alterations, in turn, carry with them implications for host health anddisease. Due to this putative role in human health and the fact that study of the gut microbiota is now rapidly evolving, it is ofparamount importance that all clinicians be aware of the most up-to-date literature in this field. Herein, we present a state-of-the-art reviewwhich aims to outline the most relevant pre-clinical and clinical knowledge around the gut microbiota-host interaction.This review focuses primarily on the development and key functions of the gut microbiota with respect to host health and disease,but also addresses the basic concept of gut dysbiosis.

Keywords Gutmicrobiota . Intestinal microbiota . Gut microbiome . Gut microbiota . Dysbiosis

Introduction

Since the beginning of the twenty-first century, the gut micro-biota has been the centrepiece of research amongst differentdisciplines around the globe [1, 2]. The gut microbiota, oftenreferred to as the body’s virtual organ [3], is a uniquely com-plex ecosystem consisting of approximately 100 trillion mi-croorganisms, which includes bacteria, viruses, fungi and pro-tozoa. [4] As its name indicates, the gut microbiota resides inthe alimentary tract, but it is most populous in the colon,representing the vast majority of bacterial cells in the body[5, 6]. In fact, the bacterial count gradually increases fromabout 104/mL content in the stomach and duodenum, to ap-proximately 1011/mL content in the colon [6].

The gut microbiota genesis begins in early stages of lifeand it is further shaped by a series of external factors, such asmode of delivery, pharmaceuticals, diet, exercise and air pol-lution [4, 7–11]. Dysbiosis of the gut microbiota has beenimplicated in multiple non-communicable disease states, suchas obesity [12], atopy [8], autoimmunity [13] and malignancy[14], amongst others. In contrast, a ‘healthy’ microbiota ap-pears to provide a plethora of beneficial effects to the host,resulting in a degree of protection and better health outcomesoverall [3, 8, 15]. In light of such associations, and persuasivenovel clinical data, it is now crucial for clinicians to becomefamiliar with the fundamental concepts of gut microbiota re-search (see Table 1 for the glossary of terms), as well as thepotential implications of this research for their patient cohorts.This article represents a state-of-the-art review and aims topresent the essential aspects of the gut microbiota, focusingprimarily on the factors which impact upon its developmentand its functions with respect to host health and disease.

Search Strategy and Selection Criteria

In August 2018, we systematically searched the PubMed/MEDLINE, ResearchGate, Mendeley and Google Scholar

This article is part of the Topical Collection on Medicine

* David Avelar Rodriguezdavidavelar1@outlook.com

1 Pediatric Nutrition and Gastroenterology Department, InstitutoNacional de Pediatría, Mexico City, Mexico

2 School of Medicine, University College Cork, Cork, Ireland

https://doi.org/10.1007/s42399-018-0036-1SN Comprehensive Clinical Medicine (2019) 1:188–199

/Published online: 18 December 2018

databases using the terms ‘intestinal microbiota’, ‘intestinalmicrobiome’, ‘intestinal microflora’, ‘gut microbiota’, ‘gutmicrobiome’, ‘intestinal dysbiosis’ and ‘gut dysbiosis’. Forindividual sections, we built search blocks using Boolean op-erators (e.g. intestinal microbiota AND obesity). We consid-ered experimental studies, reviews, systematic reviews andmeta-analyses, and no date range was specified. The last lit-erature search was conducted on November 29, 2018.

How Is the Gut Microbiota Acquired and HowDoes It Evolve Throughout Life?

Whether the acquisition of the gut microbiota takes place atbirth (‘sterile womb hypothesis’) or in utero (‘in utero coloni-sation hypothesis’) remains a controversial topic (Fig. 1; forreview, see [16, 17]). However, the former has been recentlychallenged by an increasing number of studies in which, con-trary to previous belief, the placenta and amniotic fluid havebeen found to harbour a microbiome, strongly suggesting thatthe genesis of the gut microbiome occurs in utero [18–23].

