The role of bile acid metabolism recovery in treatment of C. difficile infection

描述（由申请人提供）：在过去的二十年中，由于出现了更强毒的病原体菌株，艰难梭菌感染（CDI）已达到流行病的程度。粪便微生物群移植（FMT）已成为许多难以单独抗生素治疗的患者的潜在解决方案。我们和其他人之前已经证明，FMT可以迅速恢复与捐赠者相似的正常粪便细菌组成。我们还表明，正常肠道微生物生态的恢复伴随着粪便代谢组的重大变化，其中重要的是粪胆汁酸组成的正常化。对胆汁酸的关注与机制相关，因为已知胆汁酸在艰难梭菌的生命周期中起重要作用。具体来说，牛磺胆酸（一种主要的初级胆汁酸）是一种

DESCRIPTION (provided by applicant): Over the past two decades Clostridium difficile infection (CDI) has reached epidemic proportions due to emergence of more virulent strains of the pathogen. Fecal microbiota transplantation (FMT) has emerged as a potential solution for many patients refractory to antibiotic treatment alone. We and others have previously shown that FMT promptly restores normal fecal bacterial composition similar to that of the donors. We had also shown that recovery of normal microbial gut ecology is accompanied by major changes in the fecal metabolome, which importantly includes normalization of fecal bile acid composition. The focus on bile acids is mechanistically relevant because they are known to play important roles in the lifecycle of C. difficile. Specifically, taurocholate (a major primary bile acid) is a potent germinant of C. difficile spores, and a critical component of C. difficile growth media in the laboratory. In contrast, lithocholate and deoxycholate (dominant secondary bile acids) are inhibitors of C. difficile spore germination and vegetative growth, respectively. We found that fecal samples from RCDI patients before FMT contain no detectable secondary bile acids, but do have elevated concentrations of primary bile acids. Fecal samples taken from the same patients after FMT contain donor-like fecal bile acid composition. Therefore, our central hypothesis is that antibiotics used to treat CDI patients alter bile acid metabolism to favor C. difficile germination and growth, and FMT restores the normal bile acid composition that is inhospitable to C. difficile expansion. In this proposal we will extend our exploratory preliminary results and test this hypothesis by performing quantitative analysis of bile acid metabolism in patients with RCDI pre- and post-FMT and testing pre- and post-FMT fecal samples for germinant activity and growth inhibition on clinical isolates of C. difficile bacteria. In additionwe will test one non-FMT approach to alter bile acid composition unfavorable to C. difficile: a bile acid sequestrant resin, cholestyramine, in combination with lovastatin. The latter will be used to inhibit compensatory increase in de novo bile acid synthesis in the liver. Results of this work wil inform future clinical trials in treating patients with refractory CDI by targeting bile acid metabolism.