A number of recent studies have implicated tissue hypoxia in both acute and chronic inflammatory diseases, particularly as they relate to mucosal surfaces involving epithelial cells. In this context, a protective role for the transcriptional regulator hypoxia-inducible factor (HIF) was demonstrated through conditional deletion of epithelial HIF-1α in a murine model of colitis (J. Clin. Invest. 2004; 114:1098−1106. Here, we hypothesized that pharmacologic activation of HIF would similarly provide a protective adaptation to murine colitic disease. For these purposes, we used a novel prolyl hydroxylase (PHD) inhibitor (FG-4497) which readily stabilizes HIF-1α and subsequently drives the expression downstream HIF target genes (e.g. erythropoietin). Our results show that the FG-4497-mediated induction of HIF-1α provides an overall beneficial influence on clinical symptoms (weight loss, colon length, tissue TNFα) in murine TNBS colitis, most likely due to their barrier protective function and wound healing during severe tissue hypoxia at the site of inflammation. Taken together these findings emphasize the role of epithelial HIF-1α during inflammatory diseases in the colon and may provide the basis for a therapeutic use of PHD inhibitors in inflammatory mucosal disease.

Neudecker et al. define a role for a microRNA, miR-223, in regulating the inflammatory tone of the intestine by constraining nlrp3 inflammasome activation in CCR2+ monocytes and attenuating excessive IL-1β–driven inflammation. Therapeutic nanoparticle delivery of miR-223 mimetics limits experimental colitis.

Interactions between the gut microbiota and the host are important for health, where dysbiosis has emerged as a likely component of mucosal disease. The specific constituents of the microbiota that contribute to mucosal disease are not well defined. The authors sought to define microbial components that regulate homeostasis within the intestinal mucosa. Using an unbiased, metabolomic profiling approach, a selective depletion of indole and indole-derived metabolites was identified in murine and human colitis. Indole-3-propionic acid (IPA) was selectively diminished in circulating serum from human subjects with active colitis, and IPA served as a biomarker of disease remission. Administration of indole metabolites showed prominent induction of IL-10R1 on cultured intestinal epithelia that was explained by activation of the aryl hydrocarbon receptor. Colonization of germ-free mice with wild-type Escherichia coli, but not E. coli mutants unable to generate indole, induced colonic epithelial IL-10R1. Moreover, oral administration of IPA significantly ameliorated disease in a chemically induced murine colitis model. This work defines a novel role of indole metabolites in anti-inflammatory pathways mediated by epithelial IL-10 signaling and identifies possible avenues for utilizing indoles as novel therapeutics in mucosal disease.

IL10 is a potent anti-inflammatory cytokine that inhibits the production of pro-inflammatory mediators. Signaling by IL10 occurs through the IL10 receptor (IL10R), which is expressed in numerous cell types, including intestinal epithelial cells (IEC), where it is associated with development and maintenance of barrier function. Guided by an unbiased metabolomics screen, we identified tryptophan (Trp) metabolism as a major modifying pathway in IFN-γ-dominant murine colitis. In parallel, we demonstrated that IFN-γ induction of IDO1, an enzyme that catalyzes the conversion of Trp to kynurenine (Kyn), induces IL10R1 expression. Based on these findings, we hypothesized that IL10R1 expression on IEC is regulated by Trp metabolites. Analysis of the promoter region of IL10R1 revealed a functional aryl hydrocarbon response element (AHRE), which is induced by Kyn in luciferase-based IL10R1 promoter assays. Additionally, this analysis confirmed that IL10R1 protein levels were increased in response to Kyn in IEC in vitro. Studies utilizing in vitro wounding assays revealed that Kyn accelerates IL10-dependent wound closure. Finally, reduction of murine DSS colitis through Kyn administration correlates with colonic IL10R1 expression. Together, these results provide evidence on the importance of IL10 signaling in intestinal epithelia and implicate AHR in the regulation of IL10R1 expression in the colon.

Intestinal microbial dysbiosis, intestinal inflammation, and Th17 immunity are all linked to the pathophysiology of spondyloarthritis (SpA); however, the mechanisms linking them remain unknown. One potential hypothesis suggests that the dysbiotic gut microbiome as a whole produces metabolites that influence human immune cells. To identify potential disease-relevant, microbiome-produced metabolites, we performed metabolomics screening and shotgun metagenomics on paired colon biopsies and fecal samples, respectively, from subjects with axial SpA (axSpA, N=21), Crohn’s disease (CD, N=27), and Crohn’s-axSpA overlap (CD-axSpA, N=12), as well as controls (HC, N=24). Using LC-MS based metabolomics of 4 non-inflamed pinch biopsies of the distal colon from subjects, we identified significant alterations in tryptophan pathway metabolites, including an expansion of indole-3-acetate (IAA) in axSpA and CD-axSpA compared to HC and CD and indole-3-acetaldehyde (I3Ald) in axSpA and CD-axSpA but not CD compared to HC, suggesting possible specificity to the development of axSpA. We then performed shotgun metagenomics of fecal samples to characterize gut microbial dysbiosis across these disease states. In spite of no significant differences in alpha-diversity among the 4 groups, our results confirmed differences in gene abundances of numerous enzymes involved in tryptophan metabolism. Specifically, gene abundance of indolepyruvate decarboxylase, which generates IAA and I3Ald, was significantly elevated in individuals with axSpA while gene abundances in HC demonstrated a propensity towards tryptophan synthesis. Such genetic changes were not observed in CD, again suggesting disease specificity for axSpA. Given the emerging role of tryptophan and its metabolites in immune function, altogether these data indicate that tryptophan metabolism into I3Ald and then IAA is one mechanism by which the gut microbiome potentially influences the development of axSpA.