SN Comprehensive Clinical Medicine

, Volume 1, Issue 3, pp 188–199 | Cite as

The Gut Microbiota: A Clinically Impactful Factor in Patient Health and Disease

  • David Avelar RodriguezEmail author
  • Rubén Peña Vélez
  • Erick Manuel Toro Monjaraz
  • Jaime Ramirez Mayans
  • Paul MacDaragh Ryan
Part of the following topical collections:
  1. Topical Collection on Medicine


The gut microbiota, often referred to as the body’s virtual organ, is a complex ecosystem made up of trillions of microorganisms that interact with host physiology in a myriad of ways. This lifelong interaction begins in the early stages of life, and it is subject to alterations exerted by environmental factors, especially those that characterise modern societies such as ultra-processed foods and pharmaceutical interventions, amongst others. These alterations, in turn, carry with them implications for host health and disease. Due to this putative role in human health and the fact that study of the gut microbiota is now rapidly evolving, it is of paramount importance that all clinicians be aware of the most up-to-date literature in this field. Herein, we present a state-of-the-art review which 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.


Gut microbiota Intestinal microbiota Gut microbiome Gut microbiota Dysbiosis 


Since the beginning of the twenty-first century, the gut microbiota has been the centrepiece of research amongst different disciplines around the globe [1, 2]. The gut microbiota, often referred to as the body’s virtual organ [3], is a uniquely complex ecosystem consisting of approximately 100 trillion microorganisms, which includes bacteria, viruses, fungi and protozoa. [4] As its name indicates, the gut microbiota resides in the 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 from about 104/mL content in the stomach and duodenum, to approximately 1011/mL content in the colon [6].

The gut microbiota genesis begins in early stages of life and it is further shaped by a series of external factors, such as mode of delivery, pharmaceuticals, diet, exercise and air pollution [4, 7, 8, 9, 10, 11]. Dysbiosis of the gut microbiota has been implicated in multiple non-communicable disease states, such as obesity [12], atopy [8], autoimmunity [13] and malignancy [14], amongst others. In contrast, a ‘healthy’ microbiota appears to provide a plethora of beneficial effects to the host, resulting in a degree of protection and better health outcomes overall [3, 8, 15]. In light of such associations, and persuasive novel clinical data, it is now crucial for clinicians to become familiar with the fundamental concepts of gut microbiota research (see Table 1 for the glossary of terms), as well as the potential implications of this research for their patient cohorts. This article represents a state-of-the-art review and aims to present the essential aspects of the gut microbiota, focusing primarily on the factors which impact upon its development and its functions with respect to host health and disease.
Table 1




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 microbial DNA and sequenced to generate a census of what microbes are present and in what relative proportions.

Shotgun metagenomic sequencing

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.


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


The degree of variation in taxa compositions between samples

Search Strategy and Selection Criteria

In August 2018, we systematically searched the PubMed/MEDLINE, ResearchGate, Mendeley and Google Scholar databases using the terms ‘intestinal microbiota’, ‘intestinal microbiome’, ‘intestinal microflora’, ‘gut microbiota’, ‘gut microbiome’, ‘intestinal dysbiosis’ and ‘gut dysbiosis’. For individual sections, we built search blocks using Boolean operators (e.g. intestinal microbiota AND obesity). We considered experimental studies, reviews, systematic reviews and meta-analyses, and no date range was specified. The last literature search was conducted on November 29, 2018.

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

Whether the acquisition of the gut microbiota takes place at birth (‘sterile womb hypothesis’) or in utero (‘in utero colonisation hypothesis’) remains a controversial topic (Fig. 1; for review, see [16, 17]). However, the former has been recently challenged by an increasing number of studies in which, contrary to previous belief, the placenta and amniotic fluid have been found to harbour a microbiome, strongly suggesting that the genesis of the gut microbiome occurs in utero [18, 19, 20, 21, 22, 23].
Fig. 1

