Mucosal metabolism and intestinal inflammation
Recent studies from our lab revealed that colonic intestinal epithelial cells (IEC) express IL-10R1 in response to cytokine stimulation through poorly understood mechanisms. In order to better understand the underlying pathways, we have employed unbiased metabolomics analysis and identified tryptophan (Trp) metabolism as a major modifying pathway in murine colitis. Based on these findings, we hypothesize that IL-10R1 expression on IEC is regulated by Trp metabolites.
Analysis of the promoter region of IL-10R1 revealed a functional aryl hydrocarbon response element (AHRE), which can be induced by Trp catabolites . Expression analysis demonstrates an increase in gene expression in response to the AHR agonists. Additionally, protein analysis confirms that IL-10R1 levels are increased in response to AHR activation in IEC in vitro. Importantly, in vitro models demonstrate that AHR activation accelerates epithelial restitution in the presence of IL-10.
Together, these results provide compelling evidence on the importance of IL-10 signaling in intestinal epithelia and implicate the AHR pathway in regulation of IL-10R1 expression. Ongoing studies focus on interrogating the role of AHR activation in both the maintenance of barrier during homeostasis as well as restitution of barrier following an inflammatory insult.
Salmonella typhimurium is a zoonotic, opportunistic enteric pathogen that represents a major source of food borne illness throughout the world. S. typhimurium invades the intestinal epithelium where it multiplies and escapes, free to infect other epithelial cells and cells of the immune system. While many of the factors contributing to S. typhimurium pathogenesis have been elucidated, the metabolic pathways that influence invasiveness are not well elucidated.
Purine metabolism is central to the virulence of some enteric pathogens. The intestinal epithelium plays a central role in purine metabolism and we hypothesize that these mechanisms play a role in the invasiveness of S. typhimurium. Previous work has shown that epithelial nucleotide turnover facilitates transepithelial bacterial translocation and dissemination of the Salmonella typhimurium.
Based on these results, current work in the lab focuses on interrogating the role of purine metabolism in S. typhimurium epithelial invasion and systemic dissemination. Results generated from these studies will have important implications for the role of epithelial metabolism in bacterial pathogenesis and in the modulation of homeostasis in the intestinal microbiome.