Genes, bacteria, and immunity contribute to the pathogenesis of inflammatory bowel disease. Most genetic risk relates to defective sensing of microbes and their metabolites or defective regulation of the host response to the microbiota. Because the composition of the microbiota shapes the developing immune system and is determined in early life, the prospect of therapeutic manipulation of the microbiota in adulthood after the onset of disease is questionable. However, the microbiota may be a marker of risk and a modifier of disease activity and a contributor to extraintestinal manifestations and associations in some patients with inflammatory bowel disease.
Key points
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Environmental factors that shape the composition and function of the microbiota are maximally active during the earliest perinatal and postnatal phase of life.
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The neonatal and infant microbiota shapes the development and maturation of the immune system.
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Most of the genetic risk factors for inflammatory bowel disease code for proteins that sense or regulate the host response to the microbiota.
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The molecular mechanisms by which genes, microbes, and the immune system interact in the pathogenesis of inflammatory bowel disease are becoming clarified.
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Strategies for manipulating the microbiota have been remarkably effective in experimental animals but attempts to translate these to the human context have been resoundingly disappointing.
Introduction
Therapeutic strategies for inflammatory bowel disease (IBD) have increased over the past decade, but considerable unmet needs remain. Increasingly, patients seek safer, long-term options and alternatives to immunomodulatory and immunosuppressive drugs. The prospect of modulating the microbiota in both Crohn’s disease and ulcerative colitis is conceptually appealing and is based on sound rationale. However, clinicians wait expectantly for translation of advances in understanding the gut microbiota to clinical therapeutics and some may feel blinded by a blizzard of inconclusive publications. In this overview, we try to make clinical sense of a large body of factual data, explore the clinical implications of the relationship between the microbiota and IBD and summarise the lessons learned.
Introduction
Therapeutic strategies for inflammatory bowel disease (IBD) have increased over the past decade, but considerable unmet needs remain. Increasingly, patients seek safer, long-term options and alternatives to immunomodulatory and immunosuppressive drugs. The prospect of modulating the microbiota in both Crohn’s disease and ulcerative colitis is conceptually appealing and is based on sound rationale. However, clinicians wait expectantly for translation of advances in understanding the gut microbiota to clinical therapeutics and some may feel blinded by a blizzard of inconclusive publications. In this overview, we try to make clinical sense of a large body of factual data, explore the clinical implications of the relationship between the microbiota and IBD and summarise the lessons learned.
Broken biome or broken host?
For many years, the cardinal question surrounding the pathogenesis of IBD has been: Is this an abnormal immune response to a normal microbiota or is this an appropriate response to an abnormal microbiota? It is now clear from various animal models that both situations may arise and may overlap. Genetically determined anomalies of the innate immune system can lead to a modification of the microbiota, which becomes colitogenic upon transfer to an otherwise normal recipient. In addition, because the microbiota shapes the maturation of the immune system in early life, any disruption of the microbiota such as that caused by antibiotic exposure may lead to suboptimal immunity and/or risk of IBD in later life.
The environmental influence on inflammatory bowel disease
Despite much focus on genetics within the past decade, 2 lines of evidence confirm the environment as a risk factor for IBD. First, the concordance rate in genetically identical twins (approximately 40%-50% for Crohn’s disease and approximately 10% for ulcerative colitis) suggests a substantial environmental influence, particularly in ulcerative colitis. Second, the increasing frequency of both conditions has occurred over too short a period to be owing to changes in the population pool of genetic risk factors. Indeed, the known genetic risk factors are relatively common in society and, in most instances, are insufficient alone to cause disease.
