The commensal microbiota, most of which is resident within the colon, has become a focus of convergent interest from once separate fields. Arguably, the microbiota is a form of testimony to the unity of knowledge or consilience . Contributions to the body of knowledge of the microbiota have been generated by gastroenterologists, nutritionists, microbiologists, immunologists, molecular biologists, systems biologists, anthropologists, bioinformaticists and many others. The microbiota has attracted commercial interest from both the food and pharmaceutical sectors, and its relevance to human health and to animal husbandry is increasingly apparent. The scale and scientific importance of this field is shown by the accelerating rate of publications addressing host–microbe interactions within the gut over the past decade . The point of inflexion on this exponential rise was probably the application of metagenomics and high-throughput sequencing, whereby the composition of the microbiota can be analysed molecularly without needing to culture the individual components. Clinicians who are perplexed by the techniques used to study the gut microbiota are referred to a useful guide . In addition to technological advances, several factors have driven the research, and these include the discovery of Helicobacter pylori as a cause of peptic ulceration, the contribution of the microbiota to the pathogenesis of inflammatory bowel disease and to extraintestinal immune and metabolic disorders, the impact of antibiotics on the microbiota and the emergence of opportunistic organisms, such as Clostridium difficile. In this overview, the major themes and developments within the past year will be emphasized; readers are referred to other recent reviews for specific aspects of the field or for earlier work and for other perspectives [4–9].
HOST–MICROBE SPATIAL RELATIONSHIPS
The fecal microbiota has been a surrogate for the colonic microbiota in most studies. Although there is lingering debate regarding differences between the luminal versus the mucosa-adherent microbiota , it may be more noteworthy that host–microbe interactions within the colon differ in several respects from those in the proximal gut. First, the colonic microbiota greatly exceeds that of the small bowel with a transition across the ileocecal valve of several log fold in total bacterial numbers and in degree of diversity . Second, although host–microbe interactions are bidirectional and continually required for mucosal homeostasis, direct contact by bacteria with the surface epithelium is restricted. This is attributed to a physical barrier of mucus and a functional barrier created by epithelial production of antimicrobial factors, such as defensins and REGIIIγ [10▪,11]. Colonic mucus has an inner stratified and firmly attached layer that is devoid of bacteria and a looser outer layer of variable thickness that is associated with bacteria, whereas small intestinal mucus is a single-layered incomplete barrier [12▪▪]. In the small intestine in which structure/function adaptation favours nutrient absorption over a large surface area, antimicrobial factors, and REGIIIγ, in particular, may be more important in controlling spatial segregation of the microbiota from the surface epithelium [10▪].
Further compartmentalization of the commensal microbiota is mediated by the immune system. Low levels of translocation may occur from proximal and distal gut, including transepithelial uptake by dendritic cells and by M cells overlying lymphoid follicles, but access to the systemic circulation is limited by the immune system with the mesenteric lymph node acting as a gatekeeper and a site from which an acquired immune response may be regulated or amplified .
HOST–MICROBE AGE-SENSITIVE RELATIONSHIPS
Timing of exposure to the microbiota is critical not only for optimal development and maturation of the immune response but also for protection against later development of immunoallergic disease. The gut microbiota is required for education of the mucosal [14,15] and the systemic immune response [16–18]. This is age sensitive; disturbance of the microbiota at a critical time when the immune system is maturing, as might be caused by antibiotics in infancy, increases the risk of development of immunoallergic disorders like asthma [19▪,20▪] and pediatric inflammatory bowel disease [21▪,22].
At the other end of the age spectrum, host–microbe relationships are also important for health and avoidance of disease. The microbiota in elderly humans differs from that of younger adults and exhibits a high degree of interindividual variation . More importantly, a study of the composition of the fecal microbiota in a large population of elderly patients in different living conditions has revealed important correlations with the quality of dietary intake and with markers of health and disease including parameters of frailty, nutritional status and levels of proinflammatory cytokines [24▪▪]. The microbiota of those in long-stay care was significantly less diverse than that of community dwellers. Loss of community-associated microbiota correlated with increased frailty. The findings underscore the importance of ensuring dietary diversification in the elderly.
RECIPROCAL MICROBE–HOST SIGNALLING
Although direct contact between microbes and host cells is limited, signalling from the microbiota involves several different pathways and a range of bacterial metabolites [4–7,11]. The latter includes short-chain fatty acid, for which the colonic epithelium expressed G protein-coupled receptors and which transduce a downregulatory influence on inflammatory responses . Short-chain fatty acids, such as acetate, may also have a direct protective effect against enteric pathogens , whereas other immunomodulatory bacterial products include ATP, CpG DNA and polysaccharides. An example of the latter is polysaccharide A produced by the commensal Bacteroides fragilis, and which signals through Toll-like receptor 2 (TLR2) on regulatory T cells to suppress an adverse immune response, thereby favouring colonization [27▪▪]. In the small bowel, the microbiota initiates a sequence of molecular events leading to vascular remodelling, by glycosylation of tissue factor localized to the enterocyte surface .
