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Keywords:

  • Crohn's disease;
  • inflammatory bowel disease;
  • ulcerative colitis

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT
  5. A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE
  6. AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY
  7. THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS
  8. THE LANGUAGE OF HOST-MICROBE DIALOGUE
  9. THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE
  10. CONCLUSION
  11. Acknowledgment
  12. REFERENCES

Ulcerative colitis and Crohn's disease, collectively known as inflammatory bowel disease, represent the heterogeneous outcome of three colliding influences: genetic risk factors, environmental modifiers, and immune effector mechanisms of tissue injury. The nature of these inputs is complex, with each having distinct and overlapping contributions to ulcerative colitis and Crohn's disease. Identification of specific genetic risk factors has improved the understanding of specific pathways to disease, but the primacy of environmental or lifestyle factors linked to changes in the gut microbiota, particularly in early life, is increasingly evident. Clarification of the molecular basis of host-microbe interactions in health and in susceptible individuals promises novel therapeutic strategies.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT
  5. A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE
  6. AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY
  7. THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS
  8. THE LANGUAGE OF HOST-MICROBE DIALOGUE
  9. THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE
  10. CONCLUSION
  11. Acknowledgment
  12. REFERENCES

Ulcerative colitis and Crohn's disease are chronic relapsing and remitting inflammatory syndromes that are responsible for much personal suffering and a significant burden on healthcare resources. While ulcerative colitis and Crohn's disease are referred to as inflammatory bowel disease, this collective term tends to obscure the very distinct nature of these conditions. The limited repertoire of response to injury exhibited by all tissues, including the gut, means that different pathways of disease may share clinicopathologic features that may confound the differential diagnosis. Language may also hide other important distinctions. For example, ulcerative colitis is a poor descriptor because the mucosa seldom ulcerates, and when it does, it occurs only in patients with advanced, severe disease. An absence of ulceration with diffuse, uninterrupted mucosal inflammation from the distal to the proximal colon is the characteristic feature of ulcerative colitis, whereas ulceration is an early and characteristic feature of Crohn's disease. Indeed, the presence or absence of ulceration probably accounts in large part for the restriction of inflammation to the colonic mucosa in colitis, while Crohn's disease is frequently more penetrating, with attendant complications.

In addition to shared and separate clinicopathologic features, the genetic, environmental, and immunologic contributions to ulcerative colitis and Crohn's disease are also distinct and overlapping. The purpose of this overview is to provide a perspective on the central role of the gut microbiota as an environmental risk factor for inflammatory bowel disease in susceptible individuals. Although this review will focus on the conditions and factors relevant to inflammatory bowel disease in humans, insight gained from experimental animal models that can be extrapolated to Crohn's disease and ulcerative colitis will be included. Recent advances are emphasized, and readers are referred elsewhere for earlier work and comprehensive reviews.1–6

A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT
  5. A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE
  6. AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY
  7. THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS
  8. THE LANGUAGE OF HOST-MICROBE DIALOGUE
  9. THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE
  10. CONCLUSION
  11. Acknowledgment
  12. REFERENCES

Of the three main contributory factors to the pathogenesis of Crohn's disease and ulcerative colitis – genes, immunity, and the environment – genes have yielded insights into previously unknown pathways of tissue injury, whereas the environment has, until recently, received the least attention but may offer the greatest potential in terms of prevention and treatment. There is, however, an emerging theme of molecular interdependency amongst this triad of risk factors.

Many of the genetic risk factors for Crohn's disease and ulcerative colitis involve genes coding for proteins that either sense the microbial environment (e.g., NOD2/CARD15) or regulate host responses to that environment (e.g., the IL-12-IL23R pathway and autophagy)7,8 or, in the case of ulcerative colitis, have a bearing on barrier function at the host interface with the microenvironment.9 The molecular complexity of these genetic linkages is shown by the multifunctionality of NOD2/CARD15, which not only recognizes bacterial wall muramyl dipeptide but also has a regulatory influence on commensal bacteria, regulatory T cells, and viral recognition.7 In addition, the interdependency of different genetic risk factors and disease pathways is shown by the discovery that NOD2-induced autophagy through ATG16L1 regulates bacterial handling and antigen presentation.10,11

