Gut microbial composition can differentially regulate bile acid synthesis in humanized mice.

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)