Human Defensin-5 Blocks Ethanol and Colitis-Induced Dysbiosis, Tight Junction Disruption and Inflammation in Mouse Intestine

Roshan G Rao,Radhakrishna Rao,Vaishnavi Rao,Pradeep K Shukla,Avtar S Meena,Louisa Balazs

doi:10.1038/s41598-018-34263-4

Roshan G Rao, Radhakrishna Rao + Show 4 more

Open Access

https://doi.org/10.1038/s41598-018-34263-4

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Abstract

Alcohol consumption has been shown to cause dysbiosis, but the mechanism involved in it is unknown. Recurrent colitis is known to induce expression of α-defensins in the colon, but the effect of alcohol consumption on it is not known. We investigated the effect of ethanol on α-defensin expression in the small intestine and colitis-induced expression in colon in mice. Furthermore, we evaluated the effect of human defensin-5 (HD5) on ethanol and colitis-induced gut barrier dysfunction and mucosal damage. Recurrent colitis was induced by feeding dextran sulfate sodium (DSS), 3 cycles of 5-days each with 15 days intervals, followed by 30-days remission. Ethanol was fed during the intervals and recovery in a liquid diet with or without HD5. Expression of α-defensins, tight junction (TJ) integrity and cytokine/chemokine expression were analyzed. Chronic ethanol feeding reduced α-defensin expression in the small intestine and colitis-induced defensin expression in the colon. HD5 attenuated the growth of enterotoxigenic Bacteriodes fragilis and E. coli, but had no effect on non-toxigenic Bacteriodes fragilis or probiotics, the Lactobacilli. Ethanol and colitis elevated Enterobacteriaceae, Firmicutes and Firmicutes to Bacteriodetes ratio in colonic mucosa. HD5 feeding attenuated ethanol and colitis-induced dysbiosis, disruption of intestinal epithelial TJ, mucosal inflammation, expression of pro-inflammatory cytokines and chemokines in the small intestine and colon, and endotoxemia. These results demonstrate that ethanol suppresses intestinal α-defensin expression, leading to dysbiosis, barrier dysfunction, inflammation and endotoxemia. HD5 feeding attenuates intestinal injury caused by ethanol and colitis, indicating that defensin expression is a potential target for treatment of alcoholic tissue injury and colitis.

Highlights

The clinical and experimental evidence indicates that chronic alcohol consumption disrupts intestinal epithelial tight junctions (TJ) and adherens junctions (AJ), leading to barrier dysfunction and endotoxemia[11]
While evidence indicates that the defensins are required for the maintenance of intestinal bacterial composition, the factors that regulate the expression of these antibacterial peptides are poorly understood
We provide evidence that alcohol consumption compromises expression of intestinal defensins, and that human defensin-5 (HD5) prevents alcohol and colitis-induced gut barrier disruption, mucosal inflammation and endotoxemia in mice

Summary

Introduction

The clinical and experimental evidence indicates that chronic alcohol consumption disrupts intestinal epithelial tight junctions (TJ) and adherens junctions (AJ), leading to barrier dysfunction and endotoxemia[11]. The expression of Defa[4], Defa[5] and Defa[6] genes was induced by colitis in the colon and EtOH feeding abolished this effect of colitis (Fig. 2F–H). HD5 feeding partially blocked the effect of EtOH on colitis-induced defensin expression. Junctional distribution of E-cadherin and β-catenin was reduced by EtOH feeding and DSS-induced colitis (Fig. 5B).

Results

Conclusion