Identification of Intestinal Bacteria Protective against C. Difficile Colitis

鉴定可预防艰难梭菌结肠炎的肠道细菌

• 批准号: 8206591
• 负责人: ALEXANDER KHORUTS
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206591
• 关键词: Adult; Antibiotic Therapy; Antibiotics; Bacteria; Bioinformatics; Birth; Case Study; Clinical; Clostridium difficile; Colitis; Colon; Complementarity Determining Regions; Computing Methodologies; DNA Sequence; Data; Dependency; Disease; Drug Formulations; Elements; Ensure; Environment; Esthetics; Exotoxins; Exposure to; Feces; Foundations; Functional disorder; Funding; Future; Gastrointestinal Diseases; Gastrointestinal tract structure; Goals; Grant; Growth; Human; Individual; Infection; Institution; Intestines; Lead; Life; Medical; Metagenomics; Metronidazole; Molecular; Patients; Performance; Play; Preparation; Probiotics; Procedures; Public Health; Recurrence; Recurrent disease; Refractory; Role; Sampling; Specific qualifier value; Staging; Study Subject; System; Therapeutic; Time; Transplantation; Vancomycin; Work; commensal microbes; conventional therapy; disorder control; microbial; microbial host; microbiome; microorganism; microorganism interaction; mortality; next generation; prevent; programs; public health relevance; rRNA Genes; reconstitution; restoration; success

DESCRIPTION (provided by applicant): Clostridium difficile associated disease (CDAD) is a major growing public health problem. The growth of C. difficile bacteria in the colon is thought to be inhibited by normal constituents of the mutualist bacteria flora. Therefore, the major trigger for the C. difficile infection is exposure to antibiotics which alter the composition of the normal intestinal microbiota. About 20% of patients with CDAD fail conventional therapy with antibiotics and develop recurrent disease. A significant fraction of these patients develop life-long dependency on antibiotics and often dysfunction of their gastrointestinal tract. Other patients develop fulminant disease, which is associated with high mortality rate. The protective role of the normal intestinal flora is supported by clinical success of bacteriotherapy by way of fecal transplantation. In this procedure the intestinal tracts of patients with recurrent CDAD are inoculated with fecal material from healthy donors. We had recently demonstrated in a case report that this procedure indeed is associated with establishment of donor bacteria in the recipient's colon. However, fecal transplantation is not widely available because of practical and aesthetic considerations. Our long-term goal is to develop a standardized, easy-to- administer formulation of colonic bacteria that can efficiently treat patients with CDAD. In this proposal we will use massively parallel pyrosequencing of hypervariable regions from SSU rRNA genes to characterize the composition of fecal material from patients with recurrent CDAD and their donors. In this exploratory work we will obtain critical data in pursuit of the following specific aims: 1) Determine the composition and diversity of the patient fecal microbiome before and after bacteriotherapy, 2) Determine the rate of recolonization and stability of the fecal microbiome following bacteriotherapy, and 3) Determine if a fecal sample from a single donor can be preserved and later used to restore normal bowel functioning to several CDAD patients. The data obtained from the first aim will form the foundation for future extension of this work requiring more patients. The results will allow us to perform power calculations to determine the number of patients needed in such studies to obtain more definitive results. Bacteriotherapy of patients with CDAD represents a unique opportunity to study establishment of new microflora in an adult patient. The data obtained from the second aim will lay the foundation into future studies that will be further investigate host- microbial interactions in this unique clinical situation. Finally, the third aim represents the first step toward our ultimate goal and has the potential to significantly reduce the complexity of the pursuit for the signature of healthy, protective colonic microflora. PUBLIC HEALTH RELEVANCE: Clostridium difficile is the major known cause of antibiotic associated disease, and represents a growing problem. We are normally protected against this infection by normal bacteria that live in our intestines. Antibiotics used in medical practice weaken this protection. A significant fraction of patients with this infection cannot be treated by conventional treatments, which also involve antibiotics. Our ultimate goal is to develop a standardized formulation of protective bacteria. In this grant we will make critical initial steps toward this goal by studying composition of intestinal bacteria in patients undergoing fecal transplantation for C. difficile infection refractory to conventional treatment.