Illustration of the two proposed theories by which the gut microbiota is established. a The sterile womb hypothesis argues that the uterus and foetus are sterile and that the infant alimentary tract is colonised during birth by the mother’s skin (caesarean delivery) or vaginal microbiota (vaginal delivery). b In utero colonisation hypothesis. It has been postulated that the mother’s gut microorganisms are selectively transported to the placenta, which consequently colonise the foetus alimentary tract in utero. [17] Aagaard et al. [16] investigated the microbiome of different body site niches (oral, skin, nasal, vaginal) in nonpregnant subjects and found that, of these body sites, the oral microbiota was the most akin to the placenta, suggesting a possible source of colonisation; however, the mechanism through which the bacteria reach the placenta was not elaborated. In line with these findings, a more recent study by Gomez-Arango et al. [20] found that the placental microbiome was most similar to the mother’s oral microbiome, but less alike to the maternal gut microbiome. In contrast, Ferretti et al. [19] found that the maternal gut microbiome was the largest donor of the infant gut microbiome, whereas the least common source of colonisation was the mother’s oral cavity. Although these findings are contradictory in regard to the seeding sources, they all support the notion that the acquisition of the infant gut microbiome potentially occurs in utero. Created with BioRender

The first 3 years of life represent a crucial time period for the development of the gut microbiota, which includes a variety of factors that determine its composition, such as mode of delivery, gestational age, diet and pharmaceutical interventions [8, 9, 24, 25, 26, 27]. Some authors consider this time a ‘window of opportunity for microbial modulation’ [20], as the child is exposed to a multitude of external factors with microbiota-modifying potential [4, 28]. During the first year of life, its composition is characterised by reduced diversity and stability as compared with the adult microbiota. By 2.5 to 3 years of age, an adult-like microbiota is fully established (i.e. Bacteroidetes and Firmicutes predominance, although each individual harbours an entirely unique composition) [4, 5, 8]. Interestingly, the functions of the gut microbiota and its genetic machinery (the intestinal microbiome) undergo major changes as solid foods are introduced. During the weaning process, 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 complex one with degradative and synthetic properties [8, 29]. The human gut microbiota comprises four predominant phyla across the lifespan: Actinobacteria, Firmicutes, Bacteroidetes and Proteobacteria. Generally speaking, the phylum Actinobacteria predominates during the first 3 years of life and substantially decreases after weaning. As Actinobacteria decreases, Firmicutes increases, representing the most numerous phylum throughout life. Furthermore, the relative abundance of Bacteroidetes remains relatively stable up to 70 years of life and thereafter increases gradually. Proteobacteria, on the other hand, mirror—although in a lesser percentage—Actinobacteria and Bacteroidetes during the first 3 years of life and from 70 years of age onwards, respectively [30].

Mode of Delivery

Multiple studies have shown that the development of the infant’s gut microbiota is significantly shaped by mode of delivery [31]. Vaginally delivered infants are thought to undergo a ‘bacterial baptism’ during birth [32]. Thus, their microbiota resembles the mother’s vaginal flora (e.g. Lactobacillus, Prevotella and Sneathia), displaying a more diverse microbiota and a greater number of Bacteroides and Bifidobacterium than their caesarean-delivered counterparts. On the other hand, infants delivered by caesarean section bypass this vaginal ‘bacterial baptism’, and their microbiota more closely resembles that of their mother’s skin flora (e.g. Staphylococcus, Corynebacterium and Propionibacterium) [4, 26, 33, 34]. Nonetheless, these main discrepancies generally persist only up to 6 months of age, and the microbiota composition of both groups tends to converge thereafter [31, 35, 36]. The resultant microbiota changes in caesarean-born children, particularly the lower numbers of Bacteroides and Bifidobacterium, may increase the risk of allergic diseases such as asthma [37] and allergic rhinitis [8, 35]. Although it is important to note that the mode-of-delivery factor does not seem to affect the microbiota diversity and composition of preterm neonates [38].