The first 3 years of life represent a crucial time period forthe development of the gut microbiota, which includes a va-riety of factors that determine its composition, such asmode ofdelivery, gestational age, diet and pharmaceutical interven-tions [8, 9, 24–27]. Some authors consider this time a ‘win-dow of opportunity for microbial modulation’ [20], as thechild is exposed to a multitude of external factors withmicrobiota-modifying potential [4, 28]. During the first yearof life, its composition is characterised by reduced diversityand stability as compared with the adult microbiota. By 2.5 to3 years of age, an adult-like microbiota is fully established (i.e.Bacteroidetes and Firmicutes predominance, although eachindividual harbours an entirely unique composition) [4, 5,8]. Interestingly, the functions of the gut microbiota and itsgenetic machinery (the intestinal microbiome) undergo majorchanges as solid foods are introduced. During the weaningprocess, the microbiome must adapt to a more complex diet

that includes carbohydrates, vitamins and xenobiotics,resulting in a shift from a lactose-metabolism to a more com-plex one with degradative and synthetic properties [8, 29]. Thehuman gut microbiota comprises four predominant phylaacross the lifespan: Actinobacteria, Firmicutes, Bacteroidetesand Proteobacteria. Generally speaking, the phylumActinobacteria predominates during the first 3 years of lifeand substantially decreases after weaning. As Actinobacteriadecreases, Firmicutes increases, representing the most numer-ous phylum throughout life. Furthermore, the relative abun-dance of Bacteroidetes remains relatively stable up to 70 yearsof life and thereafter increases gradually. Proteobacteria, onthe other hand, mirror—although in a lesser percentage—Actinobacteria and Bacteroidetes during the first 3 years oflife and from 70 years of age onwards, respectively [30].

Mode of Delivery

Multiple studies have shown that the development of the in-fant’s gut microbiota is significantly shaped by mode of de-livery [31]. Vaginally delivered infants are thought to undergoa ‘bacterial baptism’ during birth [32]. Thus, their microbiotaresembles the mother’s vaginal flora (e.g. Lactobacillus,Prevotella and Sneathia), displaying a more diverse microbi-ota and a greater number of Bacteroides and Bifidobacteriumthan their caesarean-delivered counterparts. On the otherhand, infants delivered by caesarean section bypass this vag-inal ‘bacterial baptism’, and their microbiota more closelyresembles that of their mother ’s skin flora (e .g.Staphylococcus, Corynebacterium and Propionibacterium)[4, 26, 33, 34]. Nonetheless, these main discrepancies gener-ally persist only up to 6 months of age, and the microbiotacomposition of both groups tends to converge thereafter [31,35, 36]. The resultant microbiota changes in caesarean-bornchildren, particularly the lower numbers of Bacteroides andBifidobacterium, may increase the risk of allergic diseasessuch as asthma [37] and allergic rhinitis [8, 35]. Although itis important to note that the mode-of-delivery factor does not

Table 1 Glossary

Terms Definition

Gut microbiota Community of microorganisms themselves residing in the intestinal tract—mainly in the colon

Intestinal microbiome The collective genomes of the gut microbiota

Gut dysbiosis Alterations in composition, taxonomy, quantity or function of the gut microbiota, resulting in negative effects upon the host

16S rRNA sequencing 16S is highly conserved gene within the prokaryotic ribosome which can be amplified from a diverse sample of microbialDNA and sequenced to generate a census of what microbes are present and in what relative proportions.

Shotgun metagenomicsequencing

A technique in which long segments of DNA are cleaved into smaller fragments and sequenced in a random manner.Post-sequencing bioinformatics tools are used to realign these fragments into contiguous pieces.From this, we can garner information about not only on what microbes are present, but also what they are doing.

α-Diversity The diversity of taxa observed within a single sample or sampled site

β-Diversity The degree of variation in taxa compositions between samples

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seem to affect the microbiota diversity and composition ofpreterm neonates [38].

Gestational Age

Pre t e rm neona tes have a dec reased number o fBifidobacterium spp. and their microbiota exhibits less diver-sity as compared with term neonates. These discrepancies arethe result of a multifactorial process wherein more than oneexternal factor may coexist (namely, delayed enteral feeding,use of total parenteral nutrition and maternal and neonatalprophylactic antibiotic therapy) [15, 35]. In addition, pretermneonates may have higher levels of potentially pathogenicbacteria (Proteobacteria bloom) and multi-drug-resistant

bacteria, such as Escherichia, Klebsiella and Enterobacterspecies [20, 35]. Intestinal dysbiosis in preterm neonates hasbeen implicated in the pathogenesis of life-threateningnecrotising enterocolitis (NEC) [39]. A recent systematic re-view and meta-analysis [40] found that dysbiosischaracterised by an increase in phylum Proteobacteria and adecrease in Firmicutes and Bacteroidetes preceded NEC inpreterm neonates. Moreover, late-onset sepsis (LOS) repre-sents another common complication in preterm neonates,which has been associated with gut dysbiosis characterisedby depleted numbers of Bifidobacteria and a Proteobacteriabloom [41–43]. Though it is important to mention that thesestudies had a small sample size and antibiotics were adminis-tered to nearly all neonates; thus, the microbial composition

