Alcohol Effects on Colon Epithelium are Time‐Dependent

Bishehsari, Faraz; Zhang, Lijuan; Voigt, Robin M.; Maltby, Natalie; Semsarieh, Bita; Zorub, Eyas; Shaikh, Maliha; Wilber, Sherry; Armstrong, Andrew; Mirbagheri, Seyed Sina; Preite, Nailliw Z.; Song, Peter I.; Stornetta, Alessia; Balbo, Silvia; Forsyth, Christopher B.; Keshavarzian, Ali

doi:10.1111/acer.14141

Cited by 4 publications

(2 citation statements)

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“…Intestinal gene expression has been shown to be affected by the microbial composition ( 17 ). Positive interactions of circadian disruption and alcohol have been previously reported by our group ( 11 – 13 , 43 , 44 ). Therefore, we next studied the colonic fecal microbiota that was in direct contact to the colonic cecum mucosa used for the gene expression analyses.…”

Section: Resultssupporting

confidence: 80%

Abnormal Food Timing Promotes Alcohol-Associated Dysbiosis and Colon Carcinogenesis Pathways

et al. 2020

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Background: Alcohol consumption is an established risk factor for colorectal cancer (CRC). Identifying cofactor(s) that modulate the effect of alcohol on colon inflammation and carcinogenesis could help risk stratification for CRC. Disruption of circadian rhythm by light/dark shift promotes alcohol-induced colonic inflammation and cancer. More recently, we found that abnormal food timing causes circadian rhythm disruption and promotes alcohol associated colon carcinogenesis. In this study, we examined the interaction of wrong-time feeding (WTF) and alcohol on CRC-related pathways, in relation to changes in microbial community structure. Methods: Polyposis mice (TS4Cre × cAPC Δ468 ) underwent four conditions: alcohol or water and feeding during the light (wrong-time fed/WTF) or during the dark (right-time fed). Colonic cecum mucosal gene expression was analyzed by RNA-seq. Microbiota 16S ribosomal RNA sequencing analysis was used to examine colonic feces. Modeling was used to estimate the extent of the gene expression changes that could be related to the changes in the colonic microbial composition. Results: The circadian rhythm pathway was the most altered pathway by the WTF treatment, indicating that WTF is disruptive to the colonic circadian rhythm. Pathway analysis revealed interaction of WTF with alcohol in dysregulating pathways related to colon carcinogenesis. Similarly, the interaction of alcohol and WTF was detected at multiple parameters of the colonic microbiota including α and β diversity, as well as the community structure. Our modeling revealed that almost a third of total gene alterations induced by our treatments could be related to alterations in the abundance of the microbial taxa. Conclusion: These data support the promoting effect of abnormal food timing alcohol-associated CRC-related pathways in the colon and suggest colon dysbiosis as a targetable mechanism.

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Section: Resultssupporting

confidence: 80%

Abnormal Food Timing Promotes Alcohol-Associated Dysbiosis and Colon Carcinogenesis Pathways

et al. 2020

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“…Male C57BL6/J mice (aged 6-8 weeks; Jackson Laboratories) were fed a standard chow diet (Teklad Envigo #2018) for 4 weeks as described [20], within IACUC-approved, ventilated, light-tight cabinets. Mice were maintained on a constant 12-h light/dark cycle for the duration of the experiment.…”

Section: Animal Modelmentioning

confidence: 99%

Alcohol-Induced Immune Dysregulation in the Colon Is Diurnally Variable

Grumish¹,

Armstrong²,

Voigt³

et al. 2020

Visc Med

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Introduction: Alcohol increases the risk of colon cancer. Colonic inflammation mediates the effects of alcohol on colon carcinogenesis. Circadian rhythm disruption enhances the alcohol's effect on colonic inflammation and cancer. Objective: Here, we investigate the diurnal variation of lymphocyte infiltration in the colonic mucosa in response to alcohol. Methods: Sixty C57BL6/J mice were fed a chow diet, and gavaged with alcohol at a specific time once per day for 3 consecutive days. Immunohistochemistry and immunofluorescence staining were used to quantify total, effector, and regulatory T cells in the colon. Student's t test, one-way ANOVA, and two-way ANOVA were used to determine significance. Results: Following the alcohol binge, the composition of immune T cell subsets in the mouse colon was time-dependent. Alcohol did not alter the total number of CD3 + T cells. However, upon alcohol treatment, T-bet + T helper 1 (Th1) cells appeared to dominate the T cell population following a reduction in Foxp3 + regulatory T cell (Treg) numbers. Depletion of Tregs was time-dependent, and their numbers were dramatically reduced when alcohol was administered during the rest phase. A reduction in Tregs significantly increased the Th1/Treg ratio, resulting in a more proinflammatory milieu. Conclusions: Alcohol enhanced the proinflammatory profile in the colon mucosa, as demonstrated by a higher T-bet + /Foxp3 + ratio, especially during the rest phase. These findings may partly account for the interaction of circadian rhythm disruption with alcohol in colon inflammation and cancer.

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