Alcohol abuse contributes significantly to disease burden and mortality in the UnitedStates, with an annual healthcare cost of $223 billion and death toll of nearly 88,000. Itis well known that chronic alcohol consumption leads to gut injury,malnutrition/malabsorption, and increased incidence of colorectal cancers. Studies haveimplicated quantitative and qualitative alterations of gut microbiota as well asdysregulation of tight junction proteins as key contributors to gut injury, but ourunderstanding of the mechanisms underlying ethanol-induced pathologies remainsincomplete. Gut homeostasis is achieved through tightly regulated interactions betweenepithelial cells, immune cells, and the microbiome. Deeper understanding of theinterplay among these three components is necessary to fully identify processes ofalcohol-induced gut injury. However, studies to date have not fully uncovered ethanol-induced changes in epithelial cell gene expression or specific microbial shifts that areresponsible for tissue injury. More importantly, dose- and region- specific changes havebeen largely understudied despite the fact that they are likely to play distinct roles in theinitiation or exacerbation of various aspects of ethanol-induced pathophysiology. In thisapplication, we will simultaneously define ethanol-mediated changes in the (i)microbiome, (ii) mucosal, and (iii) immune cell gene expression within all major sectionsof the gut (duodenum, jejunum, ileum, and colon) using a translational nonhumanprimate model of voluntary ethanol self-administration. This unique animal modelprovides us with an unprecedented opportunity to investigate region- and dose-dependent alterations in gut homeostasis caused by alcohol. Completion of thesestudies will provide us with the knowledge necessary to design interventions to repairalcohol-induced tissue injury.
The proposed research is relevant to public health because heavy alcohol drinking results insignificant injury to the gut; but the mechanisms of this injury are not well understood. We will addressthis knowledge gap by simultaneously defining ethanol-mediated changes in gut microbiome andgene expression in gut biopsies obtained from a nonhuman primate model of ethanol self-administration. These results will positively impact future studies by identifying pathways that can betargeted therapeutically to overcome the adverse effects of alcohol use disorder.
| 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 |