Fig. 1 Illustration of the two proposed theories by which the gutmicrobiota is established. a The sterile womb hypothesis argues that theuterus and foetus are sterile and that the infant alimentary tract iscolonised during birth by the mother’s skin (caesarean delivery) orvaginal microbiota (vaginal delivery). b In utero colonisationhypothesis. It has been postulated that the mother’s gut microorganismsare selectively transported to the placenta, which consequently colonisethe foetus alimentary tract in utero. [17] Aagaard et al. [16] investigatedthe microbiome of different body site niches (oral, skin, nasal, vaginal) innonpregnant subjects and found that, of these body sites, the oralmicrobiota was the most akin to the placenta, suggesting a possible

source of colonisation; however, the mechanism through which thebacteria reach the placenta was not elaborated. In line with thesefindings, a more recent study by Gomez-Arango et al. [20] found thatthe placental microbiome was most similar to the mother’s oralmicrobiome, but less alike to the maternal gut microbiome. In contrast,Ferretti et al. [19] found that the maternal gut microbiome was the largestdonor of the infant gut microbiome, whereas the least common source ofcolonisation was the mother’s oral cavity. Although these findings arecontradictory in regard to the seeding sources, they all support the notionthat the acquisition of the infant gut microbiome potentially occurs inutero. Created with BioRender

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present in these neonates appears to be the result of antibioticadministration rather than gestational age itself. Furthermore,increasing evidence suggests that probiotics may decrease theincidence of NEC and LOS in preterm neonates [44, 45], andemerging modalities such as ‘para-probiotics’, inactivatedforms of microbial therapeutic, could become safe alternativesto probiotics in neonates, although these are yet to be evalu-ated in clinical studies [46].Moreover, a recent study that used16S rRNA amplicon sequencing to analyse the gut microbiotaof 45 breastfed very low birth weight preterm infants, sug-gested that hospitalised preterm infants receiving breast milkmay develop a microbiota resembling that of term neonates[47]. These findings emphasise the importance of human milkand the window of opportunity for preterm infants to possiblydevelop a ‘normal’ gut microbiota and to catch up with theirfull-term contemporaries.

Feeding Type and Diet

During the first days of life, facultative anaerobic bacteriasuch as Escherichia coli, Enterococcus and Staphylococcuscolonise the infant alimentary tract. Thereafter, the depletionof oxygen and the presence human milk oligosaccharides shiftthe microbiota composition to anaerobic bacteria, such asBacteroides, Bifidobacterium and Clostridium spp. [9, 20,21]. Human milk is a dynamic and bioactive fluid that con-tains macronutrients, micronutrients and immunologic andbioactive factors [48]. The presence of oligosaccharides inhuman milk (e.g. galactooligosaccharides) is a key for thedevelopment of the infant’s gut microbiota, particularlythrough growth stimulation of colonic Bifidobacteriumlongum [8, 20, 49]. Moreover, the infant’s alimentary tract isfurther colonised by the humanmilk microbiota (mainly strep-tococci and staphylococci), which has been shown to be asignificant source of bacterial colonisation [50]. Infant formu-la, on the other hand, is sterile and thus lacks this naturalfeature [20, 35]. Even maternal diet can influence the infantmicrobiota composition through vertical transfer duringbreastfeeding [51]. Thus, breastfed infants have aBifidobacterium and Lactobacillus predominance and displaya more stable and diverse microbiota than formula-fed infants[4, 15].

