ObjectivesSustained alcohol abuse initiates a progressive disease pathogenesis involving simple steatosis, steatohepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. There is mounting evidence that microbes resident in the human intestine represent a key transmissible factor promoting inflammatory diseases including alcoholic liver disease (ALD). However, mechanisms by which gut microbiota synergize with excessive alcohol intake to promote ALD are poorly understood. We have recently revealed a metaorganismal pathway where nutrients in high fat foods can be metabolized by gut microbes to generate trimethylamine (TMA), which is subsequently metabolized by the host enzyme flavin‐containing monooxygenase 3 (FMO3) to produce the pro‐atherogenic metabolite trimethylamine‐N‐oxide (TMAO). Hepatic FMO3 mRNA levels are suppressed in alcoholics and breath levels of TMA correlate with the severity of alcoholic hepatitis. Thus, this study investigates whether pharmacological inhibition of gut microbe‐derived TMA production can blunt ethanol‐induced liver injuryMethods and ResultsWe first determined if ethanol feeding would alter circulating TMA and TMAO levels in mice. Acute (6% vol/vol Lieber DiCarli) and chronic (25 days Lieber DiCarli) isocaloric pair‐ and ethanol‐feeding elicited increases in both TMA and TMAO levels. We then employed a novel approach to block TMA production by using a small molecule inhibitor (CC08) targeting the gut microbial TMA‐producing enzyme CutC/D. CC08 treatment effectively abolished ethanol‐elicited increases in TMA and TMAO. In parallel, CC08 treated mice were completely protected against ethanol‐induced hepatic fat deposition, hepatocellular inflammation, and elevated alanine aminotransferase levels. Collectively, these results suggest inhibiting gut microbial production of TMA can blunt ethanol‐induced liver injury.ConclusionsOur results establish the TMA/TMAO pathway as an important regulator of ethanol‐induced liver injury. Inhibition of TMA production by utilizing small molecule inhibitors targeting the TMA lyase, such as CC08, may represent a novel therapeutic approach to combat ethanol‐induced liver injury.Support or Funding InformationP50 (AA024333‐01)
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