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Probiotics are promising treatments for obesity-related diseases. Probiotics may work through a
variety of mechanisms, including altering gut bacteria and reducing inflammation. Dr. Harpavat hypothesizes that probiotics may work through another mechanism, by converting bile acids into metabolites that activate receptors essential for glucose and lipid homeostasis. These receptors include the G-protein coupled receptor TGR5 and the nuclear receptor farnesoid-X-receptor (FXR).
Dr. Harpavat’s methods consist of culturing probiotic strains with bile acids, collecting the bile acid metabolites produced, and testing the metabolites in a cell-based TGR5 or FXR reporter system. From these experiments, he will determine whether probiotic strains can generate bile acid metabolites that activate TGR5 and FXR. For those strains that can, Dr. Harpavat will categorize the strains as strong or weak activators of the two receptors.
Finally, he will search for bacterial genes involved in bile acid metabolism. Dr. Harpavat’s initial focus will be on export pumps, with the hypothesis that strains with mutations in export pumps do not generate TGR5- or FXR-activating metabolites.
Dr. Harpavat’s results may help establish a new “liver-gut bacteria-host cell” axis mediated by bile acids, as well as provide candidate probiotic strains to test in obese animal models.
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