Tributyrin Administration Targets Alcohol‐induced Pathogenic Mechanisms in the Gut‐liver Axis: Relevance to the Development of Therapeutic Strategies in Alcoholic Liver Disease
Authors: DONDE HRIDGANDH M. , Wilson Garrett , Ghare Smita , Zhang JingWen , Vadhanam Manicka , Joshi‐Barve Swati , McClain Craig , Barve Shirish 
Published: June 2021

Introduction

Emerging evidence has established the important role of the “gut‐liver” axis in the development of alcoholic liver disease (ALD). Alcohol‐induced enteric dysbiosis plays an essential role in the pathogenesis of alcoholic liver disease on the gut liver axis. Tributyrin (Tb) is a triglyceride that is rapidly absorbed and metabolized to butyrate by pancreatic lipases. Butyrate is the primary fuel source for colonocytes and improves gut barrier function. Moreover, butyrate is a known HDAC inhibitor.

Objective

Tributyrin modulates alcohol‐induced gut microbiome and barrier function and prevents hepatic steatosis via HDAC inhibition at CPT‐1 promoter

Methods

Mice were fed liquid Lieber‐DeCarli diet without or with alcohol (5% v/v) for a duration 7 weeks. A subset of mice were administered tributyrin (orally gavaged). Metagenomic analysis of the gut microbiome was performed by analyzing the fecal DNA by amplification of the V3–V5 regions of the 16S rRNA gene and large‐scale parallel sequencing on the Illumina MiSeq platform. Primary rat hepatocytes were exposed to alcohol (50 mM) with/without butyrate pre‐treatment for 24 hrs. Isolation of RNA was carried out using Trizol. Chromatin immunoprecipitation (ChIP) analysis was performed to examine the epigenetic modifications occurring in response to alcohol and butyrate at CPT‐1 promoter.

Results

Effect of tributyrin on alcohol‐induced intestinal dysbiosis and hepatic injury was evaluated. Tributyrin co‐administration prevented chronic alcohol‐induced i) microbial dysbiosis as documented by decrease in the diversity of the gut microbiome, ii) increase in systemic endotoxemia iii) hepatic steatosis and injury. Additionally, pharmacokinetic studies showed increase in plasma butyrate concentration in the hepato‐portal vein after tributyrin gavage. Notably, tributyrin prevented the ethanol‐induced down‐regulation of hepatic CPT‐1, a key enzyme in free fatty acid β‐oxidation. Specifically the effect of butyrate as HDAC inhibitor was evaluated in primary rat hepatocytes by examining CPT‐1 promoter region. Hepatocytes exposed to alcohol showed an increase in HDAC1 recruitment at the CPT‐1 promoter, which was prevented by butyrate. Correspondently, butyrate led to an increase in p300 recruitment with a subsequent increase in transcriptionally permissive histone acetylation at the proximal region of CPT‐1 promoter. This butyrate induced open chromatin configuration further allowed recruitment of RNA‐Pol II leading to CPT‐1 transcription.

Conclusions

In conclusion, tributyrin administration increases the diversity of the bacterial communities and prevents alcohol induced gut dysbiosis. Moreover, Tb attenuates hepatic steatosis by affecting alcohol‐induced, HDAC‐mediated epigenetic mechanisms the down regulate CPT‐1 gene expression. Taken together, these data also support that Tb supplementation is a potential therapeutic strategy in the treatment of ALD.

Support or Funding Information

This work is supported by NIH/NIAAA grants.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.