The composition of the gut microbiota continues to expe-rience changes throughout life, mainly induced by dietaryhabits. For example, the Western-style diet, characterised bylow-fibre, high-fat, refined carbohydrate content and ultra-processed ingredients, negatively influences the gutmicrobiome [52]. De Filippo et al. used high-throughput16S rRNA sequencing and biochemical analyses to studythe microbiota composition of European children andAfrican children from the Burkina Faso village, whose dietaryhabits resemble those of the Neolithic period, characterised byhigh-fibre content. The authors found that, compared with

European children, African children exhibited an increasednumber of Bacteroidetes and a low number of Firmicutes,were colonised with unique bacteria from the genusPrevotella and Xylanibacter (which are known to metabolisedietary fibres readily) and exhibited increased short-chain fat-ty acid (SCFA) production [53]. Furthermore, observationalstudies have demonstrated lower microbial diversity in theadult American microbiota compared with people living inrural areas such as Malawi and Venezuela [54]. Interestingly,a novel study [55] that used 16S and deep shotgunmetagenomic DNA sequencing to evaluate the gut microbiotaof immigrants from non-Western countries who migrated tothe USA, found that, these subjects not only experienced adecrease in microbial diversity and plant-fibre degradationability, but also experienced a shift from the non-Western-associated genus Prevotella to the Western-associated genusBacteroides (which may explain the reduction in fibre degra-dation). The authors found that this phenomenon, which hasbeen referred to as ‘microbiomeWesternisation’, begins with-in 9 months of immigration. A recent meta-analysis [56] ofshotgun metagenomic datasets compared the gut microbiomeof healthy adults across different countries, including 13industrialised societies and two hunter-gatherer, pre-agricultural communities. The authors concluded that theurbanisation/industrialisation process and resultant dietarychanges have shaped the gut microbiota, particularly throughthe acquisition and/or loss of specific microbes, such asBarnesiella intestinihominis and Treponema succinifaciens.Moreover, non-caloric sweeteners are increasingly being usedin many processed foods in Western-style diets, mainly be-cause they enhance flavours and have been shown reduce therisk of obesity [57]. However, they can induce negativechanges on the gut microbiota, as shown in murine modelsin which a reduction in beneficial bacteria after administrationof sucralose and saccharin was demonstrated [58]. Indeed,these microbiota-modifying attributes may carry importantimplications for host health in the longer term. Dietary poly-phenols, on the other hand, have been found to stimulate thegrowth of beneficial bacteria and inhibit the proliferation ofpathogenic bacteria [3, 59]. Taken together, these findingshighlight the role of diet in shaping the microbiota composi-tion across different ethnicities and geographies, especially thenegative impact of the Western-style diet and industrialisationupon the gut microbiota.

Pharmaceuticals and the Gut Microbiota

Antibiotics are the most prescribed drugs in neonates andchildren in the USA [29]. They not only cause bacterial resis-tance, but also affect the development and composition of thegut microbiota throughout life [15, 34, 35, 60]. Antibiotictreatment in neonates, most commonly gentamicin and ampi-cillin [29], has been associated with a decreased number of

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Bifidobacteria which can persist up to 8 weeks of life aftertreatment [20, 29]. Even maternal intrapartum antibiotic pro-phylaxis (IAP) can alter the neonate’s gut microbiota; infantswhose mothers received IAP display a less diverse microbiotaas compared with those whose mothers did not [61]. A recentstudy that used shotgun sequencing-based metagenomics toanalyse the microbiota of healthy young adults before andafter administration of a 4-day course broad-spectrum antibi-otic cocktail (meropenem, gentamicin and vancomycin) foundthat, in fact, there was a depletion of Bifidobacterium spp. andother butyrate-producing bacteria within 8 days after cocktailadministration. In addition, the study reported an increase inlow-abundance commensals such as Escherichia coli,Veillonella spp. and Klebsiella spp., and by 1.5 months, themicrobiota of all patients recovered to near baseline. The au-thors concluded that the gut microbiome of young, healthyadults are resilient to a 4-day broad-spectrum antibiotic treat-ment, which is modulated by antibiotic resistance genes—alsoknown as the ‘resistome’ [62]. Although antibiotics are knownto significantly alter the intestinal microenvironment, they arefrequently a lifesaving intervention when used judiciously.