Gestational Age

Preterm neonates have a decreased number of Bifidobacterium spp. and their microbiota exhibits less diversity as compared with term neonates. These discrepancies are the result of a multifactorial process wherein more than one external factor may coexist (namely, delayed enteral feeding, use of total parenteral nutrition and maternal and neonatal prophylactic antibiotic therapy) [15, 35]. In addition, preterm neonates may have higher levels of potentially pathogenic bacteria (Proteobacteria bloom) and multi-drug-resistant bacteria, such as Escherichia, Klebsiella and Enterobacter species [20, 35]. Intestinal dysbiosis in preterm neonates has been implicated in the pathogenesis of life-threatening necrotising enterocolitis (NEC) [39]. A recent systematic review and meta-analysis [40] found that dysbiosis characterised by an increase in phylum Proteobacteria and a decrease in Firmicutes and Bacteroidetes preceded NEC in preterm neonates. Moreover, late-onset sepsis (LOS) represents another common complication in preterm neonates, which has been associated with gut dysbiosis characterised by depleted numbers of Bifidobacteria and a Proteobacteria bloom [41, 42, 43]. Though it is important to mention that these studies had a small sample size and antibiotics were administered to nearly all neonates; thus, the microbial composition present in these neonates appears to be the result of antibiotic administration rather than gestational age itself. Furthermore, increasing evidence suggests that probiotics may decrease the incidence of NEC and LOS in preterm neonates [44, 45], and emerging modalities such as ‘para-probiotics’, inactivated forms of microbial therapeutic, could become safe alternatives to probiotics in neonates, although these are yet to be evaluated in clinical studies [46]. Moreover, a recent study that used 16S rRNA amplicon sequencing to analyse the gut microbiota of 45 breastfed very low birth weight preterm infants, suggested that hospitalised preterm infants receiving breast milk may develop a microbiota resembling that of term neonates [47]. These findings emphasise the importance of human milk and the window of opportunity for preterm infants to possibly develop a ‘normal’ gut microbiota and to catch up with their full-term contemporaries.

Feeding Type and Diet

During the first days of life, facultative anaerobic bacteria such as Escherichia coli, Enterococcus and Staphylococcus colonise the infant alimentary tract. Thereafter, the depletion of oxygen and the presence human milk oligosaccharides shift the microbiota composition to anaerobic bacteria, such as Bacteroides, Bifidobacterium and Clostridium spp. [9, 20, 21]. Human milk is a dynamic and bioactive fluid that contains macronutrients, micronutrients and immunologic and bioactive factors [48]. The presence of oligosaccharides in human milk (e.g. galactooligosaccharides) is a key for the development of the infant’s gut microbiota, particularly through growth stimulation of colonic Bifidobacterium longum [8, 20, 49]. Moreover, the infant’s alimentary tract is further colonised by the human milk microbiota (mainly streptococci and staphylococci), which has been shown to be a significant source of bacterial colonisation [50]. Infant formula, on the other hand, is sterile and thus lacks this natural feature [20, 35]. Even maternal diet can influence the infant microbiota composition through vertical transfer during breastfeeding [51]. Thus, breastfed infants have a Bifidobacterium and Lactobacillus predominance and display a more stable and diverse microbiota than formula-fed infants [4, 15].

The composition of the gut microbiota continues to experience changes throughout life, mainly induced by dietary habits. For example, the Western-style diet, characterised by low-fibre, high-fat, refined carbohydrate content and ultra-processed ingredients, negatively influences the gut microbiome [52]. De Filippo et al. used high-throughput 16S rRNA sequencing and biochemical analyses to study the microbiota composition of European children and African children from the Burkina Faso village, whose dietary habits resemble those of the Neolithic period, characterised by high-fibre content. The authors found that, compared with European children, African children exhibited an increased number of Bacteroidetes and a low number of Firmicutes, were colonised with unique bacteria from the genus Prevotella and Xylanibacter (which are known to metabolise dietary fibres readily) and exhibited increased short-chain fatty acid (SCFA) production [53]. Furthermore, observational studies have demonstrated lower microbial diversity in the adult American microbiota compared with people living in rural areas such as Malawi and Venezuela [54]. Interestingly, a novel study [55] that used 16S and deep shotgun metagenomic DNA sequencing to evaluate the gut microbiota of immigrants from non-Western countries who migrated to the USA, found that, these subjects not only experienced a decrease in microbial diversity and plant-fibre degradation ability, but also experienced a shift from the non-Western-associated genus Prevotella to the Western-associated genus Bacteroides (which may explain the reduction in fibre degradation). The authors found that this phenomenon, which has been referred to as ‘microbiome Westernisation’, begins within 9 months of immigration. A recent meta-analysis [56] of shotgun metagenomic datasets compared the gut microbiome of healthy adults across different countries, including 13 industrialised societies and two hunter-gatherer, pre-agricultural communities. The authors concluded that the urbanisation/industrialisation process and resultant dietary changes have shaped the gut microbiota, particularly through the acquisition and/or loss of specific microbes, such as Barnesiella intestinihominis and Treponema succinifaciens. Moreover, non-caloric sweeteners are increasingly being used in many processed foods in Western-style diets, mainly because they enhance flavours and have been shown reduce the risk of obesity [57]. However, they can induce negative changes on the gut microbiota, as shown in murine models in which a reduction in beneficial bacteria after administration of sucralose and saccharin was demonstrated [58]. Indeed, these microbiota-modifying attributes may carry important implications for host health in the longer term. Dietary polyphenols, on the other hand, have been found to stimulate the growth of beneficial bacteria and inhibit the proliferation of pathogenic bacteria [3, 59]. Taken together, these findings highlight the role of diet in shaping the microbiota composition across different ethnicities and geographies, especially the negative impact of the Western-style diet and industrialisation upon the gut microbiota.

