Defining the role of S1p and myeloid cells during enterotoxigenic B. fragilis infection

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Enterotoxigenic Bacteroides fragilis (ETBF) has been associated with acute diarrheal, inflammatory bowel disease, and colorectal cancer (CRC). ETBF oncogenesis requires the coordinated action of its toxin, BFT, and an inflammatory response to orchestrate the recruitment of myeloid cells, but how ETBF recruits colonic myeloid cells remains poorly understood. S1p acts as bioactive sphingolipid messengers, influencing the myeloid cells migration and regulating colonic inflammation. However, whether ETBF integrates sphingolipid metabolites to determine the metabolism of colonic myeloid cells needs to be explored. Recent evidence indicates that remodeling of myeloid cells metabolism is central to the induction of innate immune response. We found ETBF infection alters the activity of sphingosine kinase, which is linked to metabolic remodeling, histone acetylation and PGE2 production in myeloid cells. Two integrated specific aims are proposed to test: Aim 1 will determine how ETBF infection regulates inflammatory myeloid cells accumulation in the colon. Aim 2 will determine if ETBF alteration of acetyl-CoA contributes to metabolic remodeling in myeloid cells via PPARγ activation. Deeper understanding of the proper role of sphingolipids and their enzymes in controlling the intestinal immune properties and in promoting the pathogenesis and progression of colitis will generate new perspectives in the development of “sphingolipid-centered” therapeutic strategies that control the onset and perpetuation of the ETBF-induced gut inflammation.