Despite our reasonably extensive understanding of themanner in which antibiotics manipulate the intestinal micro-biota, we are only now beginning to recognise the sizeableimpact which other commonly prescribed medications haveon even the established adult microbiota. Several recent clin-ical studies have highlighted the effects of proton pump inhib-itors on the composition and functionality of the intestinalmicrobiome [63, 64], while metformin has received consider-able attention for its potentiating effects on the metabolichealth–associated microbe Akkermansia muciniphila [65,66]. The study of a combined Belgian-Dutch cohort of exten-sively phenotyped participants revealed a far more inclusivelist of microbiota-modulating pharmaceuticals, including os-motic laxatives, antidepressants, female hormone therapiesand TNF-alpha inhibitors [67]. Furthermore, the BritishTwinsUK study, perhaps the most highly powered study ofthis kind, recently went on to assess microbiota associationsfor 51 commonly prescribed medications [68]. The authorsuncovered a plethora of associations, or rather associated per-turbations, with the most commonly implicated compounds(i.e. proton pump inhibitors and antibiotics), but also withentirely unsuspected therapies, such as anticholinergic in-halers, paracetamol, SSRIs and opioids. Furthermore, chemo-therapy has also been implicated in the disruption of the intes-tinal microbiota, which can lead to lower gut microbiota di-versity and numbers of anaerobic beneficial bacteria [69].

Conversely, the metabolically active mass of enzyme-secreting microbes which comprises our intestinal microbiotais beginning to be considered as a structural and pharmacoki-netics modifier of certain oral medicines [70]. These microbesare granted true first-pass metabolism and are capable of al-tering structure and function through oxidation, hydrolysis

and dehydroxylation reactions, amongst others [71]. For ex-ample, the commonly prescribed inotrope digoxin is known tobe inactivated by the intestinal microbe Eggerthella lenta, anundesirable attribute which is thought to contribute to thepharmacokinetic variability of the drug in vivo [72]. In addi-tion, there is evidence to suggest that the modification of lu-minal bile acids by intestinal microbes has implications fordrug solubility and absorption [73, 74]. The importance ingenetic polymorphisms in drug metabolism and stratificationof patients according to their likelihood of response to therapyis now an area of great interest; however, it seems likely thatthe individual microbiota of a patient may also be a significantcontributor in this regard.

Exercise

Recent evidence suggests that the human gut microbiota canbe modulated by exercise (Fig. 2 demonstrates the factors thatshape and alter the gut microbiota throughout life). A recentlypublished systematic review of the literature available on theexercise-microbiota interaction in mammals [75] found a con-sistent diversification of the Firmicutes phylum and increasein butyrate production following implementations of exerciseregimes. Such increases in SCFA production may indeed con-fer beneficial effects on the host system. In an attempt toassess the microbiome-modifying effects of exercise in previ-ously sedentary lean and obese individuals, Allen et al. [10]enrolled participants in a supervised 6-week aerobic exerciseregimen (30–60 min/week of moderate-to-vigorous intensity)without dietary changes. Following the 6-week intervention,there was a substantial increase in faecal SCFAs (mainly ace-tate and butyrate) in the lean, which was not observed in theobese group. In addition, the authors found that the increase infaecal SCFAs paralleled improvements in body lean mass.These findings indicate key discrepancies in the manner inwhich lean and obese individuals may respond to exerciseregimes. A recent observational study [76] compared the gutmicrobiome of professional international rugby players(athletes) with controls. The authors found that athletesdisplayed increased microbial diversity, metabolic pathwaysand faecal metabolites (including SCFAs) compared to thecontrol group and that these parameters associated with en-hanced fitness and health. These findings demonstrate anotherbenefit of exercise and highlight its role in boosting the pro-duction of beneficial metabolites by the gut microbiota.

Functions of the Gut Microbiota

The intestinal microbiome is a relatively plastic and complexmetabolic system which is most numerous and active in thelumen of the colon. This microbial mass of genetic potentialprovides a myriad of metabolic and immunoregulatory

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functions to the host, from fibre fermentation and vitaminproduction to education of our immature immune system[77, 78]. The seminal studies, which initially uncovered thevital role that our intestinal microbes play in normal systemicdevelopment, were conducted in ‘germ-free’ mouse models.These mice, which are delivered by caesarean section understerile conditions, are maintained in an environment free ofdetectable microorganisms. Studies in germ-free mice havedemonstrated the wide range of systemic and organ-specificdeficiencies that such sterile animals acquire. Indeed, germ-free animals display altered gall bladders and bile pools [79],arrested intestinal angiogenesis [80] and engrossed caecums[81], in addition to abnormal behaviour [82] and an immatureinnate immune system [83]. Taken together, this catalogue ofcritical dysfunctions indicates that our intestinal microbiomeis in fact an essential factor in normal host development andhealth maintenance.