描述（由申请人提供）：艰难梭菌相关疾病（CDAD）是一个主要的日益严重的公共卫生问题。C.结肠中的艰难梭菌被认为受到互利共生细菌植物群的正常成分的抑制。因此，C.艰难梭菌感染是暴露于改变正常肠道微生物群组成的抗生素。约20%的CDAD患者常规抗生素治疗失败，并出现疾病复发。这些患者中有很大一部分会终生依赖抗生素，并经常出现胃肠道功能障碍。其他患者发展为暴发性疾病，这与高死亡率相关。正常肠道植物群的保护作用得到了粪便移植细菌治疗临床成功的支持。在该过程中，用来自健康供体的粪便材料接种患有复发性CDAD的患者的肠道。我们最近在一份病例报告中证明，这种方法确实与受体结肠中供体细菌的建立有关。然而，由于实用和美观方面的考虑，粪便移植并不广泛。我们的长期目标是开发一种标准化，易于管理的结肠细菌制剂，可以有效地治疗CDAD患者。在这项提案中，我们将使用大规模平行焦磷酸测序的高变区从SSU rRNA基因的粪便材料的组成特征与复发性CDAD患者和他们的捐助者。在这项探索性工作中，我们将获得关键数据，以实现以下具体目标：1）确定细菌疗法之前和之后患者粪便微生物组的组成和多样性，2）确定细菌疗法之后粪便微生物组的细菌化速率和稳定性，和3）确定是否可以保存来自单个供体的粪便样品，并随后用于恢复几个CDAD患者的正常肠功能。从第一个目标中获得的数据将为未来需要更多患者的这项工作的扩展奠定基础。这些结果将使我们能够进行功效计算，以确定此类研究中所需的患者数量，以获得更明确的结果。CDAD患者的细菌治疗代表了研究成年患者中新微生物群建立的独特机会。从第二个目标获得的数据将为未来的研究奠定基础，这些研究将进一步研究这种独特临床情况下的宿主-微生物相互作用。最后，第三个目标代表了实现我们最终目标的第一步，并有可能显着降低追求健康，保护性结肠微生物群落的复杂性。 公共卫生相关性：艰难梭菌是抗生素相关疾病的主要已知原因，并代表了一个日益严重的问题。我们通常通过生活在我们肠道中的正常细菌来保护我们免受这种感染。医疗实践中使用的抗生素削弱了这种保护。很大一部分患有这种感染的患者无法通过常规治疗进行治疗，这些治疗也涉及抗生素。我们的最终目标是开发一种标准化的保护性细菌配方。在这项资助中，我们将通过研究接受粪便移植治疗C。传统治疗难以治愈的艰难感染。

项目成果

Large proximal serrated polyps: natural history and colorectal cancer risk in a retrospective series.

大近端锯齿状息肉：回顾性系列的自然史和结直肠癌风险。

• DOI: 10.1097/mcg.0b013e318293a656
• 发表时间: 2013
• 期刊: Journal of clinical gastroenterology
• 影响因子: 2.9
• 作者: Bouwens,MariëlleWE;Riedl,RobertG;Bosman,FredT;Driessen,Ann;Sanduleanu,Silvia
• 通讯作者: Sanduleanu,Silvia

Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection.

• DOI: 10.1186/s40168-015-0070-0
• 发表时间: 2015
• 期刊: Microbiome
• 影响因子: 15.5
• 作者: Weingarden A;González A;Vázquez-Baeza Y;Weiss S;Humphry G;Berg-Lyons D;Knights D;Unno T;Bobr A;Kang J;Khoruts A;Knight R;Sadowsky MJ
• 通讯作者: Sadowsky MJ

From stool transplants to next-generation microbiota therapeutics.

• DOI: 10.1053/j.gastro.2014.01.004
• 发表时间: 2014-05
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Petrof EO;Khoruts A
• 通讯作者: Khoruts A

Interaction of gut microbiota with bile acid metabolism and its influence on disease states.

• DOI: 10.1007/s00253-016-8006-6
• 发表时间: 2017-01
• 期刊: APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
• 影响因子: 5
• 作者: Staley, Christopher;Weingarden, Alexa R.;Khoruts, Alexander;Sadowsky, Michael J.
• 通讯作者: Sadowsky, Michael J.

Resolution of severe Clostridium difficile infection following sequential fecal microbiota transplantation.

连续粪便微生物移植后严重艰难梭菌感染的解决。

• DOI: 10.1097/mcg.0b013e31829004ae
• 发表时间: 2013
• 期刊: Journal of clinical gastroenterology
• 影响因子: 2.9
• 作者: Weingarden,AlexaR;Hamilton,MatthewJ;Sadowsky,MichaelJ;Khoruts,Alexander
• 通讯作者: Khoruts,Alexander