Pharmaceuticals and the Gut Microbiota

Antibiotics are the most prescribed drugs in neonates and children in the USA [29]. They not only cause bacterial resistance, but also affect the development and composition of the gut microbiota throughout life [15, 34, 35, 60]. Antibiotic treatment in neonates, most commonly gentamicin and ampicillin [29], has been associated with a decreased number of Bifidobacteria which can persist up to 8 weeks of life after treatment [20, 29]. Even maternal intrapartum antibiotic prophylaxis (IAP) can alter the neonate’s gut microbiota; infants whose mothers received IAP display a less diverse microbiota as compared with those whose mothers did not [61]. A recent study that used shotgun sequencing-based metagenomics to analyse the microbiota of healthy young adults before and after administration of a 4-day course broad-spectrum antibiotic cocktail (meropenem, gentamicin and vancomycin) found that, in fact, there was a depletion of Bifidobacterium spp. and other butyrate-producing bacteria within 8 days after cocktail administration. In addition, the study reported an increase in low-abundance commensals such as Escherichia coli, Veillonella spp. and Klebsiella spp., and by 1.5 months, the microbiota of all patients recovered to near baseline. The authors concluded that the gut microbiome of young, healthy adults are resilient to a 4-day broad-spectrum antibiotic treatment, which is modulated by antibiotic resistance genes—also known as the ‘resistome’ [62]. Although antibiotics are known to significantly alter the intestinal microenvironment, they are frequently a lifesaving intervention when used judiciously.

Despite our reasonably extensive understanding of the manner in which antibiotics manipulate the intestinal microbiota, we are only now beginning to recognise the sizeable impact which other commonly prescribed medications have on even the established adult microbiota. Several recent clinical studies have highlighted the effects of proton pump inhibitors on the composition and functionality of the intestinal microbiome [63, 64], while metformin has received considerable attention for its potentiating effects on the metabolic health–associated microbe Akkermansia muciniphila [65, 66]. The study of a combined Belgian-Dutch cohort of extensively phenotyped participants revealed a far more inclusive list of microbiota-modulating pharmaceuticals, including osmotic laxatives, antidepressants, female hormone therapies and TNF-alpha inhibitors [67]. Furthermore, the British TwinsUK study, perhaps the most highly powered study of this kind, recently went on to assess microbiota associations for 51 commonly prescribed medications [68]. The authors uncovered a plethora of associations, or rather associated perturbations, with the most commonly implicated compounds (i.e. proton pump inhibitors and antibiotics), but also with entirely unsuspected therapies, such as anticholinergic inhalers, paracetamol, SSRIs and opioids. Furthermore, chemotherapy has also been implicated in the disruption of the intestinal microbiota, which can lead to lower gut microbiota diversity and numbers of anaerobic beneficial bacteria [69].

Conversely, the metabolically active mass of enzyme-secreting microbes which comprises our intestinal microbiota is beginning to be considered as a structural and pharmacokinetics modifier of certain oral medicines [70]. These microbes are granted true first-pass metabolism and are capable of altering structure and function through oxidation, hydrolysis and dehydroxylation reactions, amongst others [71]. For example, the commonly prescribed inotrope digoxin is known to be inactivated by the intestinal microbe Eggerthella lenta, an undesirable attribute which is thought to contribute to the pharmacokinetic variability of the drug in vivo [72]. In addition, there is evidence to suggest that the modification of luminal bile acids by intestinal microbes has implications for drug solubility and absorption [73, 74]. The importance in genetic polymorphisms in drug metabolism and stratification of patients according to their likelihood of response to therapy is now an area of great interest; however, it seems likely that the individual microbiota of a patient may also be a significant contributor in this regard.


