Bile acid-independent protection against Clostridioides difficile infection

Abstract

Clostridioides difficile infections occur upon ecological / metabolic disruptions to the normal colonic microbiota, commonly due to broad-spectrum antibiotic use. Metabolism of bile acids through a 7α-dehydroxylation pathway found in select members of the healthy microbiota is regarded to be the protective mechanism by which C. difficile is excluded. These 7α-dehydroxylated secondary bile acids are highly toxic to C. difficile vegetative growth, and antibiotic treatment abolishes the bacteria that perform this metabolism. However, the data that supports the hypothesis that secondary bile acids protect against C. difficile infection is supported only by in vitro data and correlative studies. Here we show that bacteria that 7α-dehydroxylate primary bile acids protect against C. difficile infection in a bile acid-independent manner. We monoassociated germ-free, wildtype or Cyp8b1-/- (cholic acid-deficient) mutant mice and infected them with C. difficile spores. We show that 7α-dehydroxylation (i.e., secondary bile acid generation) is dispensable for protection against C. difficile infection and provide evidence that Stickland metabolism by these organisms consumes nutrients essential for C. difficile growth. Our findings indicate secondary bile acid production by the microbiome is a useful biomarker for a C. difficile-resistant environment but the microbiome protects against C. difficile infection in bile acid-independent mechanisms.

The Stickland Reaction Precursor trans -4-Hydroxy- l -Proline Differentially Impacts the Metabolism of Clostridioides difficile and Commensal Clostridia

“…This is particularly interesting given the previous finding that C. hylemonae shows upregulation of the bai operon when exposed to cholate in a defined medium, but not when exposed to cholate in BHI ( 16 , 41 ). Despite recent work that suggests bile acids do not play an essential role in protection against CDI, this study provides further evidence that there is a relationship between nutrient availability and secondary bile acid production in commensal Clostridia ( 42 ). Further work combining bile acids and hydroxyproline, and other amino acids important for Stickland metabolism, are needed to fully dissect transcriptional networks in these organisms and define their individual and combinatorial roles in colonization resistance against C. difficile .…”

Gut feelings: the microbiota-gut-brain axis on steroids

“…However, future studies that characterize microbiota changes in the absence of specific intestinal bile acid species are still required to evaluate their modulatory role on gut microbiota community structure and function. For example, CYP8B1-deficient mice lacking cholic acid and its secondary bile acid derivatives did not demonstrate marked shifts in microbiota composition or function (3). In this same bile-acid deficient model rederived under germfree conditions, microbiota protection (both human and murine) against neurogenic inflammation of the colon was demonstrated to occur independently of bile acid signaling.…”

The gut bacterial community potentiates Clostridioides difficile infection severity

“…Bile acids metabolized by the gut bacteria can inhibit C. difficile growth and affect toxin production (9,10). Bacteria in the gut also can compete more directly with C. difficile through antibiotic production or nutrient consumption (11)(12)(13). While the relationship between the gut bacteria and C. difficile has been established, the effect the gut bacteria can have on CDI disease severity is unclear.…”