Chronic alcohol consumption leads to gut injury and increased incidence of gastrointestinal cancers. Studies have implicated quantitative and qualitative alterations of gut microbiota as well as dysregulation of tight junction proteins as key contributors to gut injury, leading to increased gut permeability. This in turn results in the translocation of bacteria and bacterial endotoxins into the portal blood flow that stimulate the production of pro-inflammatory mediators in the liver, culminating in alcoholic liver disease and other organ damage. However, our understanding of the mechanisms underlying these pathologies remains incomplete. Studies to date have not exhaustively identified ethanol-induced changes in gastrointestinal mucosal gene expression or specific microbial shifts that are responsible for tissue injury. The gut barrier is tightly regulated through interactions between epithelial cells, immune cells, and the microbiome. Deeper understanding of the interplay among these three components in the mucosa is necessary to identify processes of alcohol-induced gut injury. In this application, I will simultaneously define ethanol-mediated changes in the intestinal microbiome and mucosal gene expression within all major sections of the gut (duodenum, jejunum, ileum, and colon) using a translational nonhuman primate model of voluntary ethanol self-administration. This unique animal model provides us with an unprecedented opportunity to investigate region- and dose- dependent alterations in gut homeostasis under the influence of alcohol. Completion of these studies will provide us with the knowledge necessary to design interventions to repair mucosal injury and improve health outcomes in those with alcohol use disorders.
It is well established that excessive alcohol consumption is toxic to human health. Understanding how ethanol consumption leads to mucosal damage and ultimately disrupts intestinal homeostasis is important in order to develop new interventions to improve health outcomes in alcoholics. This proposed research will simultaneously investigate the ethanol- induced changes in microbial communities and mucosal gene expression within the different segments of the gastrointestinal tract.
| Barr, Tasha; Sureshchandra, Suhas; Ruegger, Paul et al. (2018) Concurrent gut transcriptome and microbiota profiling following chronic ethanol consumption in nonhuman primates. Gut Microbes 9:338-356 |
| Zillikens, M Carola; Demissie, Serkalem; Hsu, Yi-Hsiang et al. (2017) Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. Nat Commun 8:80 |
