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

胆汁酸代谢恢复在治疗艰难梭菌感染中的作用

• 批准号: 9057950
• 负责人: Chi Chen
• 金额: $ 18.82万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-22 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057950
• 关键词: Affect; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bile Acid Biosynthesis Pathway; Bile Acids; Biological Availability; Cholestyramine; Clinical; Clinical Trials; Clostridium difficile; Collection; Colon; Communities; Culture Media; Diarrhea; Disease; Ecology; Epidemic; Excretory function; Feces; Foundations; Future; Germination; Growth; Health; Health care facility; Hepatic; Hour; Infection; Intestines; Investigation; Laboratories; Liver; Lovastatin; Mainstreaming; Measures; Mediating; Metabolism; Nosocomial Infections; Organism; Patients; Plant Resins; Plasma; Play; Procedures; Production; Protocols documentation; Recovery; Recurrence; Refractory; Relapse; Reporter; Reproduction spores; Risk; Risk Factors; Role; Sampling; Serum; Structure; Syndrome; Taurine Cholate; Taurocholic Acid; Test Result; Testing; Transplantation; Virulent; Work; aqueous; cholest-4-en-3-one; deoxycholate; experience; fecal transplantation; inhibitor/antagonist; metabolome; microbial; microbiota; novel; novel therapeutics; pathogen; prevent; relapse patients; restoration

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.

描述（由申请人提供）：在过去的二十年中，由于出现了更强的病原体菌株，艰难梭菌感染（CDI）已达到流行病的比例。粪便微生物群移植（FMT）已成为许多单独抗生素治疗难治性患者的潜在解决方案。我们和其他人以前已经表明，FMT迅速恢复正常的粪便细菌组成类似于捐助者。我们还表明，正常微生物肠道生态的恢复伴随着粪便代谢组的重大变化，其中重要的是包括粪便胆汁酸组成的正常化。对胆汁酸的关注在机制上是相关的，因为已知它们在C的生命周期中起重要作用。很难具体而言，牛磺胆酸盐（主要的初级胆汁酸）是一种抗氧化剂。 C.的有力萌芽。艰难梭菌孢子是C.在实验室中培养艰难梭菌。相反，石胆酸盐和脱氧胆酸盐（主要次级胆汁酸）是C。difficile孢子萌发和营养生长。我们发现，FMT前RCDI患者的粪便样本中不含可检测到的次级胆汁酸，但初级胆汁酸浓度升高。FMT后从相同患者采集的粪便样品含有供体样粪便胆汁酸成分。因此，我们的中心假设是，用于治疗CDI患者的抗生素改变了胆汁酸代谢，有利于C。艰难梭菌的萌发和生长，FMT恢复正常的胆汁酸组成，这是不适合C。艰难的扩张在本提案中，我们将扩大我们的探索性初步 结果，并通过对FMT前后RCDI患者的胆汁酸代谢进行定量分析，并测试FMT前后粪便样本对临床分离的C.艰难杆菌此外，我们将测试一种非FMT方法来改变对C不利的胆汁酸组成。difficile：一种胆汁酸螯合剂树脂，考来烯胺，与洛伐他汀组合。后者将用于抑制肝脏中胆汁酸从头合成的代偿性增加。这项工作的结果将为未来通过靶向胆汁酸代谢治疗难治性CDI患者的临床试验提供信息。

项目成果

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

• DOI: 10.1097/mcg.0000000000000427
• 发表时间: 2016-09
• 期刊: Journal of clinical gastroenterology
• 影响因子: 2.9
• 作者: Weingarden AR;Chen C;Zhang N;Graiziger CT;Dosa PI;Steer CJ;Shaughnessy MK;Johnson JR;Sadowsky MJ;Khoruts A
• 通讯作者: Khoruts A

Predicting recurrence of Clostridium difficile infection following encapsulated fecal microbiota transplantation.

• DOI: 10.1186/s40168-018-0549-6
• 发表时间: 2018-09-18
• 期刊: Microbiome
• 影响因子: 15.5
• 作者: Staley C;Kaiser T;Vaughn BP;Graiziger CT;Hamilton MJ;Rehman TU;Song K;Khoruts A;Sadowsky MJ
• 通讯作者: Sadowsky MJ

Successful Resolution of Recurrent Clostridium difficile Infection using Freeze-Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study.

• DOI: 10.1038/ajg.2017.6
• 发表时间: 2017-06
• 期刊: The American journal of gastroenterology
• 作者: Staley C;Hamilton MJ;Vaughn BP;Graiziger CT;Newman KM;Kabage AJ;Sadowsky MJ;Khoruts A
• 通讯作者: Khoruts A

Gut-sparing treatment of urinary tract infection in patients at high risk of Clostridium difficile infection.

艰难梭菌感染高危患者尿路感染的肠道保护治疗。

• DOI: 10.1093/jac/dkw499
• 发表时间: 2017
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Staley,Christopher;Vaughn,ByronP;Graiziger,CarolynT;Sadowsky,MichaelJ;Khoruts,Alexander
• 通讯作者: Khoruts,Alexander

Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial.

• DOI: 10.7326/m16-0271
• 发表时间: 2016-11-01
• 期刊: Annals of internal medicine
• 影响因子: 39.2
• 作者: Kelly CR;Khoruts A;Staley C;Sadowsky MJ;Abd M;Alani M;Bakow B;Curran P;McKenney J;Tisch A;Reinert SE;Machan JT;Brandt LJ
• 通讯作者: Brandt LJ