Recent evidence suggests that the human gut microbiota can be modulated by exercise (Fig. 2 demonstrates the factors that shape and alter the gut microbiota throughout life). A recently published systematic review of the literature available on the exercise-microbiota interaction in mammals [75] found a consistent diversification of the Firmicutes phylum and increase in butyrate production following implementations of exercise regimes. Such increases in SCFA production may indeed confer beneficial effects on the host system. In an attempt to assess the microbiome-modifying effects of exercise in previously sedentary lean and obese individuals, Allen et al. [10] enrolled participants in a supervised 6-week aerobic exercise regimen (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 acetate and butyrate) in the lean, which was not observed in the obese group. In addition, the authors found that the increase in faecal SCFAs paralleled improvements in body lean mass. These findings indicate key discrepancies in the manner in which lean and obese individuals may respond to exercise regimes. A recent observational study [76] compared the gut microbiome of professional international rugby players (athletes) with controls. The authors found that athletes displayed increased microbial diversity, metabolic pathways and faecal metabolites (including SCFAs) compared to the control group and that these parameters associated with enhanced fitness and health. These findings demonstrate another benefit of exercise and highlight its role in boosting the production of beneficial metabolites by the gut microbiota.
Fig. 2

Factors that shape and alter the gut microbiota throughout life. Created with BioRender

Functions of the Gut Microbiota

The intestinal microbiome is a relatively plastic and complex metabolic system which is most numerous and active in the lumen of the colon. This microbial mass of genetic potential provides a myriad of metabolic and immunoregulatory functions to the host, from fibre fermentation and vitamin production to education of our immature immune system [77, 78]. The seminal studies, which initially uncovered the vital role that our intestinal microbes play in normal systemic development, were conducted in ‘germ-free’ mouse models. These mice, which are delivered by caesarean section under sterile conditions, are maintained in an environment free of detectable microorganisms. Studies in germ-free mice have demonstrated the wide range of systemic and organ-specific deficiencies 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 immature innate immune system [83]. Taken together, this catalogue of critical dysfunctions indicates that our intestinal microbiome is in fact an essential factor in normal host development and health maintenance.

Metabolic Functions

Perhaps our first major reliance upon our intestinal microbiome 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 a sterile or near sterile gastrointestinal tract, standard care has long since required the administration of intramuscular vitamin K, until such point as the infant microbiome and diet are established. It would seem that this is the beginning of an intricate relationship played out between microbe and man for millennia.

As we mature, so too does the composition of our intestinal microbiome, as well as the functions with which it provides us. Diet begins to greatly determine the composition and, therefore, a significant degree of interpersonal variation is observed [85]. However, in general terms, the relative abundances of human milk oligosaccharide-metabolising Bifidobacteria begin to fall steadily, while fibre-fermenting anaerobes 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 metabolites likely initially garnered attention due to their relative ease of detection 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 range of effects upon host physiology. Although acetate is the most abundant of these fatty acids in circulation, current research suggests that it is comparatively inert in biological terms. Having said this, acetate participates in key biochemical 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 energy for colonic enterocytes, thereby bolstering the integrity of the enteric gut barrier and preventing the leakage of inflammatory microbial fragments, such as lipopolysaccharides [89]. Propionate, on the other hand, modulates hepatic gluconeogenesis [90] and is currently being evaluated in a phase II clinical trial for its ability to reduce low-density lipoprotein cholesterol in hypercholesterolaemia adults ( ID: NCT03590496). Each of these fatty acids appears to display varying degrees of affinity for the enteric G protein–coupled receptors GPR-41 and GPR-43 [91], both of which have been shown to promote the secretion of metabolically important gut hormones glucagon-like peptide (GLP)-1 and peptide YY (Fig. 3; for review, see [92]). Finally, there is evidence to suggest that SCFA may be of clinical importance due to their tight junction promoting effects, which reduces the influx of microbial fragments and the associated low-grade inflammation which is thought to disrupt normal host metabolic homeostasis [93].
Fig. 3

Immune and endocrine pathways through which the gut microbiota contributes to host homeostasis. The gut microbiota interacts intimately with host immune system maturation and metabolic function. This figure depicts several pathways through which the components of the microbiota can contribute to or attenuate systemic disease. LCA lithocholic acid, CA cholic acid, DCA deoxycholic acid, CDCA chenodeoxycholic acid, GLP-1 glucagon-like peptide-1, SCFA short-chain fatty acids, GPR41/43 G protein–coupled receptor 41/43, TJ tight junction, GIP gastric inhibitory polypeptide, PYY peptide YY, LPS lipopolysaccharide, iDC inflammatory dendritic cell, TH T helper cell, IFNγ interferon gamma, IL interleukin, M1 classically activated macrophage, M2 regulatory macrophage, Treg regulatory T cell, tDC tolerogenic dendritic cell, TLR4 toll-like receptor 4. Created with BioRender

