Obeticholic acid ameliorates severity of Clostridioides difficile infection in high fat diet-induced obese mice

Shinsmon Jose,Senad Divanovic,Maria E Moreno-Fernandez,Kenneth D.R Setchell,David B Haslam,Divya Sharma,Heidi Andersen,Anindita Mukherjee,Olivia Horrigan,Wujuan Zhang,Rajat Madan

doi:10.1038/s41385-020-00338-7

Abstract

Severe Clostridiodes difficile infection (CDI) is life-threatening and responds poorly to treatment. Obesity is associated with development of severe CDI. Therefore, to define the mechanisms that exacerbate disease severity, we examined CDI pathogenesis in high-fat diet (HFD)-fed obese mice. Compared to control mice, HFD-fed mice failed to clear C. difficile bacteria which resulted in protracted diarrhea, weight loss and colonic damage. After infection, HFD-induced obese mice had an intestinal bile acid (BA) pool that was dominated by primary BAs which are known promoters of C. difficile spore germination, and lacked secondary BAs that inhibit C. difficile growth. Concurrently, synthesis of primary BAs from liver was significantly increased in C. difficile-infected HFD-fed mice. A key pathway that regulates hepatic BA synthesis is via feedback inhibition from intestinal Farnesoid X receptors (FXRs). Our data reveal that the proportion of FXR agonist BAs to FXR antagonist BAs in the intestinal lumen was significantly reduced in HFD-fed mice after CDI. Treatment of HFD-fed mice with an FXR agonist Obeticholic acid, resulted in decreased primary BA synthesis, fewer C. difficile bacteria and better CDI outcomes. Thus, OCA treatment holds promise as a therapy for severe CDI.

Highlights

Clostridioides difficile (C. difficile), the leading cause of nosocomial infections in the U.S, is responsible for >400,000 cases and 29,000 deaths every year.[1]
Congruent with published studies that diet and obesity affect bile acid (BA) metabolism and their composition,[26,27] we found significant differences between cecal BA profiles of uninfected mice (Fig. 5a, left 2 panels): high-fat diet (HFD)-fed mice had higher levels of both primary and secondary BAs compared to RD-fed mice (Fig. 5b, c and Disease severity was evaluated based on diarrhea score (b), duration of diarrhea (c), and percentage change in body weight after C. difficile infection (CDI) (d)
We show that HFD-induced obese mice: (i) failed to clear C. difficile bacteria and exhibited protracted diarrhea and tissue injury; (ii) had delayed restoration of gut microbiome and BA metabolome after CDI; and (iii) exhibited increased primary BA synthesis after CDI

Summary

Introduction

Clostridioides difficile (C. difficile), the leading cause of nosocomial infections in the U.S, is responsible for >400,000 cases and 29,000 deaths every year.[1]. An important biological mechanism by which gut commensals resist CDI is by modulating intestinal bile acid (BA) metabolome that in turn affects the bacterial lifecycle.[3,5,6,7,8] Primary BAs [Cholic acid (CA) and chenodeoxycholic acid (CDCA)] are synthesized in the liver, conjugated with glycine or taurine, and released into the intestinal lumen where they are converted to unconjugated primary and secondary BAs by bacteria-derived enzymes.[9,10] These BA metabolites directly influence various aspects of the C. difficile life cycle. Most secondary BAs (e.g. deoxycholate, DCA; lithocholate, LCA; ursodeoxycholic acid, UDCA; hyodeoxycholate, HDCA; omega-muricholic acid, ωMCA) resist spore germination and arrest the growth of vegetative C. difficile bacteria.[7] In vivo, the fecal BA profile of patients with recurrent and protracted CDI is dominated by primary BAs with fewer secondary BAs.[11]

Methods

Results

Conclusion