Clinicians might despair at inconclusive and occasionally futile epidemiologic surveys chasing putative environmental risks, such as notional north/south and east/west gradients but amid this fog one can make cogent epidemiologic conclusions. First, the environmental influences on Crohn’s and ulcerative colitis seem to be similar but with 2 noteworthy exceptions. Cigarette smoking has a polarizing influence on the 2 main forms of IBD, whereby smoking is both a risk and aggravating influence for Crohn’s disease, whereas in ulcerative colitis, the cessation of smoking is a risk factor for relapse and active smoking has a modest beneficial influence. In addition, an episode of acute appendicitis, particularly in childhood or early adolescence, has a protective influence on the risk of developing ulcerative colitis but not Crohn’s disease or celiac disease. Second, like many immunoallergic disorders, both forms of IBD may be considered as diseases of a modern lifestyle. As countries undergo socioeconomic development, the incidence and prevalence of ulcerative colitis increases first and then is followed by similar trends in Crohn’s disease. Thus, many of the epidemiologic observations of the past actually represent the variable influence of socioeconomic development.
Microbiota as a proxy marker of environmental influence in inflammatory bowel disease
Although some environmental and lifestyle factors such as stress, drug therapy, pollution and radiation might have independent influences on disease activity, most, if not all, of the elements of a modern lifestyle in socioeconomically developed countries shape the composition and functional activity of the gut microbiota. Because the microbiota is critical for maturation of the host immune–inflammatory response, it is plausible that the microbiota is the predominant and proximate environmental influence on the risk of developing chronic inflammatory disorders in later life such as IBD ( Fig. 1 ). The same seems to be true of obesity and metabolic disorders. In particular, there is persuasive evidence for the adverse influence of diet and antibiotics on the progressive reduction in microbial diversity and loss of certain protective microbial species (“old friends”). In contrast with the earlier hygiene hypothesis, the old friends concept proposes that the key microbial exposures in early life are not the crowd infections such as childhood viral infections, but rather ancestral microbes that were present during the hunter–gatherer phase of mankind’s existence when the immune system was evolving. Such ancestral old friends include the indigenous microbiota, Helicobacter pylori , helminths, and hepatitis A virus.
The early life window of influence
Environmental or lifestyle risk factors for developing IBD exert their influence early in life. This has been well-demonstrated by studies of human migrants from low-incidence developing countries to high-incidence developed countries. The earlier one migrates from a low-risk, developing country to a modern society with a high incidence of IBD, the greater the risk of acquiring the risk of the new country. This window of time in early perinatal and postnatal life is when the microbiota is developing and becoming stabilized. It is also a critical period of maturation of the immune system, inflammatory response, mucosal barrier and several extraintestinal systems including the brain–gut axis, stress responses, and adipogenesis. The central role of the microbiota in promoting optimal maturation of the host immune and metabolic function has been in evidence since the first comparative studies of germ-free and conventionally raised animals. One implication of this early window of influence is that preventive strategies for IBD based on microbial manipulation should focused on early life, perhaps even prenatally at the level of the maternal microbiome. In addition, microbial manipulation after the onset of the disease may be futile, too late.
A nexus of genes, immunity, and microbes
The 3 main contributors to the pathogenesis of IBD are genes (which provide predisposition), immunity (mechanism of tissue injury) and, microbes (environmental stimuli; Fig. 2 ). The molecular mechanisms by which they interact are beginning to emerge. Most of the risk genes for IBD code for intracellular sensors of the microbiota (eg, NOD2) or code for regulators of the host response to the microbiota (eg, interleukin [IL]-12/IL23R pathway), including barrier function and autophagy. Thus, susceptibility might arise when mutant genes lead to inappropriate or inadequate clearance of bacteria from the mucosa. Alternatively, there may be a loss of protective organisms and their antiinflammatory metabolites or defective sensing of protective signals. In some individuals, there seems to be loss of Faecalobacter prausnitzii , which produces an antiinflammatory protein that inhibits the nuclear factor-κB pathway in the intestinal epithelium. Furthermore, the commensal bacterium Bacteroides fragilis has immunoregulatory properties by which its capsular polysaccharide A is presented to the host immune system packaged within outer membrane vesicles and leads to the generation of regulatory T cells. In susceptible humans with the genetic risk variant in ATG16L1, there is defective sensing and failure of the protective T regulatory response to the outer membrane vesicles.
