Hepatic inflammation caused by dysregulated bile acid synthesis is reversible by butyrate supplementation

Abstract

Dysregulated bile acid (BA) synthesis or reduced farnesoid X receptor (FXR) levels are found in patients having metabolic diseases, autoimmune hepatitis, and liver cirrhosis or cancer. The objective of this study was to establish the relationship between butyrate and dysregulated BA synthesis-induced hepatitis as well as the effect of butyrate in reversing the liver pathology. Wild-type (WT) and FXR knockout (KO) male mice were placed on a control (CD) or western diet (WD) for 15 months. In the presence or absence of butyrate supplementation, feces obtained from 15-month-old WD-fed FXR KO mice, which had severe hepatitis and liver tumors, were transplanted to 7-month-old WD-fed FXR KO for 3 months. Hepatic phenotypes, microbiota profile, and BA composition were analyzed. Butyrate-generating bacteria and colonic butyrate concentration were reduced due to FXR inactivation and further reduced by WD intake. In addition, WD-fed FXR KO male mice had the highest concentration of hepatic β-muricholic acid (β-MCA) and bacteria-generated deoxycholic acid (DCA) accompanied by serious hepatitis. Moreover, dysregulated BA and reduced SCFA signaling co-existed in both human liver cancers and WD-fed FXR KO mice. Microbiota transplantation using butyrate-deficient feces derived from 15-month-old WD-fed FXR KO mice increased hepatic lymphocyte numbers as well as hepatic β-MCA and DCA concentrations. Furthermore, butyrate supplementation reduced hepatic β-MCA as well as DCA and eliminated hepatic lymphocyte infiltration. In conclusion, reduced butyrate contributes to the development of hepatitis in the FXR KO mouse model. In addition, butyrate reverses dysregulated BA synthesis and its associated hepatitis.

Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet–induced systemic inflammation, microglial activation, and reduced neuroplasticity

“…Dysregulation of BA synthesis is implicated in inflammation, immunologic diseases, and liver carcinogenesis (14–16). To understand the role of BAs in those processes, we quantified and compared BAs in the brains, livers, and sera of CD‐ and WD‐fed mice.…”

“…In the gut, bacteria-generated, taurine-conjugated lithocholic acid (TLCA) activates G protein-coupled bile acid receptor (TGR5), which controls the production of peptide YY (PYY) and glucagon-like peptide 1 (GLP1), thereby regulating food intake and insulin sensitivity, respectively (13). The anti-inflammatory effect of BAs has been revealed by the observations that BA receptor farnesoid X receptor (FXR) knockout mice spontaneously develop steatohepatitis and have increased susceptibility to dextran sodium sulfate-induced colitis (14)(15)(16)(17)(18). Retinoid X receptor (RXR), which forms a dimer with FXR, also has an antiinflammatory effect in the digestive tract (19).…”

The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice

“…Specifically, the reinforcement of gut immunity induced by vildagliptin could result in a lower exposure of the liver to microbial stimuli. It would be useful to evaluate how vildagliptin influences gut microbial activity and the gut–liver axis, since microbial metabolites that are prone to reach the liver through the portal vein, such as bile acids (via the farnesoid X receptor) or SCFA (like butyrate), modulate hepatic inflammation and thereby the occurrence of non-alcoholic fatty liver disease [48, 49]. …”

Gut Microbial Metabolism and Nonalcoholic Fatty Liver Disease

“…These data suggest that significantly elevated fecal SCFAs, indicative of increased energy extraction from dietary input, are a hallmark of obesity. However, in contrast to these findings, an increase in butyrate‐producing bacteria has been shown to prevent diet‐induced hepatic steatosis and bile acid dysregulation and its associated hepatitis in murine models . Moreover, in humans, increasing colonic propionate prevented weight gain in overweight adults, and the beneficial metabolic effects of FMT from lean to obese donors were primarily associated with an increased abundance of butyrate‐producing bacterial strains in the gut .…”

“…However, in contrast to these findings, an increase in butyrate-producing bacteria has been shown to prevent diet-induced hepatic steatosis and bile acid dysregulation and its associated hepatitis in murine models. (111,112) Moreover, in humans, increasing colonic propionate prevented weight gain in overweight adults, (113) and the beneficial metabolic effects of FMT from lean to obese donors were primarily associated with an increased abundance of butyrate-producing bacterial strains in the gut. (114) These contradictory findings are likely attributable to differing end-organ effects of individual or combinations of SCFAs, including varying effects on energy expenditure, production of satiety hormones, and central appetite regulation.…”