Scope: Pilot Project-Alam: COBRE in Pharmaceutical Research and Innovation

The mammalian gastrointestinal tract (GI) harbors a highly complex and abundant ensemble of bacteria that flourish in a nutrient-rich environment while profoundly influencing many aspects of host biology. The alteration in gut microbiota, which is termed microbial dysbiosis, is associated with many diseases, including inflammatory bowel disease (IBD), neurological disorders, obesity, diabetes, cardiovascular, and other metabolic syndromes. Besides, the dysbiotic gut microbiota has been reported to influence the pathogenesis of many human pathogens, including Salmonella, Escherichia, Yersinia, and Vibrio, which cause GI infections and inflammation. The mammalian intestine harbors a diverse array of microbial metabolites, which are small molecules produced by cells. To determine the mechanistic functions of microbiota-associated (microbial) metabolites, we performed (1) ultra-performance liquid chromatograph-mass spectrometry (QEHF)-based global metabolomic profiling, (2) metagenomic analysis and 16s profiling, and (3) metatranscriptomic analysis. Our preliminary meta’omic analysis identified microbiota, microbial genes, and metabolites differentially abundant during chronic inflammation. We found that the specific microbiome-associated metabolites are abundantly present during inflammation. Furthermore, our data show that microbiota-associated metabolite stimulates expression and activation of proinflammatory G-protein coupled receptor GPR4 in gut enterocytes. Our central hypothesis is that gut microbial-specific metabolite is the key regulator of the dysbiotic bacterial survival, fitness, and virulence during intestinal dysbiosis and requires GPR4 for the expansion in the intestine during inflammation and infections. The information generated from this CPRI award will provide high-impact preliminary data to prepare R01 applications by harnessing the knowledge of gut microbial metabolites and molecules, which could provide novel therapeutic potentials by targeting microbial metabolism to restore a healthy microbiome, eliminate pathogens and ameliorate diseases.