Ursodeoxycholic Acid Inhibits Clostridium difficile Spore Germination and Vegetative Growth, and Prevents the Recurrence of Ileal Pouchitis Associated With the Infection

Abstract

Goals: To test whether ursodeoxycholic acid (UDCA) is inhibitory to Clostridium difficile and can be used in the treatment of C. difficile-associated ileal pouchitis.

Background: The restoration of secondary bile metabolism may be the key mechanism for fecal microbiota transplantation (FMT) in treating recurrent C. difficile infections (RCDI). Therefore, it is possible that exogenous administration of inhibitory bile acids may be used directly as nonantibiotic therapeutics for this indication. The need for such a treatment alternative is especially significant in patients with refractory C. difficile-associated pouchitis, where the efficacy of FMT may be limited.

Study: We measured the ability of UDCA to suppress the germination and the vegetative growth of 11 clinical isolate strains of C. difficile from patients treated with FMT for RCDI. In addition, we used oral UDCA to treat a patient with RCDI pouchitis that proved refractory to multiple antibiotic treatments and FMT.

Results: UDCA was found to be inhibitory to the germination and the vegetative growth of all C. difficile strains tested. Fecal concentrations of UDCA from the patient with RCDI pouchitis exceeded levels necessary to inhibit the germination and the growth of C. difficile in vitro. The patient has remained infection free for over 10 months after the initiation of UDCA.

Conclusions: UDCA can be considered as a therapeutic option in patients with C. difficile-associated pouchitis. Further studies need to be conducted to define the optimal dose and duration of such a treatment. In addition, bile acid derivatives inhibitory to C. difficile that are able to achieve high intracolonic concentrations may be developed as therapeutics for RCDI colitis.

Figures

Figure 1. UDCA inhibits germination and growth of C. difficile isolated from patient stool

A) Relative OD600 of spores isolated from patient exposed to 0.5 mM (■), 1 mM (♦), or 2 mM (▲) UDCA in the presence of 2 mM TA vs. 2 mM TA alone (●). OD600(t)/OD600(t0) = OD600 normalized to initial OD600 (relative OD600). B) Growth of vegetative cells from C. difficile isolate in BHIS alone (●) or BHIS with 2 mM UDCA (▲). * = p<0.01, ** = p<0.0001. TA: taurocholate; UDCA: ursodeoxycholic acid. Data represent mean ± SEM.

Figure 2. UDCA is detectable in patient feces

Concentration of UDCA (●) and taurocholate (▲) in patient feces before and after initiation of UDCA therapy. Timing of significant clinical events is noted. TA: taurocholate; UDCA: ursodeoxycholic acid.

Figure 3. UDCA inhibits C. difficile spore germination

A) Mean relative OD600 of spores from 10 isolates after 20 min exposure to 0.5, 1, or 2 mM UDCA in the presence of 2 mM TA vs. 2 mM TA alone. OD600(t)/OD600(t0) = OD600 normalized to initial OD600 (relative OD600); * = p<0.01. TA: taurocholate; UDCA: ursodeoxycholic acid. Data represent mean ± SEM. B) Mean OD600 at 24 hr across 10 isolates. UDCA: ursodeoxycholic acid. * = p<0.0001. Data represent mean ± SEM.