Role of Bile Acids in Human Susceptibiity to Clostridium difficile Infection

描述（由申请方提供）：艰难梭菌已成为腹泻相关性腹泻的最常见原因。此外，预防/治疗C.菌感染 (CDI)随着CDI的严重性增加，有效地进行干预变得更加紧迫。虽然在过去CDI很少是一种致命的疾病，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）未能消除10-20%患者的CDI症状。此外，在那些明显治愈，一个显着的分数遭受多次复发的CDI。原则上，预防感染的发生比依赖感染后的治疗更好。C. difficile是孢子;一旦孢子进入胃肠道，它们必须发芽以恢复营养生长，定殖并产生引起疾病症状的毒素蛋白。以前的工作表明C.艰难梭菌孢子萌发依赖于某些胆汁酸。迄今为止，最有效的发芽剂是主要的胆汁盐，牛磺胆酸钠。牛磺胆酸盐的代谢产物脱氧胆酸盐由正常微生物区系产生，已知其可杀死C。很难有趣的是，鹅去氧胆酸盐家族的胆汁酸与胆酸盐家族的区别在于单个羟基，其是竞争性抑制牛磺胆酸盐依赖性萌发的抗萌发剂。这些发现提出了某些胆汁酸或其衍生物可用于预防性降低高危患者发生CDI的可能性的可能性。然而，在此之前，关键是要确定患有CDI或有感染风险的患者的肠道胆汁酸谱有利于C。艰难孢子萌发。如果是这样的话，我们可以想象向有风险的患者提供适当的抗萌发剂或生长抑制胆汁酸，以防止CDI的发作。在该提案中，我们试图通过分析胆汁酸谱和CDI患者、接受抗生素治疗的患者（这是CDI的主要风险因素）和复发性CDI患者中某些关键微生物群成员的存在，揭示胆汁酸谱和CDI可能性之间的关系。

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.