Another promising pathway through which the intestinal microbiome is thought to interact with host physiology is the metabolism of bile acids. The presence of bile acids in the intestinal lumen represents a genuine ecological threat to microbial life [94]. Therefore, those microorganisms typically endemic to this hostile environment commonly express enzymes which render these corrosive molecules open to subsequent degradation or detoxification [95]. In doing so, the gut microbiome manipulates the composition of bile acids that pass through the small intestine and are readily reabsorbed into circulation [96]. Traditionally, the purpose of bile acids was considered to be limited to their role as lipid emulsifiers in the enteric lumen; however, we now realise that the multitude of bile acid entities that circulate through our bodies actually represents potent cell surface and nuclear receptor ligands [97]. Furthermore, the receptors in question are known to modulate 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 impact potently upon aspects of metabolic health by triggering the release of GLP-1 once activated by microbially modified bile acids (Fig. 3) [99]. Moreover, the bile acid nuclear receptor farnesoid X receptor is revealing itself as a target for the prevention of non-alcoholic fatty liver disease [100], suggesting a potential role for bile modifying microbes in the maintenance of hepatic health. Finally, there is even evidence to suggest that our gut microbiome may interact with and modulate host circadian rhythm genes through the modification of the circulating bile pool [101]. Taken together, these studies demonstrate that bile acids represent a putative language in the host-microbe crosstalk.

Neurological Functions

The gut microbiota is now recognised to secrete an intriguing group of metabolites which closely relate to the endogenous molecules that mediate human neuronal transmission and their precursors. These include compounds such as serotonin, tryptophan, kynurenine and ү-aminobutyric acid, amongst others [102, 103, 104]. These potentially neuroactive peptides form one of the arms of the gut-brain axis, a hypothesis that there exists a bidirectional crosstalk between the gut microbiome and host neurophysiology. In addition, significant emphasis has been placed on the potential role of the autonomic nervous system and in particular the vagus nerve, in the transmission of this crosstalk [105]. Finally, other microbial metabolites such as propionate have also recently been implicated in the maintenance of a healthy blood-brain barrier [106]. Despite the fascinating nature of this concept, insufficient clinical data is currently available to sway many clinicians at present; although recent data from APC Microbiome Ireland has revealed a potential role for targeted microbial therapies in the modulation of anxiety. The study demonstrated through both self-reporting survey and biochemical means that the touted ‘psychobiotic’ Bifidobacterium longum 1714 conferred anxiolytic effects upon the subjects [107, 108]. This data builds upon and translates the conclusions of previous pre-clinical studies, which have outlined the potential efficacy of such microbial therapeutics 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 microbial basis to the ‘gut feeling’ phenomenon.

Immunomodulatory Functions

The innate immune system combines with the intestinal epithelial barrier to act as the first point of contact for gut microbes, their associated metabolites and all ingested nutrients. In this respect, innate immunity represents one of the most important lines of communication in the host-microbe crosstalk. The endogenous microbes within our intestines act to educate our naïve immune system and to create a basal tolerance for non-pathogenic or commensal organisms [110]. In line with this, there is now good clinical evidence indicating 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 come from the analysis of the microbiome and dominant intestinal lipopolysaccharide (LPS) of a large-scale Russian and Finish infant cohort [111]. This study demonstrated that children raised with a particular type of LPS were far less likely to develop diseases of autoimmunity and atopy. Moreover, research has shown that exposure to pets and farm animals in childhood breeds microbiome diversification [112, 113] and is associated with reduced risk of atopy and other non-communicable diseases later in life [114], suggesting that the hygiene hypothesis may now be more appropriately termed the microbiome hypothesis [115]. The foundations of the hygiene hypothesis are thought to hinge on the adaptive immune system TH1 and TH2 population balance [116]. While the microbiome has been repeatedly shown to interact with the adaptive immune system through lamina propria Treg and TH17 populations [117], strong evidence is somewhat more scarce for a direct TH1 and TH2 effect. Therefore, one must be cautious in implicating the microbiome in this phenomenon; however, several authors have regularly explored this concept in greater detail [118, 119] and we must not dismiss the significant biological plausibility which remains in favour of this theory.

