Role of Bile Acids in Human Susceptibiity to Clostridium difficile Infection

胆汁酸在人类对艰难梭菌感染易感性中的作用

• 批准号: 8571142
• 负责人: Yoav Golan
• 金额: $ 25.56万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8571142
• 关键词: Anaerobic Bacteria; Anti-Infective Agents; Antibiotic Therapy; Antibiotics; Appearance; Bacteria; Bacteroides; Bile Acids; Bile fluid; Biological Assay; Blinded; Characteristics; Cholates; Clostridium; Clostridium difficile; Colon; Communities; Community-Acquired Infections; Detection; Diagnosis; Diagnostic; Diarrhea; Disease; Disease Outbreaks; Disease Outcome; Elderly; Exposure to; Family; Feces; Frequencies; Gastrointestinal tract structure; Germination; Growth; Hospitals; Human; Infection; Inflammation; Intestines; Laboratories; Liver; Metabolic; Metabolism; Metronidazole; North America; Nosocomial Infections; Patients; Predisposition; Proteins; Recurrence; Relapse; Relative (related person); Reproduction spores; Research Personnel; Resistance; Risk; Risk Factors; Role; Sampling; Severities; Specimen; Symptoms; Taurine Cholate; Taurocholate Sodium; Toxin; Vaccines; Vancomycin; Virulence Factors; Work; absorption; analog; bile salts; chenodeoxycholate; combat; deoxycholate; factor C; high risk; hydroxyl group; intestinal epithelium; killings; member; novel; prevent; prospective; public health relevance; research study; tertiary care

DESCRIPTION (provided by applicant): Clostridium difficile has become the most frequent cause of antibiotic-associated diarrhea. Moreover, the need to prevent/treat C. difficile infection (CDI) effectively has become more urgent as the severity of CDI has increased. Whereas in the past CDI was rarely a fatal disease, it now kills a significant number of patients, especially among the elderly or immunologically suppressed. Currently employed antibiotics (chiefly vancomycin and metronidazole) fail to eliminate CDI symptoms in 10-20% of patients. In addition, among those apparently cured, a significant fraction suffers multiple recurrences of CDI. In principle, it is better to prevent the occurrence of infection than to rely on post-infectin treatments. The infectious form of C. difficile is the spore; once spores enter the GI tract, they must germinate in order to return to vegetative growth, colonize and produce the toxin proteins that cause the symptoms of the disease. Previous work has shown that C. difficile spore germination is dependent on certain bile acids. The most effective germinant identified so far is the primary bile salt, sodium taurocholate. A metabolic product of taurocholate, deoxycholate, is produced by the normal microflora and is known to kill C. difficile. Interestingly, bile acids of te chenodeoxycholate family, which differ from the cholate family by a single hydroxyl group, are anti-germinant that competitively inhibit taurocholate-dependent germination. These findings have raised the possibility that certain bile acids or their derivatives could be used prophylactically to reduce the likelihood of CDI in patients who are at risk. Before doing so, however, it is critical to establish that patients who have CDI or who are at risk of becoming infected have an intestinal bile acid profile that favors C. difficile spore germination. If so, on could imagine delivering appropriate anti-germinant or growth-inhibiting bile acids to patients at risk to prevent the onset on CDI. In this proposal, we seek to reveal the relationship between bile acid profiles and likelihood of CDI by analyzing the bile acid profiles and presence of certai key members of the microflora in patients with CDI, in patients undergoing antibiotic therapy (which is a major risk factor for CDI) and in patients with recurrent CDI.

描述（由申请人提供）：艰难梭菌已成为抗生素相关性腹泻的最常见原因。此外，需要预防/治疗艰难梭菌感染 随着 CDI 严重程度的增加，（CDI）有效地变得更加紧迫。过去，CDI 很少是致命疾病，但现在它会导致大量患者死亡，特别是老年人或免疫抑制患者。目前使用的抗生素（主要是万古霉素和甲硝唑）无法消除 10-20% 患者的 CDI 症状。此外，在那些明显治愈的患者中，很大一部分患有 CDI 多次复发。原则上，预防感染的发生比依赖感染后治疗更好。艰难梭菌的传染性形式是孢子；一旦孢子进入胃肠道，它们必须发芽才能恢复营养生长、定殖并产生引起疾病症状的毒素蛋白。先前的工作表明，艰难梭菌孢子的萌发依赖于某些胆汁酸。迄今为止发现的最有效的起始剂是初级胆盐牛磺胆酸钠。牛磺胆酸盐的代谢产物脱氧胆酸盐是由正常微生物群产生的，已知可以杀死艰难梭菌。有趣的是，鹅去氧胆酸家族的胆汁酸与胆酸家族的区别在于单个羟基，是抗发芽剂，可竞争性抑制牛磺胆酸依赖性发芽。这些发现提出了某些胆汁酸或其衍生物可用于预防性使用以降低高危患者发生 CDI 的可能性的可能性。然而，在此之前，至关重要的是要确定患有 CDI 或有感染风险的患者是否具有有利于艰难梭菌孢子萌发的肠道胆汁酸特征。如果是这样，我们可以想象向有风险的患者提供适当的抗芽剂或生长抑制胆汁酸，以预防 CDI 的发作。在本提案中，我们试图通过分析 CDI 患者、接受抗生素治疗的患者（这是 CDI 的主要危险因素）和复发性 CDI 患者的胆汁酸谱和微生物区系某些关键成员的存在，来揭示胆汁酸谱与 CDI 可能性之间的关系。