Bile acids impact the microbiota, host, and C. difficile dynamics providing insight into mechanisms of efficacy of FMTs and microbiota-focused therapeutics

Abstract

Clostridioides difficile is a major nosocomial pathogen, causing significant morbidity and mortality worldwide. Antibiotic usage, a major risk factor for Clostridioides difficile infection (CDI), disrupts the gut microbiota, allowing C. difficile to proliferate and cause infection, and can often lead to recurrent CDI (rCDI). Fecal microbiota transplantation (FMT) and live biotherapeutic products (LBPs) have emerged as effective treatments for rCDI and aim to restore colonization resistance provided by a healthy gut microbiota. However, much is still unknown about the mechanisms mediating their success. Bile acids, extensively modified by gut microbes, affect C. difficile's germination, growth, and toxin production while also shaping the gut microbiota and influencing host immune responses. Additionally, microbial interactions, such as nutrient competition and cross-feeding, contribute to colonization resistance against C. difficile and may contribute to the success of microbiota-focused therapeutics. Bile acids as well as other microbial mediated interactions could have implications for other diseases being treated with microbiota-focused therapeutics. This review focuses on the intricate interplay between bile acid modifications, microbial ecology, and host responses with a focus on C. difficile, hoping to shed light on how to move forward with the development of new microbiota mediated therapeutic strategies to combat rCDI and other intestinal diseases.

Keywords: Clostridioides difficile; bile acids; fecal microbiota transplantation; microbiota; nuclear receptors; recurrent CDI.

Figure 1.

The gut microbiota modifies bile acids which are able to inhibit different stages of the C. difficile life cycle. (a) Basic overview of the main bile acid altering enzymes discussed in this review. BSHs deconjugate and reconjugate bile acids with an amino acid or directly exchange the conjugated amino acid for another. Amino acids can be host or microbial conjugated. The bai operon removes a 7α-hydroxyl group producing secondary bile acids. HSDHs dehydroxylate bile acids resulting in an oxo-bile acid, in this case a oxo-secondary bile acid. (b) Effect of bile acids on different stages of the C. difficile life cycle in vitro. TCA mediated spore germination of C. difficile spores (grey arrow) is inhibited by various bile acids (red box).^, outgrowth of vegetative C. difficile is impacted by a variety of bile acids (red box).^, the production of toxin is inhibited by bile acids (red box) through reducing expression of toxin or toxin activity.^,, bile acids also bind directly to C. difficile toxin, reducing its toxicity in the host (red box). abbreviations: AA, amino acid; Ala, alanine; BSH, bile salt hydrolase; bai, bile acid inducible; CA, cholate; CDCA, chenodeoxycholate; DCA, deoxycholate; glu, glutamate; gly, glycine; HDCA, hyodeoxycholate; his, histidine; HSDH, hydroxysteroid dehydrogenase; iDCA, isodeoxycholate; iaLCA, isoallolithocholate; iLCA, isolithocholate; LCA, lithocholate; phe, phenylalanine; ser, serine; tau, taurine; trp, tryptophan; tyr, Tyrosine; UDCA, ursodeoxycholate; αMCA, α-muricholate; βMCA, β-muricholate; ωMCA, ω-muricholate; 3-oxo LCA, 3-oxolithocholate.