This proposal capitalizes on a unique team of investigators with complementary expertise to delineate and exploit the mechanistic relationships between diet, the microbiota, and inflammatory bowel disease and thus establish a framework for mapping diet-microbiota-host interactions for many biological signatures of interest. We will engineer and test an unconventional synbiotic therapy (nutrients plus microbes) for treating ulcerative colitis (UC), with in silico, ex vivo, and in vivo validation and approaches with generalizability to synbiotic formulations for many diseases. Extensive research has been performed on the anti-inflammatory role of the gut microbiota, primarily mediated through endogenous microbial molecules and fermentation end products [3]. However, few investigators have explored the capacity of the gut microbiota to metabolize bioactive molecules, specifically plant-derived dietary metabolites that ameliorate gut inflammation. Among these phytochemicals are glucosinolates, low molecular weight S-linked glycosides present in all members of the Brassicaceae family (e.g., cabbage, radishes) [4]. Glucosinolates are precursor metabolites for microbe-derived isothiocyanates (ITCs), anti-inflammatory agents that act on NF-?B and Nrf2 [5,6]. Optimal synthesis of isothiocyanates is dependent upon environmental factors that include a metabolic profile established by the gut microbiome although the mechanisms are poorly understood [7]. Using computational tools and multi-omic approaches, the outlined knowledge gap of microbe-mediated conversion of a key glucosinolate (glucoraphanin or GRN) to a key isothiocyanate (sulforaphane or SFN) presents a profound opportunity to identify bacterial species with defined capacity for optimal phytochemical processing, host responses, and subsequent mechanisms of benefit to host health. The long-term goal is to maximize localized delivery of isothiocyanates to inflamed tissue(s) through manipulation of the gut microbiota and phytochemical supplementation. The rationale for the proposed research is that once a mechanistic understanding of these conditions and species is achieved, tailored synbiotic therapies become a possibility. We plan to test our central hypothesis that specific bacteria have a mitigating effect on inflammatory bowel disease by metabolizing a plant-derived glucosinolate into an anti-inflammatory isothiocyanate by pursuing the following three specific aims: (1) Delineate mechanisms of SFN production by known microbial species. (2) Employ ex vivo human colonoids to test the impact of SFN on intestinal epithelial homeostasis. (3) Elucidate the impact of selected synbiotics on localized SFN bioavailability in murine colitis. The proposed program will be implemented by investigators with expertise in metabolic modeling and omics technologies (Dr. Papin), enteroid models and gastroenterology (Drs. Moore and Rosen), and in vivo mouse models (Drs. Kolling, Moore, and Rosen). We anticipate that completion of this work will generate mechanistic understanding of patient-centric synbiotic therapies for ulcerative colitis and other intestinal inflammatory disorders tailored to the individualized gut environment.
The proposed program leverages expertise by clinicians and research scientists to develop a framework for predicting, testing, and defining the pathways that microbes use to convert phytochemicals to compounds that benefit the host. The specific outcome expected is a mechanistic understanding of the context in which microbial species produce maximal conversion of glucosinolates to isothiocyanates and their impact on human gut epithelial inflammatory signaling. This understanding will have a direct impact on mechanistic, therapeutic strategies for inflammatory bowel diseases which affect more than 1 million people in the US as well as many other diet-microbe-host interactions of importance in disease.
