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Grant Abstract: Role of Alcohol and Circadian Disruption in Inflammation and Colon Cancer

Grant Number: 5R01AA023417-02
PI Name: Keshavarzian
Project Title: Role of Alcohol and Circadian Disruption in Inflammation and Colon Cancer

Abstract: The goal of this supplemental application (in response to PAR-14-201) is to determine if changing the colonic milieu via prebiotic administration mitigates the increased risk of colon cancer resulting from disrupted circadian homeostasis in combination with alcohol consumption. The overall goal of the parent R0-1 is to establish that colon cancer resulting from alcohol consumption is exacerbated by circadian rhythm disruption, and to reveal the underlying cellular and immunologic mechanisms. We provided compelling evidence that supported our hypothesis that circadian rhythm disruption synergizes with alcohol consumption to pathologically skew the functions of mast cells and Tregs to favor chronically elevated intestinal mucosa/inflammation and inaeased susceptibility to colorecta/ cancer. Several recent studies support the importance and central role of dysbiotic colonic microbiota in coloredal cancers (CRC) and the mucosal immune dysregulation that promotes CRC1-5. Thus, it is plausible that the microbiota also plays a central role in CRC risk associated with alcohol consumption. Indeed, we have demonstrated that alcohol consumption causes microbiota dysbiosis and gut leakiness in both human alcoholics 6 and alcohol-fed rodents 7. We and others have also shown that administration of prebiotic oats and probiotic Lactobacil/us GG corrects dysbiotic stool and prevents alcohol-induced gut leakiness, intestinal inflammation, and liver injury7-9. Pre/probiotics can increase colonic short chain fatty acid (SCFA) levels by promoting fermentation of carbohydrates by colonic bacteria and SCFA are anti-inflammatory and help maintain normal intestinal barrierintegrity10-14 . SCFAs also have epigenetic effects 12-15 and inhibit HDAC and methytransferase enzymes; thus, modifying carcinogenesis pathways by preventing DNA methylation and histone deacetylation and modification16 -17. However, it is not known whether correcting the intestinal milieu with prebiotics/probiotics can prevent alcohoVdisrupted circadian promotion of colon cancer and the goal of this supplemental application is to fill this gap in our knowledge. Hypothesis. Prebiotics will mitigate colon carcinogenesis caused by chronic alcohol consumption in combination with disrupted circadian haneostasis by correcting intestinal dysbiosis, protecting intestinal barrier integrity, and decreasing inflammation and mucosa/ immune dysregu/ation. We further hypothesize that these effects are due to increased co/one SCFAs exerting epigenetic and anti-inflammatory effects. To test our hypothesis, we will undertake experiments over 2 years with two Specific Aims: Aim 1: Determine if prebiotic use mitigates/prevents promotion of colon cancer CCRC) in circadian disrupted. alcohol-fed mice. We predid that prebiotics will correct dysbiotic colonic microbiota preventing microbiota-induced activation of mast cells, Treg dysfunction, disruption of intestinal barrier function, and persistent chronic mucosa! inflammation. We will manipulate diet (alcohol/non-alcohol) and circadian status (circadian disrupted/non-disrupted) as proposed in the parent grant in TS4CreAPC10x468 mice (genetically susceptible to polyposis) and WT BU6 mice and add additional grrups of mice that will receive either a prebiotic or vehicle. We will test if prebiotic supplementation prevents dysbiosis, gut leakiness and colonic inflammation induced by circadian rhythm disruption in alcohol-fed mice. Outcomes: stool and mucosa! associated microbiota composition (not proposed in parent grant), intestinal permeability, T J proteins/cytokines, mRNA. We will also test the hypothesis that prebiotics prevent colonic inflammation by normalizing mast cells/Treg interactions. Outcomes: mucosa! mast cells count and activation status and Treg numbers and phenotypes. Finally, Aim 1 will test the hypothesis that prebiotics decrease colon cancer development. Outcomes: number and size of polyps, cancer cells, and cancer invasion. Aim 2: To de

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