Oxalobacter as a therapy in IBD-associated urolithiasis

描述（由申请人提供）：产草酸杆菌是一种革兰氏阴性厌氧细菌，栖息于大多数（并非全部）脊椎动物（包括人类）的胃肠道中。该细菌通过调节肠道中草酸的吸收和分泌途径，从而维持血浆中的稳态水平，与其宿主发挥重要的共生关系。肠道中缺乏这种细菌已被证明与高尿酸和首次和复发草酸钙肾结石的频率增加有关;因此，缺乏O.甲酸杆菌似乎是尿石症的危险因素。流行病学研究表明，O.人类中的产甲酸杆菌定殖已经指出了几个重要的观察结果：人类通常在幼儿时被定殖;实际上所有儿童都可以自然地被定殖;全世界成年人群中的定殖率仅在60-80%之间;并且定殖对胃肠道的变化和抗生素的使用特别敏感。2003年，使用产甲酸杆菌治疗原发性高尿酸儿童高尿酸的临床试验提供了令人鼓舞的结果，从而提出了这种细菌可能有效治疗以肠高尿酸为根本原因的草酸钙肾结石疾病的幽灵。一个这样的人群是发展肾结石的肠易激综合征（IBD）患者亚组。在这项探索性R21资助申请中提出的研究是对NIDDK计划公告PA-03-065的回应，其目标之一是开发新的动物模型，可能有助于阐明肠道疾病患者草酸盐结石病的病因，并确定改进的预防和治疗方案。为此，我们建议确定（a）已知与人克罗恩病具有许多共同特征的IL-10基因KO小鼠是否代表了用于研究IBD相关的高尿酸和草酸钙肾结石疾病的适当动物模型，以及（B）O.甲酸根是一种有效的干预治疗，用于在IBD患者人群中可能存在的条件下减少高尿酸和/或草酸钙结晶。通过定义O.当宿主患有IBD时，我们将能够确定在“益生菌样”疗法中使用这种细菌来治疗IBD患者的高尿酸的限制和/或可能的风险。

DESCRIPTION (provided by applicant): Oxalobacter formigenes is a gram-negative, anaerobic bacterium inhabiting the gastrointestinal tracts of most, it not all, vertebrates, including man. This bacterium plays an important symbiotic relationship with its hosts by regulating the absorptive and secretory pathways for oxalic acid in the intestines, thereby maintaining homeostatic levels in plasma. The absence of this bacterium from the gut has been shown to correlate with hyperoxaluria and an increased frequency of first-time and recurrent calcium oxalate kidney stones; consequently, the absence of O. formigenes appears to be a risk factor for urolithiasis. Epidemiological studies of O. formigenes colonization in humans have pointed to several important observations: humans normally become colonized as young children; virtually all children can become colonized naturally; colonization rates in adult populations ranges only between 60-80% worldwide; and, colonization is especially sensitive to changes in the GI tract and the use of antibiotics. In 2003, clinical trials using O.formigenes in the treatment of hyperoxaluria in children with primary hyperoxaluria provided encouraging results, thus raising the specter that this bacterium may be effective in treating calcium oxalate kidney stone disease with enteric hyperoxaluria as an underlying cause. One such population is the subgroup of irritable bowel disease (IBD) patients that develop kidney stones. The studies being proposed in this exploratory R21 grant application are in response to NIDDK Program Announcement PA-03-065, one goal of which is to develop new animal models that may help clarify etiologic factors underlying oxalate stone disease in patients with bowel disease and the identification of improved prevention and therapy options. To this end, we are proposing to determine if (a) the IL-10 gene KO mouse, known to share many features with human Crohn's disease, represents an adequate animal model for the study of hyperoxaluria and calcium oxalate kidney stone disease associated with IBD, and (b) O. formigenes is an effective intervention treatment for reducing hyperoxaluria and/or calcium oxalate crystaluria under conditions that may exist in human patient populations with IBD. By defining the inter-relationships between O. formigenes and the host when the host has IBD, we will be able to define limitations and/or the possible risks of using this bacterium in "probiotic-like" therapies to treat hyperoxaluria in patients with IBD.