Several additional lessons have emerged from a large body of work on the genetics of inflammatory bowel disease over the past decade.12 First, Crohn's disease and ulcerative colitis are polygenic disorders. Although a rare monogenic exception involving IL-10 deficiency in early-onset Crohn's disease has been described,13 a single gene defect has neither been sufficient nor necessary for most forms of the disease to occur. Heterogeneity within both Crohn's disease and ulcerative colitis should be anticipated and is attributable to the multiplicity of susceptibility and modifying genes (numbering over 70 genetic loci for Crohn's disease alone) and to the diversity of lifestyle or environmental exposure, including the variable composition of the commensal microbiota. Second, the genetics of Crohn's disease varies in different ethnogeographic populations; some loci, such as NOD2/CARD15, are not commonly linked to Crohn's disease in Japan. Third, it is clear from experimental murine models that different genetically determined mechanisms may lead to similar phenotypes and that gene-gene interactions modify disease severity. Gene-environment interactions also have a modifying effect since enteric bacteria are necessary for full expression of disease in most animal models. Fourth, genetic factors are more important in Crohn's disease than in ulcerative colitis, although identified loci are thought to account for only about a quarter of the genetic variance.

Finally, although studies of monozygotic or so-called identical twins are usually cited in support of a genetic influence in inflammatory bowel disease, they actually reveal the primacy of environmental factors. The concordance rate for Crohn's disease in identical twins (<50%) suggests a substantial contribution from both genes and environment, but the latter's contribution is even greater in ulcerative colitis, where the concordance rate is <10%.14 It is noteworthy that molecular profiles of the microbiota in identical twins have not provided much support for a host genetic influence on the microbiota.15–17 Disease phenotype appears to outweigh the effects of genotype on the microbiome, although studies in twins do not differentiate genetic from early environmental influences on the microbiota that persist.15 An environmental or lifestyle influence on disease frequency is supported by the changing epidemiology of both disorders, whereby the idea of microbial-driven immunopathology must be entertained.

A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT
  5. A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE
  6. AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY
  7. THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS
  8. THE LANGUAGE OF HOST-MICROBE DIALOGUE
  9. THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE
  10. CONCLUSION
  11. Acknowledgment
  12. REFERENCES

The epidemiologies of Crohn's disease and ulcerative colitis are remarkably similar, but one feature polarizes the two conditions – tobacco smoking. In patients with Crohn's disease, smoking is more common and it aggravates the clinical course of the disease and antagonizes the efficacy of drug therapy, whereas the cessation of smoking is associated with the onset or worsening of ulcerative colitis. The explanation for this variance is unclear, but smoking has been associated with a diversity of biologic changes to mucosal homeostasis, including alterations in the microbiota.18,19

The most consistent epidemiologic feature of both Crohn's disease and ulcerative colitis is the rise in incidence and prevalence of both conditions when a society undergoes transition from “developing” to “developed” status.18 This is similar to what has been observed with many other immunoallergic disorders. The pace of these epidemiologic changes is too brisk to be due to changes in gene frequency and points to an environmental or lifestyle effect on the risk of disease. In addition, the early age of onset of Crohn's disease and ulcerative colitis in the second or third decade of life suggests that the environmental influence is prior to this and probably greatest during the earliest stages of life. This is supported by studies of migrants from low-risk (developing) to high-risk (developed) societies. The earlier in life one migrates to a developed society, the greater the acquisition of a high risk, whereas migration during adult life is more likely to involve retention of the low risk associated with the “old” country.18 These observations could be accounted for if lifestyle and environmental factors were to influence the developing immune system and, by turn, determine the risk of immunoallergic disease in later life.

There is compelling evidence that the alimentary microbiota is an environmental modifier of mucosal and systemic immune development and maturation.20–22 Furthermore, many of the elements of a modern lifestyle (including diet, family size, antibiotic usage, urbanization, decline in parasitism, reduced exposure to childhood infections, such as hepatitis A, and loss of Helicobacter pylori) are associated with changes in the microbiota colonizing the neonate and may be linked to changes in microbial input to the developing immune system. By extrapolation from other sensory systems, it may be deduced that reduced biodiversity within the commensal microbiota with altered microbial input to immunosensory maturation, consequent upon a modern lifestyle, might adversely affect immune perception and performance and thereby pose a risk for immunoallergic diseases.18

Reduced biodiversity in the gut may have arisen because of reduced acquisition of environmental microbes (“hygiene hypothesis”), or it might reflect the progressive loss of ancestral microorganisms (“old friends”). Examples of the latter include helminths and H. pylori, the latter of which was in decline in the Western world long before it was discovered and which has been linked with increased risk of immunoallergic disorders.23,24