The adaptive immune system appears to be a key regulator of several non-communicable disease states and one which is readily modulated by certain members of the gut microbiome and their metabolites. The detection of certain commensal or probiotic-derived metabolites can modulate mucosal associated T cell maturation [120], in some cases promoting the creation of tolerogenic dendritic cells. This in turn, induces the differentiation of T cells to IL-10-secreting Treg populations that can interact with the innate immune system to shift the polarisation of macrophages towards alternatively activated anti-inflammatory M2 populations [121, 122]. This tonal shift defers the immune system away from the classically activated M1 population, which is known to be deeply involved in the process of atherogenesis (Fig. 3) [123]. One such commensal antigen is the zwitterionic polysaccharide A produced by Bacteroides fragilis, which has been shown to direct the differentiation of Treg cells through the stimulation of TLR2 [124]. Indeed, such immunomodulation could have beneficial downstream effects on macrophage polarisation and atherogenesis. Conversely, the influx of potentially harmful inflammatory antigens through the malfunctioning intestinal tight junctions associated with metabolic dysfunction primes inflammatory dendritic cells [125], resulting in the induction of TH1 through secretion of IL-12 [126]. These TH1 populations can, in turn, polarise classically activated M1 macrophages through interferon (IFN)-γ, which secrete proinflammatory TH17-promoting cytokines, further propagating chronic inflammation and atherogenicity. These pathways demonstrate the manner in which commensal organisms contribute to host immunological function and tolerance.

Dysbiosis of the Gut Microbiota

Under normal circumstances, the gut microbiota and the human host maintain a mutualistic symbiotic relationship in which both benefit one another (eubiosis). However, when this relationship becomes disrupted (dysbiosis), health consequences may arise [127]. In general, dysbiosis refers to abnormalities of the microbiota that result in negative effects upon the host. Nevertheless, the use of the term ‘dysbiosis’ has been shown to be inconsistent across studies and it is subject to misinterpretation. Hooks et al. [128] conducted a quantitative and qualitative analysis of contemporary dysbiosis statements based on a PubMed abstract search that included 554 articles. The authors found three main uses for the term ‘dysbiosis’ in the context of the intestinal microbiome: (1) changes in the microbiota composition or loss of diversity; (2) imbalance in composition; and (3) specific taxonomic changes, with the second definition being the most common one. They also found that ‘a growing number of authors believe that a shift to functional definitions of dysbiosis will be central to more specific causal attributions in microbiota research’ [128]. In line with this, we believe that dysbiosis should not only be based on taxonomical changes and composition, but also on functionality, as assessed by functional potential and functional output analyses (metagenomics and metatranscriptomics, respectively) [1]. Figure 4 illustrates the general current understanding of intestinal eubiosis and dysbiosis.
Fig. 4

Schematic representation of the general current understanding of intestinal eubiosis and dysbiosis. It is important to note that this schematic representation only shows a generic understanding of dysbiosis and eubiosis. At the phylum level, for example, the ratio Firmicutes, Bacteroides/Proteobacteria and Actinobacteria might differ in certain diseases with which dysbiosis has been associated. The central part of the figure illustrates the functions of the gut microbiome that are yet to be elucidated by advanced techniques such as metatranscriptomic, metagenomic, proteomic and metabolomic analyses, which can possibly establish causation rather than association in the near future. Single asterisk symbol represents indigenous microorganisms with pathogenic capacity, which under normal circumstances are kept at low levels


The intestinal microbiota represents a diverse and complex ecosystem of microbes which associates and interacts intimately with host physiology. Herein, we have attempted to synthesise the relevant current knowledge around this interaction between microbe and man, by reviewing the available pre-clinical and clinical literature. Our intestinal microbiota is a plastic and ever-evolving system which is vulnerable in infancy and uniquely shaped by factors and perturbations such as genetic predispositions and environmental exposures, especially those that characterise modern societies such as ultra-processed foods and pharmaceutical interventions. Such alterations in the composition and functionality of the microbiome can, in turn, carry with them implications for host health and disease. This review has explored the role of the intestinal microbiota in the education and maturation of host immunity, in the modulation of chronic low-grade inflammatory disorders and in interactions with host neurological pathways.


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The authors declare that they have no conflict of interest.

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Pediatric Nutrition and Gastroenterology DepartmentInstituto Nacional de PediatríaMexico CityMexico
  2. 2.School of MedicineUniversity College CorkCorkIreland

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