Who gets sick?
Because the genetic and environmental/microbial risk factors for IBD are both common in socioeconomically developed societies, it is puzzling as to why these conditions are not more common and what determines who manifests clinical disease. In a highly insightful animal model, it was shown that both genetic susceptibility and the indigenous microbiota were required for pathogenesis of IBD but a combination of environmental triggers, such as chemicals and viruses determined the timing of onset of disease. The human analogy of this might be coincidental smoking and intestinal viral infection in a predisposed person. Insight into the role of infections has also been gained from animal models. Thus, when infectious or other environmental agents create a temporary break in the mucosal barrier, they expose the host immune system to the indigenous microbiota and lead to proliferation of long-lived commensal-specific effector T cells in addition to pathogen-specific T cells. Accumulation of the former may eventually tip the balance from physiologic to pathologic inflammation and the onset of IBD.
The microbiota at different phases of disease
In addition to the conditioning influence of the microbiota on the developing immune and inflammatory response, the microbiota also influences the clinical course of IBD at various phases of the disease. Bacteria and their metabolites have been shown to contribute to the development of adhesions and cicatrization, translocation and abscess formation, extraintestinal associations including liver disease, and colitis-associated cancer. In addition, the microbiota is implicated in obesity-related and other metabolic disorders increasingly linked with IBD.
The microbiota in inflammatory bowel disease
Although many investigators have reported changes in the microbiota of patients with both ulcerative colitis and Crohn’s disease, a specific microbial signature or consistent pattern of change has not been identified and certainly nothing that is of diagnostic precision. Changes in total bacterial numbers within the mucosa and reduced bacterial diversity have been reported consistently along with changes in composition. Many studies have been confounded by differences in disease duration, phase of disease, previous treatment, and variations in analysis. However, a particularly informative study of pediatric patients with Crohn’s disease is the largest to date and confirms the association between the disease state, alterations to bacterial taxa and reduction in species diversity in treatment-naïve cohort with new onset disease. Luminal and mucosal microbial analysis was performed. The most significant changes were seen in mucosal samples and included increased abundance of Enterobacteriaecae, Fusobacteriaece, Pasteurelleceae , and Bifidobacteriaeae . Of potential clinical relevance was the finding that microbiota profiles at diagnosis were predictive of subsequent clinical outcomes based on the Pediatric Crohn’s Disease Activity Index. Specifically, Enterobacteriaeceae correlated negatively with future Pediatric Crohn’s Disease Activity Index and Fusobacterium and Haemophilus positively. Interestingly, the possible use of rectal biopsies as a marker of the overall microbiota profile was suggested by the finding that disease location—colonic, ileocolonic, or ileal—did not offset the similarity between rectal and ileal biopsy-associated microbiota profiles. Thus, the more readily accessible rectal biopsies may be of use to characterize the microbiota profile regardless of disease phenotype.
The more consistent shifts in bacterial species reported in Crohn’s disease and colitis are summarized in Table 1 . Research strategies are moving away from correlative studies to those aiming to provide mechanistic insights. For example, pathogenic strains of adherent invasive Escherichia coli have been the focus of particular attention with consistent findings of increased mucosal levels in ileal Crohn’s disease. An inflamed ileum provides a niche environment for these pathabionts to propagate. They may trigger or promote further inflammation via lipopolysaccharide-mediated activation of the inflammatory cascade or through their effect on autophagy. Autophagy genes have been shown to play a key role in human intestinal Paneth cell function and mutations in autophagy genes are linked with Crohn’s disease. Individuals with genetic risk that impairs autophagy function may be particularly susceptible to the replication of adherent invasive Escherichia coli within the ileal mucusa and lack the ability to clear them effectively.
Related posts:
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Impact of Antibiotics on Necrotizing Enterocolitis and Antibiotic-Associated Diarrhea
Fecal Microbiota Transplantation
Diet and the Microbiome
The Esophageal and Gastric Microbiome in Health and Disease
Gut Microbiota and Complications of Liver Disease
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