Metabolic Functions

Perhaps our first major reliance upon our intestinalmicrobiome is for the production of vitamin K, an essential

cofactor in the synthesis of a multitude of coagulation factors[84]. As neonates are generally regarded to be born with asterile or near sterile gastrointestinal tract, standard care haslong since required the administration of intramuscular vita-min K, until such point as the infant microbiome and diet areestablished. It would seem that this is the beginning of anintricate relationship played out between microbe and manfor millennia.

As we mature, so too does the composition of our intestinalmicrobiome, as well as the functions with which it providesus. Diet begins to greatly determine the composition and,therefore, a significant degree of interpersonal variation is ob-served [85]. However, in general terms, the relative abun-dances of human milk oligosaccharide-metabolisingBifidobacteria begin to fall steadily, while fibre-fermentinganaerobes experience a gradual rise [20]. As a direct result,there is a corresponding increase in the production of SCFA—namely acetate, propionate and butyrate. These metaboliteslikely initially garnered attention due to their relative ease ofdetection and significant abundance in the intestinal lumen,with a total concentration of ~ 50–200 mM [86]. However,these entities act in vastly different ways to confer a broad

Fig. 2 Factors that shape and alterthe gut microbiota throughoutlife. Created with BioRender

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range of effects upon host physiology. Although acetate is themost abundant of these fatty acids in circulation, current re-search suggests that it is comparatively inert in biologicalterms. Having said this, acetate participates in key biochemi-cal reactions such as lipogenesis and cholesterol synthesis [87]and has been found to modulate appetite centrally [88].Butyrate, in turn, appears to act as a key source of energyfor colonic enterocytes, thereby bolstering the integrity ofthe enteric gut barrier and preventing the leakage of inflam-matory microbial fragments, such as lipopolysaccharides [89].Propionate, on the other hand, modulates hepatic gluconeo-genesis [90] and is currently being evaluated in a phase IIclinical trial for its ability to reduce low-density lipoproteincholesterol in hypercholesterolaemia adults (ClinicalTrials.gov ID: NCT03590496). Each of these fatty acids appears todisplay varying degrees of affinity for the enteric G protein–coupled receptors GPR-41 and GPR-43 [91], both of whichhave been shown to promote the secretion of metabolicallyimportant gut hormones glucagon-like peptide (GLP)-1 andpeptide YY (Fig. 3; for review, see [92]). Finally, there isevidence to suggest that SCFA may be of clinical importancedue to their tight junction promoting effects, which reducesthe influx ofmicrobial fragments and the associated low-gradeinflammation which is thought to disrupt normal host meta-bolic homeostasis [93].

Another promising pathway through which the intestinalmicrobiome is thought to interact with host physiology is themetabolism of bile acids. The presence of bile acids in theintestinal lumen represents a genuine ecological threat to mi-crobial life [94]. Therefore, those microorganisms typicallyendemic to this hostile environment commonly express en-zymes which render these corrosive molecules open to subse-quent degradation or detoxification [95]. In doing so, the gutmicrobiome manipulates the composition of bile acids that

pass through the small intestine and are readily reabsorbedinto circulation [96]. Traditionally, the purpose of bile acidswas considered to be limited to their role as lipid emulsifiers inthe enteric lumen; however, we now realise that the multitudeof bile acid entities that circulate through our bodies actuallyrepresents potent cell surface and nuclear receptor ligands[97]. Furthermore, the receptors in question are known tomodulate tasks outside of simple bile acid homeostasis,impacting on a range of cardiometabolic functions (for review,see [98]). For instance, the GPCR TGR5 is known to impactpotently upon aspects of metabolic health by triggering therelease of GLP-1 once activated by microbially modified bileacids (Fig. 3) [99]. Moreover, the bile acid nuclear receptorfarnesoid X receptor is revealing itself as a target for the pre-vention of non-alcoholic fatty liver disease [100], suggesting apotential role for bile modifying microbes in the maintenanceof hepatic health. Finally, there is even evidence to suggestthat our gut microbiome may interact with and modulate hostcircadian rhythm genes through the modification of the circu-lating bile pool [101]. Taken together, these studies demon-strate that bile acids represent a putative language in the host-microbe crosstalk.

