2023 journal article

Intestinal bile acids provide a surmountable barrier against C. difficile TcdB-induced disease pathogenesis

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 120(19).

By: S. Icho*, J. Ward*, J. Tam *, L. Kociolek *, C. Theriot n & R. Melnyk *

author keywords: toxin; host; C; difficile; pathogenesis; bile acid
MeSH headings : Humans; Mice; Animals; Bacterial Toxins; Clostridioides difficile; Bile Acids and Salts; Clostridium Infections / pathology; Intestines / pathology; Bacterial Proteins
TL;DR: It is shown that small molecules extracted from intestinal samples from mice and humans protect against low to moderate levels of TcdB; however, at higher concentrations of toxin, inhibition is overcome and an anti-toxin approach to treat disease is provided. (via Semantic Scholar)
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Source: Web Of Science
Added: August 21, 2023

Intestinal bile acids play an essential role in the Clostridioides difficile lifecycle having been shown in vitro to modulate various aspects of pathogenesis, including spore germination, vegetative growth, and more recently the action of the primary virulence determinant, TcdB. Here, we investigated whether physiological levels of the total pool of intestinal bile acids in mice and humans protect against TcdB action. Small molecules extracted from the lumenal contents of the small intestine, cecum, colon, and feces were found to inhibit TcdB in accordance with the differential amounts of total bile acids in each compartment. Extracts from antibiotic-treated and germ-free mice, despite harboring dramatically altered bile acid profiles, unexpectedly also prevented TcdB-induced cell rounding to similar extents. We show that protection, however, is surmountable and can be overcome at higher doses of TcdB—typical to those seen during severe C. difficile infection—suggesting that the protective properties of intestinal bile acids are operant primarily under low to moderate toxin levels. Taken together, these findings demonstrate a role for intestinal bile acids in attenuating virulence, provide insights into asymptomatic carriage of toxigenic C. difficile , and inform strategies to manipulate bile acid levels for therapeutic benefit.