Abstract
We previously reported that alcohol drinkers with and without cirrhosis showed a significant increase in fecal bile acid secretion compared to nondrinkers. We hypothesized this may be due to activation by alcohol of hepatic cyclic adenosine monophosphate responsive element-binding protein 3-like protein 3 (CREBH), which induces cholesterol 7α-hydroxylase (Cyp7a1). Alternatively, the gut microbiota composition in the absence of alcohol might increase bile acid synthesis by up-regulating Cyp7a1. To test this hypothesis, we humanized germ-free (GF) mice with stool from healthy human subjects (Ctrl-Hum), human subjects with cirrhosis (Cirr-Hum), and human subjects with cirrhosis and active alcoholism (Alc-Hum). All animals were fed a normal chow diet, and none demonstrated cirrhosis. Both hepatic Cyp7a1 and sterol 12α-hydroxylase (Cyp8b1) messenger RNA (mRNA) levels were significantly induced in the Alc-Hum and Ctrl-Hum mice but not in the Cirr-Hum mice or GF mice. Liver bile acid concentration was correspondingly increased in the Alc-Hum mice despite fibroblast growth factor 15, fibroblast growth receptor 4, and small heterodimer partner mRNA levels being significantly induced in the large bowel and liver of the Ctrl-Hum mice and Alc-Hum mice but not in the Cirr-Hum mice or GF mice. This suggests that the normal pathways of Cyp7a1 repression were activated in the Alc-Hum mice and Ctrl-Hum mice. CREBH mRNA was significantly induced only in the Ctrl-Hum mice and Alc-Hum mice, possibly indicating that the gut microbiota up-regulate CREBH and induce bile acid synthesis genes. Analysis of stool bile acids showed that the microbiota of the Cirr-Hum and Alc-Hum mice had a greater ability to deconjugate and 7α-dehydroxylate primary bile acids compared to the microbiota of the Cirr-Hum mice. 16S ribosomal RNA gene sequencing of the gut microbiota showed that the relative abundance of taxa that 7-α dehydroxylate primary bile acids was higher in the Ctrl-Hum and Alc-Hum groups. Conclusion: The composition of gut microbiota influences the regulation of the rate-limiting enzymes in bile acid synthesis in the liver. (Hepatology Communications 2017;1:61-70).