Neurological Functions

The gut microbiota is now recognised to secrete an intriguinggroup of metabolites which closely relate to the endogenousmolecules that mediate human neuronal transmission andtheir precursors. These include compounds such as seroto-nin, tryptophan, kynurenine and -aminobutyric acid,amongst others [102–104]. These potentially neuroactivepeptides form one of the arms of the gut-brain axis, a hypoth-esis that there exists a bidirectional crosstalk between the gutmicrobiome and host neurophysiology. In addition,

Fig. 3 Immune and endocrine pathways through which the gutmicrobiota contributes to host homeostasis. The gut microbiota interactsintimately with host immune system maturation and metabolic function.This figure depicts several pathways through which the components ofthe microbiota can contribute to or attenuate systemic disease. LCAlithocholic acid, CA cholic acid, DCA deoxycholic acid, CDCAchenodeoxycholic acid, GLP-1 glucagon-like peptide-1, SCFA short-

chain fatty acids, GPR41/43 G protein–coupled receptor 41/43, TJ tightjunction, GIP gastric inhibitory polypeptide, PYY peptide YY, LPSlipopolysaccharide, iDC inflammatory dendritic cell, TH T helper cell,IFNγ interferon gamma, IL interleukin, M1 classically activatedmacrophage, M2 regulatory macrophage, Treg regulatory T cell, tDCtolerogenic dendritic cell, TLR4 toll-like receptor 4. Created withBioRender

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significant emphasis has been placed on the potential role ofthe autonomic nervous system and in particular the vagusnerve, in the transmission of this crosstalk [105]. Finally,other microbial metabolites such as propionate have alsorecently been implicated in the maintenance of a healthyblood-brain barrier [106]. Despite the fascinating nature ofthis concept, insufficient clinical data is currently available tosway many clinicians at present; although recent data fromAPC Microbiome Ireland has revealed a potential role fortargeted microbial therapies in the modulation of anxiety.The study demonstrated through both self-reporting surveyand biochemical means that the touted ‘psychobiotic’Bifidobacterium longum 1714 conferred anxiolytic effectsupon the subjects [107, 108]. This data builds upon andtranslates the conclusions of previous pre-clinical studies,which have outlined the potential efficacy of such microbialtherapeutics as adjuncts in psychiatric medicine [109].Indeed, if greater emphasis is placed on clinical translation,it is reasonable to imagine that we may uncover truly micro-bial basis to the ‘gut feeling’ phenomenon.

Immunomodulatory Functions

The innate immune system combines with the intestinal ep-ithelial barrier to act as the first point of contact for gutmicrobes, their associated metabolites and all ingested nutri-ents. In this respect, innate immunity represents one of themost important lines of communication in the host-microbecrosstalk. The endogenous microbes within our intestines actto educate our naïve immune system and to create a basaltolerance for non-pathogenic or commensal organisms [110].In line with this, there is now good clinical evidence indicat-ing that gut microbiome plays a central role in preventing or

initiating the development of autoimmunity and atopy.Perhaps the most convincing data in this regard has comefrom the analysis of the microbiome and dominant intestinallipopolysaccharide (LPS) of a large-scale Russian and Finishinfant cohort [111]. This study demonstrated that childrenraised with a particular type of LPS were far less likely todevelop diseases of autoimmunity and atopy. Moreover, re-search has shown that exposure to pets and farm animals inchildhood breeds microbiome diversification [112, 113] andis associated with reduced risk of atopy and other non-communicable diseases later in life [114], suggesting thatthe hygiene hypothesis may now be more appropriatelytermed the microbiome hypothesis [115]. The foundationsof the hygiene hypothesis are thought to hinge on the adap-tive immune system TH1 and TH2 population balance [116].While the microbiome has been repeatedly shown to interactwith the adaptive immune system through lamina propriaTreg and TH17 populations [117], strong evidence is some-what more scarce for a direct TH1 and TH2 effect. Therefore,one must be cautious in implicating the microbiome in thisphenomenon; however, several authors have regularly ex-plored this concept in greater detail [118, 119] and we mustnot dismiss the significant biological plausibility which re-mains in favour of this theory.

