Interaction of alcohol with time of eating on markers of circadian dyssynchrony and colon tissue injury.

BACKGROUND: Alcohol increases the risk of developing colon cancer (CRC), in part via tissue inflammation and impaired barrier integrity. Circadian dyssynchrony (CD) is an understudied but common lifestyle associated factor that increases the risk of multi-organ tissue injury and number of malignancies including CRC. Our prior studies showed that the shift in light-dark cycle exacerbates barrier dysfunction and colonic inflammation in the setting of alcohol treatment, and increases the risk of CRC. Here we studied the interaction of alcohol with an abnormal eating pattern on markers of CD and colonic barrier integrity. METHOD: Mice were subjected to day (rest-phase = wrong-time WT) or night-time (active-phase = right-time RT) access to food in combination with access to water or 15% alcohol for total duration of 10 weeks. The food and liquid intake was measured. The locomotor activity data was recorded throughout the study, using a beam-break system. Mice were euthanized at two time points (ZT2 and ZT14). Time variation in the expression of the molecular marker of circadian clock (per2 gene) was measured in the central (hypothalamus) and intestinal (colon) tissue. Colonic protein expression of barrier markers (Occludin and Claudin-1) was studied. RESULTS: No significant differences were present in the weight gain and alcohol intake among the groups over the study period. We observed an interaction of WT eating with alcohol on behavioral markers of circadian rhythm. Compared to the RT + Water treated animals ("reference group"), combination of WT eating and alcohol consumption (WT + Alcohol) significantly changed the per2 oscillatory pattern, that was different between the colon and hypothalamus, indicative of worsening circadian dyssynchrony. This was associated with an overall impaired expression of barrier integrity markers in the colon. CONCLUSIONS: Alcohol induces circadian dyssynchrony which is worsened by abnormal food timing, associated with impaired barrier integrity in the colon. Future studies on the interaction of alcohol and food timing could provide further insights into alcohol associated CRC pathophysiology.

Alcohol Effects on Colon Epithelium are Time-Dependent.

BACKGROUND: Alcohol intake increases the risk of developing colon cancer. Circadian disruption promotes alcohol's effect on colon carcinogenesis through unknown mechanisms. Alcohol's metabolites induce DNA damage, an early step in carcinogenesis. We assessed the effect of time of alcohol consumption on markers of tissue damage in the colonic epithelium. METHODS: Mice were treated by alcohol or phosphate-buffered saline (PBS), at 4-hour intervals for 3 days, and their colons were analyzed for (i) proliferation (Ki67) and antiapoptosis (Bcl-2) markers, (ii) DNA damage (γ-H2AX), and (iii) the major acetaldehyde (AcH)-DNA adduct, N2 -ethylidene-dG. To model circadian disruption, mice were shifted once weekly for 12 h and then were sacrificed at 4-hour intervals. Samples of mice with a dysfunctional molecular clock were analyzed. The dynamics of DNA damage repair from AcH treatment as well as role of xeroderma pigmentosum, complementation group A (XPA) in their repair were studied in vitro. RESULTS: Proliferation and survival of colonic epithelium have daily rhythmicity. Alcohol induced colonic epithelium proliferation in a time-dependent manner, with a stronger effect during the light/rest period. Alcohol-associated DNA damage also occurred more when alcohol was given at light. Levels of DNA adduct did not vary by time, suggesting rather lower repair efficiency during the light versus dark. XPA gene expression, a key excision repair gene, was time-dependent, peaking at the beginning of the dark. XPA knockout colon epithelial cells were inefficient in repair of the DNA damage induced by alcohol's metabolite. CONCLUSIONS: Time of day of alcohol intake may be an important determinant of colon tissue damage and carcinogenicity.

Impact of microscopic duodenitis on symptomatic response to Helicobacter pylori eradication in functional dyspepsia.

BACKGROUND AND AIM: There is no consensus regarding the benefit of eradicating Helicobacter pylori (H. pylori) infection in patients with functional dyspepsia (FD). We intended to compare the symptom response to H. pylori eradication in FD patients in presence or absence of microscopic duodenitis (MD). METHODS: Patients with dyspepsia, normal upper gastrointestinal endoscopy and no psychological comorbidity according to the 12-item General Health Questionnaire underwent duodenal biopsy sampling. Of those, subjects with positive rapid urease test and H. pylori colonization in Wright-Giemsa staining were included in the study and evaluated histologically for presence of MD. All patients received sequential H. pylori eradication therapy and underwent urea breath test 4 weeks after the completion of the treatment to confirm the H. pylori eradication. The severity of dyspepsia was assessed using the Leeds Dyspepsia Questionnaire (LDQ) at baseline, 3rd and 6th months after the H. pylori infection was eradicated. RESULTS: Thirty seven patients were included in the study [mean age: 34.9 (8.1), 54.05 % female]. MD was observed in 16 (43.2 %) of the subjects. The mean LDQ score in patients with MD decreased from 12.5 (4.1) at baseline to 4.3 (2.1) at 3rd month and 2.6 (1.9) at 6th month. In patients without microscopic duodenitis, the mean LDQ score decreased from 10.6 (5.2) at baseline to 6.8 (4.1) and 6.2 (3.8) at 3rd and 6th months, respectively. The improvement in severity of symptoms in presence of MD was significantly greater than when it was absent (P < 0.001). CONCLUSION: FD patients with MD achieved greater symptomatic response with H. pylori eradication than those without microscopic duodenitis.