Epidemiologic attempts to link diet to inflammatory bowel disease in a direct or causative role have been conflicting and generally disappointing, but the role of diet may be indirect and mediated by an influence on the microbiota. Dietary changes associated with socioeconomic development and the changing epidemiology of inflammatory bowel disease have been discussed elsewhere,18 but it is noteworthy that the increased incidence of both Crohn's disease and ulcerative colitis over recent decades in Japan correlates closely with changes in dietary fat, particularly animal fat and n-6 polyunsaturated fatty acids.25 The influence of a high-fat diet on the commensal microbiota has been demonstrated elegantly in experimental mice.26 Several other lines of evidence have shown that the greatest environmental influence on the commensal microbiota is probably the diet.27–29 In addition to fat, other nutrients of relevance to patients with intestinal inflammation may have an impact on the composition or gene expression within the microbiota. These include dietary poly/oligosaccharides, otherwise known as prebiotics, which have a well-established influence on the microbiota. More recently, the modulatory influences of dietary casein and even iron on the microbiota have been reported.30,31

Antibiotics have an obvious impact on the microbiota, but whether they influence the risk of development of inflammatory bowel disease has been the source of considerable speculation. While early studies suffered from small numbers and other confounders, two recent population-based studies have linked antibiotic exposure, particularly in the first year of life, with increased likelihood of development of Crohn's disease in childhood.32,33 Thus, several lines of evidence support the concept that the elements of a modern lifestyle exert their influence on the microbiota during the earliest stage of life, at a time when the immune system is undergoing maturation, thereby possibly influencing the risk of development of inflammatory bowel disease in later life.

AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT
  5. A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE
  6. AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY
  7. THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS
  8. THE LANGUAGE OF HOST-MICROBE DIALOGUE
  9. THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE
  10. CONCLUSION
  11. Acknowledgment
  12. REFERENCES

Microbes have caused most chronic diseases that have afflicted mankind throughout the millennia. Within recent decades, there has been an impressive roll call of new entrants to the list of infectious agents that account for hitherto idiopathic disorders. Indeed, some have asked if all human diseases have an infectious basis.34 In gastroenterology, the discovery of H. pylori as a cause of peptic ulcer disease and gastric cancer should dissuade anyone from dismissing an infectious basis for any chronic disorder. One of the sobering lessons of this discovery was the failure of generations of epidemiologists to detect a transmissible factor for what was a common disease. Another was the failure of biologists to think beyond human pathophysiology in exploring the pathogenesis of the disease. More importantly, the lasting lesson was the recognition that some problems of human diseases cannot be solved by research focused exclusively on the host response, without due attention to the microenvironment.

That ulcerative colitis or Crohn's disease, or subsets thereof, might be caused by a known or unknown pathogen cannot be discounted. However, such a proposal faces considerable challenges. First, the relapsing and remitting nature of these diseases with instances of sustained mucosal healing for prolonged periods of time would suggest some form of latent infection, if an infection exists. Second, such an infection would be unlikely to respond to immunomodulatory or immunosuppressive drugs. Third, the population distribution of these diseases seems to be at variance with the involvement of a transmissible agent. Overcrowding, large family size, and poor sanitary conditions would favor a transmissible factor but seem to protect against both forms of inflammatory bowel disease.18

Finally, the distinction between a pathogen and a commensal is less clear than many might appreciate. Thus, the host immune system appears to have no specific recognition structures for distinguishing a commensal from a pathogen; pathogens share the same or similar molecular patterns by which the host senses the microenvironment.35 Recently, it has been proposed that while pathogens and commensals both signal via the same Toll-like receptors, commensals may generate additional molecules that preferentially induce regulatory T cells rather than effector cells.36 An alternative view would hold that pathogens are more likely than commensals to generate danger signals, including those arising from microbial-induced tissue damage, to which the immune system responds.

Regardless, in the same way that a weed is a flower in the wrong place, all commensals may become pathogenic in certain contexts. Thus, the commensal-pathogen separation is best viewed as polar ends of a continuum, with the degree of danger dependent on the context in which an organism is encountered by the immune system and the genetic status of the host. In most settings for most individuals, the commensal microbiota maintains homeostasis and protects against disease, but in susceptible hosts, some components of the microbiota may become a risk factor for disease. Furthermore, an experimental murine model of inflammatory bowel disease has shown that infectious agents may act as a trigger of chronic intestinal inflammation in susceptible hosts.37 Norovirus infection aggravated acute toxin-induced colitis in mice with a Crohn's-disease-linked mutant, ATG16L1, which was driven in part by the commensal microbiota. Full expression of disease required not only a genetic susceptibility but also interaction between the host and the microbiota in addition to the toxic inducer and the viral modifier. None of these contributory factors alone was sufficient.

THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT
  5. A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE
  6. AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY
  7. THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS
  8. THE LANGUAGE OF HOST-MICROBE DIALOGUE
  9. THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE
  10. CONCLUSION
  11. Acknowledgment
  12. REFERENCES

That some components of the microbiota are an essential requirement for full expression of inflammatory bowel disease in animal models and in humans has been well established and reviewed comprehensively.4 The composition of the commensal microbiota of patients with ulcerative colitis and Crohn's disease reflects, in part, the expected microbiota associated with a modern lifestyle in developed countries, but whether there are additional changes that are specific to or have a causative relationship with these conditions is uncertain.

The term “dysbiosis,” introduced many decades ago to reflect some form of microbial disturbance or imbalance, has become fashionable but is unnecessary, vague, and implies an understanding where none may exist. Neither its biologic basis nor the normal microbial balance has been defined. The more consistently observed microbial alterations linked to Crohn's disease or ulcerative colitis or both are summarized in Table 1.4,15,38–46

Table 1. Representative examples of the more consistently detected changes in the intestinal microbiota in Crohn's disease and ulcerative colitis.4,15,38–46
IncreasedReduced
  • a

    Variable or inconsistently reported; may be a feature of modern lifestyle.

Mucosal bacterial numbers (Crohn's disease)Bacterial diversity (Crohn's disease, ulcerative colitis)
Mycobacterium avium paratuberculosis (Crohn's disease)Clostridium groups IV, XIVa (Faecalibacterium prausnitzii) (Crohn's disease, ulcerative colitis)
Clostridium difficile (Crohn's disease, ulcerative colitis) 
Ruminococcus gnavus (Crohn's disease)Bifidobacteria and lactobacillia (Crohn's disease, ulcerative colitis)
Enterobacteriaceae, e.g., adherent invasive E. coli (Crohn's disease)

Exploration of the microbiota in patients with inflammatory bowel disease, though still at an early stage, has already generated interesting insights. Reduced biodiversity has been a particularly consistent but nonspecific observation. Impressive separation of patients with ulcerative colitis and Crohn's disease by principal component analysis in a metagenomic survey has been reported, but this requires confirmation and was based on only four patients with Crohn's disease.38 Compositional analyses have shown certain organisms, such as Faecalibacterium prausnitzii, to have anti-inflammatory properties,44 whereas other organisms may contribute to tissue injury because of mucolytic or proteolytic properties.47 In addition, some of the microbial alterations in the microbiota, such as the increases in mucosal-associated bacteria in Crohn's disease and the increased rates of detection of Mycobacterium avium paratuberculosis and Clostridium difficile, appear to be either secondary to the inflammatory process or due to defective innate immunity associated with this disorder.4,42 These organisms, however, may have a modifying influence on the clinical course or severity of the disease. In contrast to findings in patients with ulcerative colitis, many independent observations in patients with Crohn's disease are consistent with reduced clearance of bacteria from the mucosa,48 which has been associated with defective phagocytic cell function and impaired acute inflammation with compensatory adaptive immunologic responses.49

THE LANGUAGE OF HOST-MICROBE DIALOGUE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT
  5. A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE
  6. AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY
  7. THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS
  8. THE LANGUAGE OF HOST-MICROBE DIALOGUE
  9. THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE
  10. CONCLUSION
  11. Acknowledgment
  12. REFERENCES

A diversity of cellular and subcellular components of the commensal microbiota has the potential to engage with the host. These include microbial nucleic acids, secreted proteins, capsular polysaccharides and exopolysaccharides, and cell wall fragments, all of which may have immunomodulatory effects. Host-microbe exchanges occur over a large surface area (approximately 400 m2), with only a single layer of epithelium separating the internal milieu from the lumen. Epithelial and dendritic cells are the first to come into contact with the microbiota. Dendritic cells sample the lumen by extending intercellular dendrites across the epithelium and by encountering luminal material that has been transported by M cells overlying the lymphoid follicles.

