Gut–liver axis alterations in alcoholic liver disease: Are bile acids the answer?
Authors: Jasmohan S. Bajaj, Phillip B. Hylemon
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. SEE ARTICLE ON PAGE 2150 Supported by Department of Veterans Affairs Merit Review (I0CX001076, to J.S.B.). Alcoholic liver disease and resultant cirrhosis are a major cause of morbidity and mortality worldwide.1 There is extensive literature documenting changes in the gut–liver axis as a progenitor of the widespread inflammatory milieu in animal models and humans with alcoholic liver disease.2 While the best therapy for alcoholic liver disease remains abstinence from alcohol, this is a goal often not achieved satisfactorily or in time for a large proportion of patients. Therefore, the search for effector molecules that could be responsible for the impairment in the gut–liver axis in alcoholic liver disease could create new therapeutic targets. Prime candidates in focus are bile acids (BAs), which are pluripotent signaling molecules that undergo extensive biotransformation by the gut microbiota. This results in deconjugated BAs (an enzymatic ability found in a high percentage of gut bacteria) and secondary BAs (found only in specific Clostridium species).4 The ultimate intestinal BA pool size and composition determine the efficacy of the enterohepatic cycle, which is tightly controlled by factors in the gut lumen, intestinal mucosa, and hepatocytes and by local and systemic inflammation. In prior human studies in active drinkers with and without cirrhosis, a greater secondary BA fecal and serum concentration was found despite the farnesoid X receptor (FXR), small heterodimeric partner, fibroblast growth factor 15 (FGF‐15) loop of the enterohepatic cycle being fully engaged.3 This increase in secondary BAs is purported to be toxic to the intestinal barrier and could perpetuate alcoholic liver disease. Prior work has also shown that microbiota from an actively drinking human can replicate this BA profile after humanization of germ‐free mice who were not fed alcohol.5 In this issue, Hartmann et al. studied the effect of alcohol feeding on microbial function, focusing on BAs and their modulation of the gut–liver axis.6 The team reports that alcohol induced microbial metagenomic changes, which increased BA deconjugation and resulted in a greater total BA pool. Gut microbiota changes induced by oral antibiotics altered the serum and intestinal BA profile with impaired deconjugation and were associated with lower steatohepatitis. These effects were variably modified by intestinal FXR agonists and by using adenoviral human FGF‐19 expression vectors. However, the possibility for interactions between changes in BA metabolism and inflammation, both local and systemic, in the pathogenesis of alcoholic liver disease should not be excluded (Fig. 1). The dysbiosis in alcohol‐fed animals with the ensuing increase in inflammation in the liver and intestines could be related to alcohol‐associated repression of BA‐inducible antibacterial lectins and peptides through FXR activation.7 Inflammation may quench the BA‐associated FXR activation, possibly by c‐Jun N‐terminal kinase pathway activation by proinflammatory cytokines that results in inhibition of the AKT (insulin signaling) pathway.8 The AKT pathway activates protein kinase C zeta, which has been reported to phosphorylate and activate FXR, allowing the induction of FXR target genes FGF‐15, small heterodimeric partner, and others. This may explain why intestinal FGF‐15 is down‐regulated in the intestines and liver small heterodimeric partner is not induced where there is an excess of BAs in the study model. FGF‐15 and FGF‐19 also regulate gallbladder filling, which could also be affected by inflammation.9 Giving fexaramine, a high‐affinity FXR agonist, may allow induction of FGF‐15 and antibacterial lectins and peptides; and antibiotic‐associated reduction in inflammation could also play a part in these changes. However, a few important differences between mice and humans would make this challenging to apply widely. Firstly, mice do not develop cirrhosis as a result of alcohol; secondly, mice have the ability to rehydroxylate secondary BAs back into primary BAs in the liver; thirdly, susceptibility to alcohol and other microbial insults in mice strongly depends on the cage effects; and fourthly, using broad‐spectrum antibiotics in advanced liver disease patients may be a recipe for antibiotic resistance.10Figure 1: A schematic figure of the gut–liver axis alterations in alcoholic liver disease is shown. The pathogenesis of alcoholic liver disease starts with alcohol ingestion, which affects the gut barrier directly and indirectly, leading to alterations in the BA profile. In addition, the effect of alcohol on the liver directly and through this gut–liver axis can alter BA synthesis. This process negatively impacts the host by perpetuating local and systemic inflammation. Abbreviation: CYP7A1, cytochrome P450 7A1.Ultimately, the current evidence demonstrates that BA modification could be an important target for beneficially altering the gut–liver axis in alcoholic liver disease.