Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome

Abstract

Studies of the genetics underlying inflammatory bowel diseases have increased our understanding of the pathways involved in both ulcerative colitis and Crohn's disease and focused attention on the role of the microbiome in these diseases. Full understanding of pathogenesis will require a comprehensive grasp of the delicate homeostasis between gut bacteria and the human host. In this review, we present current evidence of microbiome-gene interactions in the context of other known risk factors and mechanisms, and describe the next steps necessary to pair genetic variant and microbiome sequencing data from patient cohorts. We discuss the concept of dysbiosis, proposing that the functional composition of the gut microbiome may provide a more consistent definition of dysbiosis and may more readily provide evidence of genome-microbiome interactions in future exploratory studies.

Keywords: CROHN'S DISEASE; GENETICS; INFLAMMATORY BOWEL DISEASE; INTESTINAL BACTERIA; ULCERATIVE COLITIS.

Figure 1. Genes and pathways in inflammatory bowel disease

More than 160 loci have been associated with susceptibility to IBD. A selected list of candidate genes is shown (left) along with the cellular pathways in which these genes are thought to function. These pathways likely interact in cellular networks (center), which, when perturbed, contribute to the clinical phenotypes of IBD (right).

Figure 2. Interaction network of host genetics, the gut microbiome and diet in overview (a) and in detail (b)

Chronic inflammation in the intestinal epithelium has been associated with increased production of Th17 cells, impaired innate immune response, decreased mucosal barrier, impaired autophagy, and a decrease in antimicrobial agents. There is a complex network of potential interactions, in some cases involving feedback, between impaired host immune functions, diet, and the taxonomic and functional dysbiosis of the gut microbiome. For example, deleterious mutations in NOD2, GPR35, ATG16L1, or IRGM may lead to impaired immune response to commensal bacteria, and subsequently to taxonomic dysbiosis, an imbalance in the taxonomic composition of the gut microbiota; taxonomic dysbiosis may cause metabolic dysbiosis, an imbalance in the metabolic capabilities of the gut microbiome; metabolic dysbiosis may include increased biosynthesis of tryptophan; increased tryptophan is expected to lead to decreased antimicrobial activity through several pathways (see text); impaired antimicrobial activity may lead to further taxonomic and metabolic dysbiosis. A similar feedback system may be proposed for the physical integrity of the epithelial barrier: impaired innate immune response and increased production of Th17 cells may lead to decreased integrity of the mucosal barrier; altered or impaired mucus production due to MUC19 deficiency may compound this effect; subsequent invasion of pathobionts, or opportunistic pathogens, may increase inflammation, leading to further breakdown of the epithelial barrier.