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Front. Microbiol. | doi: 10.3389/fmicb.2018.02849

Inhibitory effect of ursodeoxycholic acid on Clostridium difficile germination is insufficient to prevent colitis: a study in hamsters and humans

 Lola-Jade Palmieri1, 2, 3,  Dominique Rainteau1,  Harry Sokol1, 4, Laurent Beaugerie1, 4, Marie Dior5, Benoit Coffin3, 5, Lydie Humbert1,  Thibaut Eguether1, Andre Bado3, Sandra Hoys2,  Claire Janoir-Jouveshomme2 and Henri Duboc3, 5*
  • 1INSERM U1157 Microorganismes, Molécules Bioactives et Physiopathologie Intestinale, France
  • 2unité Bactéries Pathogènes et Santé, Université Paris-Sud, France
  • 3INSERM U1149 Centre de Recherche sur l'Inflammation, France
  • 4Département de Gastroentérologie et Nutrition, Hôpital Saint-Antoine, Assistance Publique Hopitaux De Paris, France
  • 5Hôpital Louis-Mourier, Assistance Publique-Hôpitaux de Paris, France

Introduction
Bile acids (BA) influence germination and growth of Clostridium difficile. Ursodeoxycholic acid (UDCA), a BA minor in human, used for cholestatic liver diseases, inhibits germination and growth of C.difficile in vitro, but was never tested in vivo with an infectious challenge versus control. We hypothesized that UDCA could prevent CDI. We evaluated the effects of UDCA on C.difficile in vitro and in hamsters, with pharmacokinetics study and with an infectious challenge. Then, we studied CDI incidence in UDCA–treated patients.

Methods
We evaluated germination and growth of C.difficile, with 0.01%, 0.05% and 0.1% UDCA. We analyzed fecal BA of hamsters receiving antibiotics and UDCA (50mg/kg/day), antibiotics, or UDCA alone. Then, we challenged with spores of C.difficile 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.

Results
In vitro, UDCA inhibited germination and growth of C.difficile at 0.05% and 0.1%, competing with 0.1% TCA (with 0,1%: 0.05% ±0.05% colony forming unit versus 100% ±0%, P<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%, n=5/8, P=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% (n=41/404) of IBD patients without PSC had a CDI, versus 25% (n=4/12) of PSC-IBD patients treated with UDCA.

Conclusion
We confirmed the inhibitory effect of UDCA on growth and germination of C.difficile in vitro, 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.

Keywords: Clostridium difficile, Ursodeoxycholic Acid, Bile acids, Growth, Germination, inflammatory bowel disease, primary sclerosing cholangitis

Received: 03 Sep 2018; Accepted: 06 Nov 2018.

Edited by:

Tamas Szakmany, Cardiff University, United Kingdom

Reviewed by:

Marcos S. Toledo, Federal University of São Paulo, Brazil
Robin Anderson, Agricultural Research Service, United States Department of Agriculture, United States  

Copyright: © 2018 Palmieri, Rainteau, Sokol, Beaugerie, Dior, Coffin, Humbert, Eguether, Bado, Hoys, Janoir-Jouveshomme and Duboc. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Henri Duboc, INSERM U1149 Centre de Recherche sur l'Inflammation, Paris, 75018, Île-de-France, France, henri.duboc@aphp.fr