Mucosal Interactions between Genetics, Diet, and Microbiome in Inflammatory Bowel Disease

Abstract

Numerous reviews have discussed gut microbiota composition changes during inflammatory bowel diseases (IBD), particularly Crohn's disease (CD). However, most studies address the observed effects by focusing on studying the univariate connection between disease and dietary-induced alterations to gut microbiota composition. The possibility that these effects may reflect a number of other interconnected (i.e., pantropic) mechanisms, activated in parallel, particularly concerning various bacterial metabolites, is in the process of being elucidated. Progress seems, however, hampered by various difficult-to-study factors interacting at the mucosal level. Here, we highlight some of such factors that merit consideration, namely: (1) the contribution of host genetics and diet in altering gut microbiome, and in turn, the crosstalk among secondary metabolic pathways; (2) the interdependence between the amount of dietary fat, the fatty acid composition, the effects of timing and route of administration on gut microbiota community, and the impact of microbiota-derived fatty acids; (3) the effect of diet on bile acid composition, and the modulator role of bile acids on the gut microbiota; (4) the impact of endogenous and exogenous intestinal micronutrients and metabolites; and (5) the need to consider food associated toxins and chemicals, which can introduce confounding immune modulating elements (e.g., antioxidant and phytochemicals in oils and proteins). These concepts, which are not mutually exclusive, are herein illustrated paying special emphasis on physiologically inter-related processes.

Sentinels at the Frontline: the Role of Intraepithelial Lymphocytes in Inflammatory Bowel Disease

“…For example, does Foxp3 Treg conversion also occur in the colon? If so, since Clostridia species involved in colonic Treg differentiation are depleted in IBD,[58, 4] will changes in microbial composition also affect the generation of this ex-Treg CD4 + IEL population? Alternatively, are there additional mechanisms that could drive the downregulation of ThPOK to increase anti-inflammatory CD4 + IELs as was shown in Foxp3 loss of function mutant mice?…”

“…[1] As a result, the symbiotic relationship between the microbiome and mucosal immunity has become a main area of focus in efforts to unravel the pathogenesis of IBD. Changes in the composition of the microbiota lead to an overall reduction in bacterial diversity in IBD,[4, 3] which has a profound effect on mucosal immunity. Although several commensal species have been shown to directly affect the differentiation of lamina propria lymphocytes,[58, 59, 3] significantly less is known regarding specific bacteria that directly influence IEL populations.…”

“…Diet not only influences the overall composition of the microbiome,[3] but dietary antigens and the production of bacterial metabolites have a profound impact on mucosal immunity. [4] Similar to microbial depletion, animals receiving an elemental antigen diet also fail to develop CD8αα + IELs. [77] Tryptophan-derived ligands that are produced as metabolites from cruciferous vegetables bind to the aryl hydrocarbon receptor (AhR); this receptor is highly expressed on CD8αα + and γδ IELs and is required for their survival.…”

“…However, advances in defining the symbiotic relationship between the immune system and resident microbiota have greatly expanded our understanding of IBD pathophysiology. [3, 4] Uncovering the mechanisms leading to the dysregulation of host defense responses has resulted in the development of new therapeutic strategies to treat IBD. [5, 6]…”

Mice Deficient in Cyp4a14 Have An Increased Number of Goblet Cells and Attenuated Dextran Sulfate Sodium-Induced Colitis

“…IBD is a refractory condition characterized by chronic inflammation involving ulcers and mucosal erosion of the lower gastrointestinal (GI) tract [1]. Although the exact causes of IBD remain unclear, multifactorial mechanisms, including genetics, immunity, microbiome and environment, contribute to the pathogenesis of IBD [2].…”