Metabolic Host-Microbiota Interactions in Autophagy and the Pathogenesis of Inflammatory Bowel Disease (IBD)

Abstract

Inflammatory bowel disease (IBD) is a family of conditions characterized by chronic, relapsing inflammation of the gastrointestinal tract. IBD afflicts over 3 million adults in the United States and shows increasing prevalence in the Westernized world. Current IBD treatments center on modulation of the damaging inflammatory response and carry risks such as immunosuppression, while the development of more effective treatments is hampered by our poor understanding of the molecular mechanisms of IBD pathogenesis. Previous genome-wide association studies (GWAS) have demonstrated that gene variants linked to the cellular response to microorganisms are most strongly associated with an increased risk of IBD. These studies are supported by mechanistic work demonstrating that IBD-associated polymorphisms compromise the intestine's anti-microbial defense. In this review, we summarize the current knowledge regarding IBD as a disease of defects in host-microbe interactions and discuss potential avenues for targeting this mechanism for future therapeutic development.

Keywords: GWAS; autophagy; butyrate; indole; inflammation; microbiota; mucosa.

Figure 1

Defects in epithelial xenophagy responses in IBD. Shown here is the xenophagic response to luminal microbes and microbial components. These components are recognized by NOD2, which, in conjunction with IRGM, recruits components of the autophagic machinery, including ATG16L1. Upon activation, ATG16L1 associates with the ATG5-ATG12 complex to recruit LC3 in the development of the membrane enclosed phagophore. The cargo-loaded phagophore fuses with cellular lysosomes to form the autophagolysosome in the final degradation and recycling of the xenophagic cargo. Components of this pathway with known IBD-related SNPs are designated with a red asterisk.

Figure 2

Microbial-derived metabolites and known functions on intestinal epithelial barrier function. Cell A depicts known response to the short-chain fatty acid butyrate. Once taken through apical membrane transporters, butyrate function as both an HDAC inhibitor and HIF stabilizer to promote expression of tight junction-associated proteins, including synaptopodin (SYNPO) and claudin-1 (CLDN1), resulting in enhanced epithelial barrier function. Cell B shows epithelial responses to the microbial tryptophan derivative indole. Once inside cells, indole(s) associate with the arylhydrocarbon receptor (AHR) to activate transcriptional induction of the interleukin-10 receptor (IL-10R), which upon activation, results in the loss of “leaky” claudin-2 (CLDN2), thereby promoting epithelial barrier function. Cell C represents the most recent observations that various microbial-derived purines (esp. hypoxanthine, Hpx) are recycled via purine salvage to be used as an energy source. Increases in intracellular ATP are associated with enhanced mucus secretion to promote enhanced epithelial barrier function.