The contribution of bile acid metabolism to the pathogenesis of Clostridioides difficile infection

Abstract

Clostridioides difficile infection (CDI) remains a major global cause of gastrointestinal infection, with significant associated morbidity, mortality and impact upon healthcare system resources. Recent antibiotic use is a key risk factor for the condition, with the marked antibiotic-mediated perturbations in gut microbiome diversity and composition that underpin the pathogenesis of CDI being well-recognised. However, only relatively recently has further insight been gained into the specific mechanistic links between these gut microbiome changes and CDI, with alteration of gut microbial metabolites - in particular, bile acid metabolism - being a particular area of focus. A variety of in vitro, ex vivo, animal model and human studies have now demonstrated that loss of gut microbiome members with bile-metabolising capacity (including bile salt hydrolases, and 7-α-dehydroxylase) - with a resulting alteration of the gut bile acid milieu - contributes significantly to the disease process in CDI. More specifically, this microbiome disruption results in the enrichment of primary conjugated bile acids (including taurocholic acid, which promotes the germination of C. difficile spores) and loss of secondary bile acids (which inhibit the growth of C. difficile, and may bind to and limit activity of toxins produced by C. difficile). These bile acid changes are also associated with reduced activity of the farnesoid X receptor pathway, which may exacerbate C. difficile colitis throughout its impact upon gut barrier function and host immune/inflammatory response. Furthermore, a key mechanism of efficacy of faecal microbiota transplant (FMT) in treating recurrent CDI has been shown to be restoration of gut microbiome bile metabolising functionality; ensuring the presence of this functionality among defined microbial communities (and other 'next generation' FMT products) designed to treat CDI may be critical to their success.

Keywords: Clostridioides difficile infection; bile acids; faecal microbiota transplant; farnesoid X receptor; gut microbiome; metabolomics.

Figure 1.

Schematic of gut microbiota–bile acid interactions in humans. The primary bile acids CA and CDCA are conjugated with taurine and glycine within the liver, and secreted through the biliary system into the small intestine. Once entering the distal gut, the enzyme BSH (found distributed widely amongst gut microbiome members) removes these taurine and glycine conjugates, reforming unconjugated CA and CDCA. Following on from this, the complex, multi-step process of 7-α-dehydroxylation also occurs through microbially derived enzymes, and converts primary to secondary bile acids (specifically, CA is converted to DCA, and CDCA is converted to LCA). A range of other microbially derived enzymes are also able to perform biotransformations upon primary bile acids, for example, 7 α/β-epimerisation to form ursodeoxycholic acid. TCA is the major endogenous trigger to Clostridioides difficile germination (with glycine as co-germinant); CA and DCA (at high concentrations) also trigger C. difficile germination. However, DCA and LCA at physiological concentrations inhibit TCA-mediated C. difficile germination^,; these and other secondary bile acids also inhibit the vegetative growth and toxin activity of C. difficile.^– CDCA also inhibits the germination of C. difficile. The altered bile acid milieu found in the CDI gut is also associated with reduced signalling via the FXR-FGF-19 pathway, which may exacerbate CDI via a number of routes (see main text). Green arrows, microbially mediated biotransformations; red dotted arrows, impacts of bile acids upon the life cycle of C. difficile; purple dotted arrows, impacts of bile acids upon the FXR pathway. Adapted from Mullish et al. BSH, bile salt hydrolase; CA, cholate, CDCA, chenodeoxycholate, DCA, deoxycholic acid; FGF, fibroblast growth factor; FXR, farnesoid X receptor; LCA, lithocholic acid; TCA, taurocholate.