Pattern recognition receptors, such as Toll-like receptors, NOD-like receptors (NLRs), and C-type lectins on/in the host cells recognize microorganism-associated molecular patterns on the surface of both commensals and pathogens. As alluded to earlier, a dual recognition system for commensals versus pathogens does not appear to exist, although one commensal, Bacteroides fragilis, has been shown to produce “a symbiosis factor” (polysaccharide A) that signals through Toll-like receptors directly on regulatory T cells to promote niche-specific mucosal immune tolerance.36 It has been proposed that the production of such symbiotic bacterial molecules may enable the host to discriminate between pathogens and commensals, but this remains to be demonstrated with other organisms. It is noteworthy that the polysaccharide A molecule has been reported to have an anti-inflammatory, preventive effect in an animal model of inflammatory bowel disease.50

The commensal microbiota is also a rich source of ATP, which is an important immunomodulatory molecule that acts on specific sensors (P2X and P2Y) to generate intestinal T helper 17 (Th17) cells.51 In susceptible individuals, Th17 cells participate in the pathogenesis of inflammatory bowel disease.52 Other commensal-derived immunomodulatory molecules of relevance to inflammatory bowel disease include short-chain fatty acids that are microbial end products of the fermentation of dietary polysaccharides. Short-chain fatty acids not only provide a nutrient source for distal colonocytes but also act on G-protein coupled receptors (GPR43) and mediate a downregulatory effect on inflammatory responses.53 The production of short-chain fatty acids such as acetate has also been reported to mediate the protective effect of bifidobacteria against enteric infection with Escherichia coli 0157:H7.54

While the microbiota shapes intestinal immunity in health and disease, host-microbe interactions in the gut are bidirectional. Thus, the mucosal immune system influences the composition and proinflammatory potential of the gut microbiota. Disturbances of innate immunity have been linked to aberrant expansion of some components of the microbiota and, in turn, may adversely influence the inflammatory response and risk of disease.55–57 A striking demonstration of this arises in an animal model of colitis in which deficiency of the transcription factor T-bet was associated with defective innate immunity leading to emergence of a “colitogenic” gut flora that was capable of transferring colitis to normal wild-type mice.58 Compositional increases in two bacterial species, Proteus mirabilis and Klebsiella pneumoniae, were associated with the transferrable colitis.59 In another animal model, however, it was shown that a transferrable colitis was induced by commensal Bacteroides species (including B. vulgatus and B. thetaiotaomicron) but not by members of the Firmicutes or Proteobacteria phyla (although the latter were increased), and this fulfilled Koch's postulates in a host-genotype-specific way.60

More recently, a mechanism by which the colonic epithelium can sense and regulate the microbiota has been described. This is dependent on the NLRP6 inflammasome, the genetic deletion of which leads to a shift toward a proinflammatory microbiota.61 Inflammasomes are multiprotein complexes that sense damage-associated molecular patterns. Deficiency of NLRP6 was associated with reduced interleukin (IL)-18 levels and expansion of Bacteroidetes (Prevotellaceae) and TM7, leading to a transferable colitogenic microbiota. It appears that, under normal conditions, epithelial cells respond to invasion by pathogens by mobilizing the NLRP6 inflammasome and initiating a cascade of molecular events that lead to the release of IL-18, which simulates γ-interferon and a bacteriocidal immune response. In the absence of this response, an altered microbiota emerges and leads to the release of chemokine from the epithelium, which results in the recruitment of neutrophils and a chronic inflammatory response.61,62

In summary, why the microbiota provides a protective effect for most individuals, yet becomes a villain for some who get inflammatory bowel disease, may depend on genetic-microbial-environmental interactions and the timing of these exchanges in early life.

THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT
  5. A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE
  6. AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY
  7. THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS
  8. THE LANGUAGE OF HOST-MICROBE DIALOGUE
  9. THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE
  10. CONCLUSION
  11. Acknowledgment
  12. REFERENCES