The adaptive immune system appears to be a key regula-tor of several non-communicable disease states and onewhich is readily modulated by certain members of the gutmicrobiome and their metabolites. The detection of certaincommensal or probiotic-derived metabolites can modulatemucosal associated T cell maturation [120], in some casespromoting the creation of tolerogenic dendritic cells. This inturn, induces the differentiation of T cells to IL-10-secretingTreg populations that can interact with the innate immune

Fig. 4 Schematic representation of the general current understanding ofintestinal eubiosis and dysbiosis. It is important to note that this schematicrepresentation only shows a generic understanding of dysbiosis andeubiosis. At the phylum level, for example, the ratio Firmicutes,Bacteroides/Proteobacteria and Actinobacteria might differ in certaindiseases with which dysbiosis has been associated. The central part of

the figure illustrates the functions of the gut microbiome that are yet tobe elucidated by advanced techniques such as metatranscriptomic,metagenomic, proteomic and metabolomic analyses, which can possiblyestablish causation rather than association in the near future. Singleasterisk symbol represents indigenous microorganisms with pathogeniccapacity, which under normal circumstances are kept at low levels

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system to shift the polarisation of macrophages towards al-ternatively activated anti-inflammatory M2 populations[121, 122]. This tonal shift defers the immune system awayfrom the classically activated M1 population, which isknown to be deeply involved in the process of atherogenesis(Fig. 3) [123]. One such commensal antigen is the zwitter-ionic polysaccharide A produced by Bacteroides fragilis,which has been shown to direct the differentiation of Tregcells through the stimulation of TLR2 [124]. Indeed, suchimmunomodulation could have beneficial downstream ef-fects on macrophage polarisation and atherogenesis.Conversely, the influx of potentially harmful inflammatoryantigens through the malfunctioning intestinal tight junc-tions associated with metabolic dysfunction primes inflam-matory dendritic cells [125], resulting in the induction ofTH1 through secretion of IL-12 [126]. These TH1 popula-tions can, in turn, polarise classically activated M1 macro-phages through interferon (IFN)-γ, which secrete proinflam-matory TH17-promoting cytokines, further propagatingchronic inflammation and atherogenicity. These pathwaysdemonstrate the manner in which commensal organismscontribute to host immunological function and tolerance.

Dysbiosis of the Gut Microbiota

Under normal circumstances, the gut microbiota and the hu-man host maintain a mutualistic symbiotic relationship inwhich both benefit one another (eubiosis). However, whenthis relationship becomes disrupted (dysbiosis), health con-sequences may arise [127]. In general, dysbiosis refers toabnormalities of the microbiota that result in negative effectsupon the host. Nevertheless, the use of the term ‘dysbiosis’has been shown to be inconsistent across studies and it issubject to misinterpretation. Hooks et al. [128] conducted aquantitative and qualitative analysis of contemporarydysbiosis statements based on a PubMed abstract search thatincluded 554 articles. The authors found three main uses forthe term ‘dysbiosis’ in the context of the intestinalmicrobiome: (1) changes in the microbiota composition orloss of diversity; (2) imbalance in composition; and (3) spe-cific taxonomic changes, with the second definition beingthe most common one. They also found that ‘a growingnumber of authors believe that a shift to functional defini-tions of dysbiosis will be central to more specific causalattributions in microbiota research’ [128]. In line with this,we believe that dysbiosis should not only be based on taxo-nomical changes and composition, but also on functionality,as assessed by functional potential and functional outputanalyses (metagenomics and metatranscriptomics, respec-tively) [1]. Figure 4 illustrates the general current under-standing of intestinal eubiosis and dysbiosis.

Conclusion

The intestinal microbiota represents a diverse and complexecosystem of microbes which associates and interacts inti-mately with host physiology. Herein, we have attempted tosynthesise the relevant current knowledge around this interac-tion between microbe and man, by reviewing the availablepre-clinical and clinical literature. Our intestinal microbiotais a plastic and ever-evolving system which is vulnerable ininfancy and uniquely shaped by factors and perturbations suchas genetic predispositions and environmental exposures, espe-cially those that characterise modern societies such as ultra-processed foods and pharmaceutical interventions. Such alter-ations in the composition and functionality of the microbiomecan, in turn, carry with them implications for host health anddisease. This review has explored the role of the intestinalmicrobiota in the education and maturation of host immunity,in the modulation of chronic low-grade inflammatory disor-ders and in interactions with host neurological pathways.

Compliance with Ethical Standards

Conflict of Interest The authors declare that they have no conflict ofinterest.

Ethical Approval N/A

Informed Consent N/A

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