AUTHOR=Palmieri Lola-Jade , Rainteau Dominique , Sokol Harry , Beaugerie Laurent , Dior Marie , Coffin Benoit , Humbert Lydie , Eguether Thibaut , Bado André , Hoys Sandra , Janoir Claire , Duboc Henri 

TITLE=Inhibitory Effect of Ursodeoxycholic Acid on Clostridium difficile Germination Is Insufficient to Prevent Colitis: A Study in Hamsters and Humans

JOURNAL=Frontiers in Microbiology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.02849

DOI=10.3389/fmicb.2018.02849

ISSN=1664-302X

ABSTRACT=<p><bold>Introduction:</bold> Bile acids (BA) influence germination and growth of <italic>Clostridium difficile</italic>. Ursodeoxycholic acid (UDCA), a BA minor in human, used for cholestatic liver diseases, inhibits germination and growth of <italic>C. difficile in vitro</italic>, but was never tested <italic>in vivo</italic> with an infectious challenge versus control. We hypothesized that UDCA could prevent CDI. We evaluated the effects of UDCA on <italic>C. difficile in vitro</italic> and in hamsters, with pharmacokinetics study and with an infectious challenge. Then, we studied CDI incidence in UDCA–treated patients.</p><p><bold>Methods:</bold> We evaluated germination and growth of <italic>C. difficile</italic>, with 0.01, 0.05, and 0.1% UDCA. We analyzed fecal BA of hamsters receiving antibiotics and UDCA (50 mg/kg/day), antibiotics, or UDCA alone. Then, we challenged with spores of <italic>C. difficile</italic> at D6 hamsters treated with UDCA (50 mg/kg/day) from D1 to D13, versus control. In human, we analyzed the database of a cohort on CDI in acute flares of inflammatory bowel disease (IBD). As PSC-IBD patients were under UDCA treatment, we compared PSC-IBD patients to IBD patients without PSC.</p><p><bold>Results:</bold><italic>In vitro</italic>, UDCA inhibited germination and growth of <italic>C. difficile</italic> at 0.05 and 0.1%, competing with 0.1% TCA (with 0.1%: 0.05% ± 0.05% colony forming unit versus 100% ± 0%, <italic>P</italic> &lt; 0.0001). In hamsters, UDCA reached high levels only when administered with antibiotics (43.5% UDCA at D5). Without antibiotics, UDCA was in small amount in feces (max. 4.28%), probably because of UDCA transformation into LCA by gut microbiota. During infectious challenge, mortality was similar in animals treated or not with UDCA (62.5%, <italic>n</italic> = 5/8, <italic>P</italic> = 0.78). UDCA percentage was high, similar and with the same kinetics in dead and surviving hamsters. However, dead hamsters had a higher ratio of primary over secondary BA compared to surviving hamsters. 9% (<italic>n</italic> = 41/404) of IBD patients without PSC had a CDI, versus 25% (<italic>n</italic> = 4/12) of PSC-IBD patients treated with UDCA.</p><p><bold>Conclusion:</bold> We confirmed the inhibitory effect of UDCA on growth and germination of <italic>C. difficile in vitro</italic>, with 0.05 or 0.1% UDCA. However, in our hamster model, UDCA was inefficient to prevent CDI, despite high levels of UDCA in feces. Patients with PSC-IBD treated with UDCA did not have less CDI than IBD patients.</p>