Signalling is bidirectional, and the conditioning influence of host immunity on the microbiota is particularly evident in the setting of deficiencies of innate immunity [29,30,31▪]. Thus, alterations in the immune response lead to changes in the composition of the microbiota that can transfer inflammatory (‘colitogenic’) or metabolic phenotypes upon fecal transplantation.
MICROBIAL DIVERSITY: FROM ENTEROTYPES TO GRADIENTS
The composition of the gut microbiota is characterized by marked variability and distinctiveness in different individuals. This variability arises primarily at species and strain levels, whereas over 90% of the gut bacteria are members of just two phyla, the Bacteroidetes and Firmicutes, the relative proportions of which exhibit a continuous gradient within the human population [23,32]. Considerable media attention was generated by a study suggesting that variation at species level may be discontinuous with three apparent clusters or ‘enterotypes’ identified by enrichment in Bacteroides (enterotype 1), in Prevotella (enterotype 2) and in Ruminococcus (enterotype 3), each independent of nationality or host characteristics such as BMI, age or sex [33▪]. In a separate study, two of the enterotypes have been associated with long-term diets enriched for protein and animal fat (Bacteroides) or carbohydrate (Prevotella) [34▪], but the Ruminococcus enterotype was not well defined. More recently, the concept of distinct enterotypes has come under further scrutiny with several investigative groups now favouring a continuum or gradient of species functionality rather than discontinuous variation [24▪▪,35–38].
MICROBES, IMMUNITY AND METABOLIC HEALTH
Several studies attest to the impact of diet and nutrition on the microbiota [8,9,24▪▪,34▪,39,40,41▪,42▪▪,43]; diet also directly influences immune  and metabolic function. Indeed, microbial, immunologic and metabolic interactions represent a signalling triad with each segment being influenced by diet. A remarkable example of this microbial-immune metabolic trialogue is embodied in a study describing how intestinal bacteria regulate metabolism and immunity through an immunoglobulin A-dependent mechanism [45▪▪]. The clinical relevance of these interactions has escalated because of evidence linking host–microbe interactions with metabolic disorders including diabetes, obesity-related conditions and atherosclerosis (reviewed in [8,9]). Perhaps the most striking aspect of the link between the microbiota and metabolic welfare of the host has been the discovery of a metabolic pathway within the microbiota which converts dietary phosphatidylcholine to metabolites that contribute to hepatic steatosis in mice  and to human atherosclerosis [47▪▪].
THE MICROBIOTA IN IRRITABLE BOWEL SYNDROME
The heterogeneity of functional bowel syndromes, including the uncertainty of whether the primary problem lies centrally, peripherally or at both locations, may have contributed to inconsistency and conflicting data on potential biomarkers. In addition, several research groups have contributed evidence in support of bidirectional peripheral–central communication tantamount to a microbiota–brain–gut axis (reviewed in ).
Despite the challenges, impressive alterations in the composition of the fecal microbiota have been demonstrated in subsets of pediatric and adult patients with irritable bowel syndrome using molecular-based techniques [49–51]. Long-term follow-up studies are now awaited to clarify whether the microbial patterns identify true subsets of disease. In the interim, circumstantial support for the biological significance of these microbial changes has been provided by evidence for activation of host innate immunity including differential mucosal expression of TLRs in some patients . The therapeutic implications of microbial alterations in irritable bowel syndrome are uncertain but may underlie evidence for the efficacy exhibited by some, but not all, probiotics in this condition (reviewed in ). In addition, although early studies of bacterial overgrowth in irritable bowel syndrome, based largely on breath testing, have not found widespread confirmation, the efficacy of the locally active, nonabsorbed antibiotic rifaximin merits further investigation .
PATHOBIONTS, INFLAMMASOMES AND INFLAMMATION
Much of the epidemiology and pathogenesis of inflammatory bowel disease from a microbial perspective have been summarized recently . Models for microbial participation in the pathogenesis of inflammatory bowel disease have broadened from those based on a ‘one microbe-one disease’ concept towards more complex host–microbe interactions with some commensals or groups of commensals becoming pathogenic in certain contexts depending on host susceptibility [5,55]. Such organisms have been termed ‘pathobionts’ . The complexity of the interplay amongst host susceptibility factors, such as the genetic risk factor ATG16L1, host immune response to the microbiota and timing of exposure to different environmental triggers, such as an enteric norovirus or chemical injury, has been elegantly shown in a murine model . Such studies have important implications for the onset of disease in humans and why some, but not all, of those at risk manifest disease.
More recently, a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, was linked with a selective alteration in microbiota composition with expansion of the sulphite-reducing pathobiont, Bilophila wadsworthia, and colitis in interleukin-10-(IL10−/−) deficient mice. Colitis was mediated by a proinflammatory T-helper type 1 response [42▪▪]. It appears that milk-derived fat promotes taurine conjugation of bile acids, thereby increasing the availability of organic sulphur for reduction by B. wadsworthia. It is unclear whether this finding will translate fully to humans, as human bile is conjugated predominantly with the nonsulphur-containing glycine rather than taurine [42▪▪]. However, the findings provide a mechanistic link between a defined dietary change and increased risk of colitis due to a selective alteration in the commensal microbiota and might have a bearing on the increased risk of inflammatory bowel disease in those consuming a western-type diet.
