Bacteria-derived xenobiotics in colon cancer prevention: Link to GPR109A and colonic ketogenesis

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Project Summary: Chemical carcinogens and xenobiotics in the diet play a significant role in colon cancer (CC) formation. The intestinal tract, including the colon, is often the first site that is exposed to these carcinogens and xenobiotics. CC is a common malignancy in men and women, and p53 mutation (p53D) or inactivation is observed in ~60% of CC and ~90% of all human cancers. As such, the development of therapeutic strategies that will rejuvenate wild-type (WT) p53 function or target p53D should have profound implications in the prevention and treatment of CC. Similarly, a high frequency (40-60%) of KRAS mutation (KRASD) is observed in organisms exposed to environmental chemical contaminants, and ~40-45% of CC is associated with KRASD. We found a reciprocal association between GPR109A expression and KRASD CC. GPR109A is a Gai-coupled receptor for the bacterial fermentation product butyrate (BTR), the ketone body b-hydroxybutyrate (bHB), and the vitamin Niacin (NA). About 85% of CC shows a reduced expression of GPR109A. GPR109A agonists NA is the precursor of NAD+ and p53 is an NAD+-dependent molecule and NA deficiency impairs p53 function. Therefore, GPR109A could be the molecular target of KRAsD and it plays an important role in the regulation of p53 signaling. Pharmacologic doses of NA, a vitamin and also an FDA-approved drug for dyslipidemia, is taken by millions of Americans. Though the role of NA in decreasing LDL and increasing HDL is well recognized, little is known about its anti-tumor potential. Similarly, the link between commensal bacteria and CC prevention is known for a long time, but the mechanisms underlying this link are not well understood. BTR, the prominent bacterial metabolite in the colon, is the endogenous agonist for GPR109A in colonic epithelia. bHB is the natural agonist for GPR109A in immune cells present in the lamina propria and this agonist is synthesized in colonic epithelia using the bacterial metabolite BTR via ketogenesis. This highlights the biological significance of the colon as a ketogenic organ. In addition, commensal bacteria control GPR109A expression and ketogenesis in the colon via their xenobiotic metabolites (butyrate, indole derivatives, 1,3-diaminopropane, and reuterin). This offers a novel molecular link between commensal bacteria and CC prevention. Our central hypothesis is that activation of GPR109A in colonic epithelia and immune cells lead to sustained activation of p53 and anti- tumor immunity. We will test this hypothesis with three specific aims: (Aim 1) Determine the role of the GPR109A- p53 axis in KRASD, chemical, and dietary carcinogen-induced CC; (Aim 2) Elucidate the molecular mechanism(s) of GPR109A agonists-induced p53 activation and test if GPR109A agonists can be used as novel therapeutic drugs to target p53D CC; and (Aim 3) Demonstrate that commensal bacterial metabolites maintain WTp53 function and prevent the immune system from undue activation in colon via GPR109A with an obligatory involvement of colonic ketogenesis. These studies will involve the use of genetically modified mouse lines with colon-specific deletion of not only Gpr109a and p53, but also the rate-limiting enzyme in ketogenesis, Hmgcs2.