Colorectal cancer (CRC) is the second leading cause of cancer mortality in the US. CRC's risk is closely linked to the modern lifestyle. Alcohol is commonly used in our society and is an established risk factor for both pre-cancerous (polyp) and cancerous lesions of the colon. However this knowledge has not been translated to our current risk stratifications for CRC as the process of alcohol-induced carcinogenesis is not predictable. Mucosal inflammation is a well-established mechanism that mediates the effect of alcohol induced tissue injury in the intestine. Inflammation also plays a crucial role in pathogenesis of CRC. Factors that promote a pro-tumorigenic inflammatory state in the setting of alcohol are unknown. Since CRC occurs only in a small subset of alcohol users, alcohol alone may not be sufficient to start the neoplastic process and additional cofactors are required. One such factor is circadian dysrhythmia that is another modern lifestyle habit, shown to be associated with an increased risk of CRC. Further, we have shown that disruption of circadian rhythm exacerbates alcohol-induced intestinal inflammation. We hypothesize that altered circadian rhythms due to ?wrong-time? eating (abnormal eating) are an important determinant in alcohol induced intestinal mucosal inflammation and carcinogenesis. Our preliminary data supports our hypothesis and shows that abnormal eating patterns accelerate alcohol-induced polyposis in a mouse model of CRC.
In Aim 1, we will establish the inflammatory profiles associated with alcohol abnormal eating patterns in the tissues collected from our animal experiments. Here, we establish a cancer-promoting inflammatory state in the colon, determined by RNA-seq and calibrated by immunostaining, linked to alcohol or abnormal eating patterns or their combination. We will then determine the effect of alcohol delayed eating patterns (4 conditions) in humans on central and peripheral circadian rhythms in Aim 2, and colon carcinogenesis and mucosal markers in Aim 3. After each intervention, subjects will undergo (1) assessment of central circadian rhythm measured by the dim light melatonin onset (DLMO); (2) assessment of intestinal circadian rhythm measured by clock gene expression in buccal mucosal cells; and (3) sigmoidoscopy sampling of the colon mucosa to assess inflammatory and carcinogenesis markers as well as microbiota. This proposal will identify delayed eating as a promoting factor for alcohol-induced colon injury leading to carcinogenesis, and will provide a paradigm shift in our understanding of the mechanisms underlying alcohol cancer promoting effects, as well as risk stratification of alcohol drinkers.

Public Health Relevance

Colorectal cancer is the second leading cause of cancer mortality in the US. Factors associated with modern lifestyle increase the risk of this cancer. One such factor is alcohol that is commonly consumed in our society. Another factor is our body's natural rhythms, called circadian rhythm, which when disrupted can increase the consumption in promoting colorectal cancer. This study is collaboration between scientists risk of several chronic diseases including colorectal cancer. Circadian rhythm is regulated by our life style including time of eating. This project is focused on the interaction of eating pattern (food timing), circadian rhythms and alcohol that study how alcohol damages the gut, scientists that study role of immune system in tumor formation, and scientists who study circadian rhythms. In this proposal we will answer whether and how delayed eating could worsen the alcohol effects on 1) circadian rhythm and 2) markers of colon cancer. Findings from these studies will result in a significant new understanding of the role of eating patterns, and circadian rhythms on alcohol induced cancer formation. These could lead to novel risk stratifications as well as preventative and therapeutic treatments for colorectal cancer and possibility other organ damages caused by alcohol.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Mentored Patient-Oriented Research Career Development Award (K23)
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National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
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Gao, Peter
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Rush University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Rossi, Marco; Mirbagheri, S E Y E D Sina; Keshavarzian, Ali et al. (2018) Nutraceuticals in colorectal cancer: A mechanistic approach. Eur J Pharmacol 833:396-402