Impact of Chronic Ethanol Consumption on Pathophysiology and Mucosal Gene Expression of the Gastrointestinal Tract in Rhesus Macaques
Authors: Barr Tasha , Sureshchandra Suhas , Rodriguez Thomas , Vargas Jonathan , Grant Kathleen , Messaoudi Ilhem 
Published: November 2023

In the United States, nearly 18 million adults suffer from alcohol use disorder (AUD) resulting in 88,000 deaths and $25 billion in health care‐related costs annually. Exposure of ethanol and its metabolites in the intestinal lumen alters tight junction proteins and bacterial metabolism increasing intestinal permeability leading to disruption of the mucosal barrier. An increased intestinal permeability further leads to translocation of gut‐derived endotoxins causing inflammatory responses in other organs, notably the liver. Furthermore, there is a positive association between excessive alcohol intake and risk for colorectal cancer. However, many gaps still remain in our understanding of the mechanisms by which AUD leads to increased gut permeability, malnutrition/malabsorption, increased incidence of colorectal cancer, and impaired cytokine productions. To address this question, we leveraged a nonhuman primate model of ethanol self‐administration. We performed RNA‐seq in duodenum, jejunum, ileum, and colon biopsies isolated from 8 ethanol‐consuming macaques and 4 controls. Our analysis revealed several differentially expressed genes (DEG) related to cancer progression and impaired immunity with heavy drinking. In the colon, we found DEG associated with cancer progression including CDC20 and ASPM to be upregulated, while DEG critical for host defense including MUC2 and DEFB1 were downregulated. The ileum harbors the majority of the gut‐associated lymphoid tissue and exhibited the most robust changes in gene expression with many upregulated DEG related to immunity such as CD4, CD14, CD19, CCL19, CCR7, TNF, and TLR4. We also observed dysregulated expression of tight junction proteins CLDN1 and CLDN2 in the ileum. In the jejunum, the primary site of nutrient absorption, there were several DEG related to nutritional and metabolic diseases including the folate transporter SLC46A1, SLC5A11, and SLC10A2. Following alcohol consumption, ethanol is rapidly absorbed in the duodenum, the shortest and most proximal segment of the small intestine; therefore we did not find any DEG between drinkers and controls. We also characterized duodenal, jejunal, ileal, and colonic mucosal pathophysiology from paraffin‐embedded tissue sections. In the colon, we discovered immune cell infiltration, sloughing of mucus membranes, and enlargement of goblet cells ‐ all features indicative of poor barrier integrity. These studies will provide us with a deeper understanding of the molecular mechanisms underlying ethanol‐induced dysregulation of mucosal homeostasis and will lay the foundation for future studies for translational interventions to restore gut homeostasis and reduce the severity of organ damage associated with AUD.

Support or Funding Information

This work was supported by National Institute of Alcohol Abuse and AlcoholismGrants R21 AA021947‐02 (IM), U01 AA013510 (KG), and R24 AA109431 (KG). Sequencing was carried out by the University of California, Riverside Genomics Core, supported by National Institutes of Health Grant 1S10RR028934‐01. Tasha Barr was supported by the NRSA training grant T32ES018827.