In addition to dietary changes, antibiotics may also promote the emergence of pathobionts. A multidrug resistant Escherichia coli pathobiont causing a sepsis-like syndrome upon gut injury in antibiotic-treated mice has been described [58▪]. The model is reminiscent of the sepsis syndromes in humans undergoing combination therapy with antibiotics and cytotoxic drugs that injure the gastrointestinal epithelium. Results showed that the sepsis-like syndrome resulted from interaction between the pathobiont and the Naip5-Nirc4 inflammasome, which led to IL-1β-driven disorder.
Inflammasomes are major regulators of host innate immunity; in the gut, they may have a regulatory or conditioning influence on the composition of the microbiota. They are multiprotein complexes that serve as intracellular sensors of danger-associated or damage-associated molecular patterns. Deficiency of the NLRP6 inflammasome has yielded an insight to how the colonic epithelium may distinguish dangerous organisms from harmless commensals [31▪]. Normally, the epithelum responds to danger signals from the microbiota by mobilizing the NLRP6 inflammasome which activates caspase-1 and downstream generation of proinflammatory cytokines and a bacteriocidal immune response. When this response is defective, an altered and transferrable ‘colitogenic’ microbiota emerges with an increased rate of colitis-associated tumorigenesis [31▪,59]. In apparent contrast to this protective role of NLRP6 against colitis, there is evidence that the same inflammasome may have an adverse role in other settings, such as bacterial infections, by dampening host responses against several bacterial pathogens and impeding their clearance . Thus, the role of inflammasomes is complex; neither is it limited to the regulation of inflammation and responses to infections, with an emerging role for some inflammasomes in metabolic disorders also [61▪].
THE MICROBIOTA AND COLON CANCER
An intriguing role for the colonic microbiota in the metabolism and toxicity of a chemotherapeutic agent, CPT-11, commonly used in treating colon cancer, has been elegantly demonstrated . More recently, a role for the microbiota in contributing to the pathogenesis of colorectal cancer has also been raised. There is now an extensive list of infectious agents linked with cancers worldwide , and various models of bacterial involvement in the genesis of colorectal cancer have been proposed [64,65]. This follows on studies of colorectal cancer-associated microbiomes and, in particular, studies linking Fusobacterium species, particularly Fusobacterium nucleatum with the disease [66,67▪]. Whether these organisms participate at initiation, progression or as passengers is uncertain, but Fusobacterium species have been linked with human disease before, including acute appendicitis and inflammatory bowel disease [68–70].
C. DIFFICILE AND FECAL TRANSPLANTATION
Several factors have conspired to exacerbate the burden on health services posed by C. difficile-associated disease (CDAD). These include increasing frequency, increasing antibiotic resistance, emergence of hypervirulent strains (such as NAP1/B1/027) and recurrence rates of about 20–25%. Retrospective analysis has suggested a potential protective role for the vermiform appendix because higher rates of recurrence have been observed after appendectomy . It is unclear whether this is due to the immune function of the appendix or whether this curious little organ acts as a sanctuary for the microbiota, from which the colon may be repopulated after disruption from antibiotics, disease or phage viruses .
Therapeutic repopulation of the colonic microbiota by fecal transplantation is an old remedy but attracting much interest lately because of the high rates of recurrence of CDAD. To borrow from Shakespeare: ‘Diseases desperate grown By desperate appliance are reliev’d, Or not at all’ (Hamlet IV, iii). Positive clinical responses have been claimed for the majority of patients, although a rigorous controlled trial has not been reported to date, and there is wide variation in procedural details . To address this, a standardized preparation and protocol has been described . Others are exploring the possibility of devising a ‘minimal microbiota’, the constituents of which would be well characterized, so that the potential risks of the procedure, including other transmissible diseases, can be minimized.
The colonic microbiota is no longer a footnote in microbiology texts or an esoteric topic for gastrointestinal physiologists. It has moved centre stage in clinical medicine, it is of direct relevance to a range of infectious, inflammatory, neoplastic and metabolic disorders within the colon and at extracolonic sites. The predominant focus has been on bacteria, but work on the virome and the fungal elements within the gut is beginning to expand and likely to feature the next time this topic is covered in this journal. Although therapeutic manipulation of the microbiota is biologically plausible, attention is likely to focus on dietary manipulation of the microbiota with a view to prevention of many disorders. The challenge will be to identify and match host resistance/susceptibility factors with microbial patterns that positively and negatively influence disease risk.
The author is supported in part by Science Foundation Ireland.
Conflicts of interest
F.S. is affiliated with a multidepartmental university campus company, Alimentary Health Ltd. which investigates inter alia host–microbe interactions. The content of this study was neither influenced nor constrained by that fact. F.S. is supported, in part, by Science Foundation Ireland.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 100–101).
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