Abnormal Food Timing and Circadian Dyssynchrony in Alcohol Induced Colon Carcinogenesis

Abnormal Food Timing and Circadian Dyssynchrony in Alcohol Induced Colon Carcinogenesis

The purpose of this study is to study the impact of Western lifestyle, including moderate alcohol consumption and delayed eating patterns on studying individuals' susceptibility to colorectal cancer. This study aims to increase our ability to identify individuals at risk for colorectal cancer in the future.

Each subject will experience four conditions (each for one week in duration with a week +/- 2 days wash-out in between): (1) "right-time eating" / no alcohol, (2) "right-time eating" / with alcohol, (3) "delayed-eating" / no alcohol, (4) "delayed-eating" / with alcohol. The order of experiments will be randomized [concealed randomization]. All subjects will undergo unprepped sigmoidoscopy after each week of intervention. In Aim 2, all subjects will have an option to undergo a 24h circadian assessment in the Biological Rhythms Research Lab after each week of intervention. The Investigator will assess (i) central circadian rhythms by collecting hourly salivary samples for melatonin assays and (ii) peripheral rhythm in the intestinal tract by buccal swabs once every 2h (12 time points) as well as by rectal sampling twice (every 12 hr). For Aim 3, sigmoidoscopy without sedation will be used to obtain colonic samples as the safe method compared to colonoscopy, which has some small but finite risks associated with the procedure (e.g, bleeding or perforation) as well as sedation.

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 user, 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, previous research has shown that disruption of circadian rhythm exacerbates alcohol-induced intestinal inflammation. The Investigator hypothesize that altered circadian rhythms due to "wrong-time" eating (abnormal eating) are an important determinant in alcohol induced 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. Each subject will experience four conditions (each for one week in duration with a week +/- 2 days wash-out in between): (1) "right-time eating" / no alcohol, (2) "right-time eating" / with alcohol, (3) "delayed-eating" / no alcohol, (4) "delayed-eating" / with alcohol. The order of experiments will be randomized [concealed randomization]. All subjects will undergo unprepped sigmoidoscopy after each week of intervention. In Aim 2, all subjects will have an option to undergo a 24h circadian assessment in the Biological Rhythms Research Lab after each week of intervention. The Investigator will assess (i) central circadian rhythms by collecting hourly salivary samples for melatonin assays and (ii) peripheral rhythm in the intestinal tract by buccal swabs once every 2h (12 time points) as well as by rectal sampling twice (every 12 hr). For Aim 3, sigmoidoscopy without sedation will be used to obtain colonic samples as the safe method compared to colonoscopy, which has some small but finite risks associated with the procedure (e.g, bleeding or perforation) as well as sedation.

Inclusion Criteria:

1. Adults (greater than 21 years old)
2. Have had advanced tubular adenoma within the last year

Exclusion Criteria:

1. Asian ethnicity (Due to common polymorphisms of enzymes involved in alcohol metabolism)

2. Does not drink alcohol

3. Alcohol use disorder/Alcohol Abuse

4. A known genetic predisposition to colorectal cancer (FAP, Lynch syndrome)

5. A history of colorectal cancer or inflammatory bowel diseases

6. Presence of comorbidities that might affect the circadian system

   1. Chronic renal failure
   2. Cirrhosis
   3. Advanced neurological conditions (e.g., Parkinson's, MS, epilepsy)
   4. Psychological disorders (e.g., PTSD, major depression)
   5. Sleep apnea
   6. Restless Leg Syndrome
   7. Inpatient Status
   8. Advanced cardiac failure
   9. Night shift workers with active shift work in the past month
   10. Planned shift work that will occur during the study
   11. Crossed more than two time zones in the previous week

7. Conditions that alter or necessitate a particular eating pattern (e.g., uncontrolled diabetes, eating disorders)

8. Conditions that alter the microbiota (infection or recent history of antibiotic use within three months, or use of pro/prebiotics within one month prior to recruitment)

9. Regular use of medications that can potentially affect melatonin profiles (e.g., Melatonin, Metoclopramide, Psychotropic medications, Hypnotics during the four weeks prior to the study)

10. Any active cancer

11. Inability to sign an informed consent