A detailed assessment of therapeutic strategies directed at the microbiota is beyond the scope of this review and may be found elsewhere.12,63,64 The following issues, however, deserve emphasis. First, although the microbiota has a pivotal role in the pathogenesis of Crohn's disease and ulcerative colitis, current therapeutic strategies are one-dimensional and directed primarily toward suppressing the host response, with a substantial proportion of patients failing to achieve sustained remission. Second, the biologic plausibility of manipulating the microbiota is, as discussed earlier, underpinned by the role of the microbiota in maintaining mucosal homeostasis, while some microbial components may become a risk for inflammatory bowel disease in susceptible individuals. Third, approaches to microbial manipulation are still crude and include antibiotics, probiotics, and prebiotics (dietary poly- and oligo-saccharides that have a bifidogenic effect) or combinations thereof (synbiotics). Heterogeneity of patient responses should be anticipated, as shown by the variable efficacy of antibiotics, depending on disease phenotype. For example, antibiotics have modest efficacy in Crohn's disease of the colon but not the small bowel, and they are a cornerstone treatment for patients with pouchitis but not for those with uncomplicated ulcerative colitis.64

Fourth, there is a disparity in the efficacy observed with probiotics in experimental models of inflammatory bowel disease versus the disappointing results noted in human trials, particularly in Crohn's disease. This may be due to the wrong timing of administration or the wrong choice of probiotic. The microbial influence on the developing immune system occurs in early postnatal life, and attempts to modify the microbiota after the onset of disease in adult life may be too late. Even more important for determining the choice of probiotic for different clinical indications may be strain-specific effects.65 Thus, the anti-inflammatory efficacy of one probiotic in experimental colitis has been molecularly defined and linked to a particular cell wall muropeptide that differs structurally from its counterpart in the cell wall of a nonprotective probiotic.66

Finally, in the future, commensals such as F. prausnitzii may be deployed as a new generation of probiotics; for example, F. prausnitzii treatment of mice with experimental colitis ameliorated intestinal inflammation.44 However, if improved strain selection and screening procedures based on the knowledge of mechanisms of action fail to generate sufficient efficacy, commensals or food-grade organisms can be genetically engineered to produce anti-inflammatory molecules. For example, Lactococcus lactis has been genetically manipulated to produce human IL-10 and shown to ameliorate experimental colitis and arthritis. It was well tolerated by patients with Crohn's disease in an encouraging phase I trial.67,68 A similar strategy by which the production of L. lactis nanobodies to tumor necrosis factor was reported to reduce inflammation in experimental colitis.69 More recently, an anaerobic commensal, Bacteroides ovatus, has been genetically engineered to produce either keratinocyte growth factor or transforming growth factor-beta under control of dietary inulin, with efficacy shown in experimental inflammatory bowel disease.70,71

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT
  5. A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE
  6. AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY
  7. THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS
  8. THE LANGUAGE OF HOST-MICROBE DIALOGUE
  9. THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE
  10. CONCLUSION
  11. Acknowledgment
  12. REFERENCES

Of the triad of pathogenic factors in inflammatory bowel disease, genetic risk factors have generated remarkable insights and have rightfully attracted the greatest attention over the past decade. Nevertheless, the impact of individual genetic factors is small, and the lesson of H. pylori and peptic ulcer disease is that genetic considerations will diminish if one can identify and eliminate an essential environmental factor. Microbiology will complement, not supplant, the genetics of inflammatory bowel disease, and rigorous typing of the microbiota will soon become part of the complete phenotyping of patients in the study of gene-environment interactions in health and disease. Thus, the complexity of inflammatory bowel disease is likely to require convergent thinking by investigators willing to cross traditional disciplines of research.

Acknowledgment

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT
  5. A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE
  6. AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY
  7. THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS
  8. THE LANGUAGE OF HOST-MICROBE DIALOGUE
  9. THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE
  10. CONCLUSION
  11. Acknowledgment
  12. REFERENCES

Funding.  The author is supported, in part, by Science Foundation Ireland, and by grants from Alimentary Health Ltd and GlaxoSmithKline Ltd. The content of this article was neither influenced nor constrained by these facts.

Declaration of interest.  The author has no relevant interests to declare. 

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. A NEXUS OF GENES, IMMUNITY, AND ENVIRONMENT
  5. A MICROBIAL PERSPECTIVE ON THE EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE
  6. AN ENVIRONMENTAL MODIFIER OF RISK OR AN INFECTION WAITING FOR DISCOVERY
  7. THE MICROBIOTA IN CROHN'S DISEASE AND ULCERATIVE COLITIS
  8. THE LANGUAGE OF HOST-MICROBE DIALOGUE
  9. THERAPEUTIC MANIPULATION OF THE MICROBIOTA IN INFLAMMATORY BOWEL DISEASE
  10. CONCLUSION
  11. Acknowledgment
  12. REFERENCES