Alcohol-Induced Immune Dysregulation in the Colon Is Diurnally Variable

Abstract

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.

Alcohol Impairs Immunometabolism and Promotes Naïve T Cell Differentiation to Pro-Inflammatory Th1 CD4+ T Cells

“…Numerous studies have demonstrated that dysregulation of either glycolysis or oxidative phosphorylation impairs CD4 + T cell differentiation ( 32 – 37 ). In this study, the in vitro ethanol-mediated dysregulation of CD4 + T cell differentiation under Th1-promoting conditions, by increasing Tbet-expressing and decreasing FOXP3-expressing CD4 + T cells, recapitulated previously reported literature that Tbet : FOXP3 ratio was higher in CD4 + T cells isolated from the colon of ethanol-administered mice ( 16 ). Treg CD4 + T cells produce anti-inflammatory cytokines IL-10, IL-35, and TGF-β ( 48 ).…”

“…Clinical studies show that alcohol-induced systemic inflammation leads to increased susceptibility to infections, impaired bacterial clearance and increased disease burden ( 5 – 9 ). Preclinical studies have shown that chronic ethanol administration increases activated, proliferating CD4 + T cells, and dysregulates effector cell differentiation by increasing pro-inflammatory Th17 CD4 + T cells in the gut while increasing the ratio of T-Box Expressed in T cells (Tbet)-expressing (Th1) to Forkhead Box P3 (FOXP3)-expressing (Treg) CD4 + T cells in the colon ( 10 – 16 ). These changes to immune cell activation and differentiation promote a pro-inflammatory environment that can increase the risk of developing autoimmune disorders ( 17 ) and susceptibility to infections, including human immunodeficiency virus (HIV), which targets activated CD4 + T cells ( 18 , 19 ).…”

Mitochondrial Dysfunction: At the Nexus between Alcohol-Associated Immunometabolic Dysregulation and Tissue Injury

“…IFNγ promotes additional M1 polarization, creating a positive feedback loop for as long as the initiating stimulus remains (Figure 2) [138]. We and others have shown that alcohol promotes a Th1 phenotype, and whether ethanol independently and directly promotes an M1 phenotype remains to be determined [147,148]. Even though M1 macrophages are reliant on glycolysis for polarization and function, lipopolysaccharide (LPS) signaling was shown to increase M1 macrophage ΔΨm, which is protective against apoptosis [149].…”

Alcohol-associated bowel disease: new insights into pathogenesis

“…3 Alcoholassociated colorectal carcinogenesis risk could be linked to accumulation of the toxic product of ethanol metabolism, namely acetaldehyde, oxidative stress as well as genetic and environmental factors. 4 Emerging evidence has highlighted that alcohol misuse is related to GI cancers and causes significant damage to the GI track, leading to alcoholassociated GI disease. 3 In this review, we mainly discuss the effects of alcohol on small and large intestinal damage, which is termed as alcohol-associated bowel disease (ABD).…”