Conjugated C-6 hydroxylated bile acids in serum relate to human metabolic health and gut Clostridia species

Anders Ø Petersen,Oluf Pedersen,S Dusko Ehrlich,Torben Jørgensen,Sirkku Jäntti,H Bjørn Nielsen,Tue H Hansen,Hanna Julienne,Torben Hansen,Yong Fan,Partho Sen,Trine Nielsen,Matej Orešič,Pernille Neve Myers,Tuulia Hyötyläinen,Helle Krogh Pedersen

doi:10.1038/s41598-021-91482-y

Abstract

Knowledge about in vivo effects of human circulating C-6 hydroxylated bile acids (BAs), also called muricholic acids, is sparse. It is unsettled if the gut microbiome might contribute to their biosynthesis. Here, we measured a range of serum BAs and related them to markers of human metabolic health and the gut microbiome. We examined 283 non-obese and obese Danish adults from the MetaHit study. Fasting concentrations of serum BAs were quantified using ultra-performance liquid chromatography-tandem mass-spectrometry. The gut microbiome was characterized with shotgun metagenomic sequencing and genome-scale metabolic modeling. We find that tauro- and glycohyocholic acid correlated inversely with body mass index (P = 4.1e-03, P = 1.9e-05, respectively), waist circumference (P = 0.017, P = 1.1e-04, respectively), body fat percentage (P = 2.5e-03, P = 2.3e-06, respectively), insulin resistance (P = 0.051, P = 4.6e-4, respectively), fasting concentrations of triglycerides (P = 0.06, P = 9.2e-4, respectively) and leptin (P = 0.067, P = 9.2e-4). Tauro- and glycohyocholic acids, and tauro-a-muricholic acid were directly linked with a distinct gut microbial community primarily composed of Clostridia species (P = 0.037, P = 0.013, P = 0.027, respectively). We conclude that serum conjugated C-6-hydroxylated BAs associate with measures of human metabolic health and gut communities of Clostridia species. The findings merit preclinical interventions and human feasibility studies to explore the therapeutic potential of these BAs in obesity and type 2 diabetes.

Highlights

Knowledge about in vivo effects of human circulating C-6 hydroxylated bile acids (BAs), called muricholic acids, is sparse
A large part of primary BAs in pigs and rodents consists of C-6 hydroxylated hyocholic acid (HCA) and hyodeoxycholic acid (HDCA) and their conjugated derivatives, called γ-muricholic a cid[14,15]
The primary BAs consist of cholic acids (CA) and chenodeoxycholic acids (CDCA), which are not hydroxylated at the C-6 p osition[15]

Summary

Introduction

Knowledge about in vivo effects of human circulating C-6 hydroxylated bile acids (BAs), called muricholic acids, is sparse It is unsettled if the gut microbiome might contribute to their biosynthesis. A large part of primary BAs in pigs and rodents consists of C-6 hydroxylated hyocholic acid (HCA) and hyodeoxycholic acid (HDCA) and their conjugated derivatives, called γ-muricholic a cid[14,15] In pigs, these C-6 hydroxylated BAs may comprise about 5% of the circulating BA pool and there is growing evidence that these specific BAs may contribute to maintain glucose homeostasis in domesticated pigs that are resistant to development of type 2 diabetes despite living in an obesogenic environment[14,15]. We tested two related hypotheses, (i) a variety of C-6 hydroxylated BAs are measurable in human serum and are associated with human metabolic health, and (ii) the serum concentration of these C-6-hydroxylated BAs are associated with distinct co-abundant microbial species in the human gut microbiota

Results

Discussion

Conclusion