Oxalobacter as a therapy in IBD-associated urolithiasis

草酸杆菌作为 IBD 相关尿石症的治疗方法

• 批准号: 6862101
• 负责人: AMMON B PECK
• 金额: $ 18.19万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862101
• 关键词: Crohn' s disease; anaerobic bacteria; gastrointestinal system; genetically modified animals; gram negative bacteria; immunotherapy; inflammatory bowel diseases; interleukin 10; laboratory mouse; nephrocalcinosis; nephrolithiasis; oxalates; polymerase chain reaction; therapy design /development; urinary calculi

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.

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，栖息在大多数（不是全部）脊椎动物（包括人类）的胃肠道中。这种细菌通过调节肠道内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草酸尿症以及首次和复发草酸钙肾结石频率增加相关。因此，O. formigenes 的缺失似乎是尿石症的一个危险因素。关于 O. formigenes 在人类中定殖的流行病学研究指出了几个重要的观察结果：人类通常在幼儿时就被定殖；几乎所有儿童都会自然而然地成为殖民地；全球成年人口的定植率仅在 60-80% 之间；而且，定植对胃肠道的变化和抗生素的使用特别敏感。 2003年，使用O.formigenes治疗原发性高草酸尿症儿童的高草酸尿症的临床试验提供了令人鼓舞的结果，从而引起人们的怀疑，即这种细菌可能有效治疗以肠道高草酸尿症为根本原因的草酸钙肾结石疾病。其中一个人群是患有肾结石的肠易激病 (IBD) 患者亚群。本次探索性 R21 拨款申请中提出的研究是为了响应 NIDDK 计划公告 PA-03-065，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以及确定改进的预防和治疗方案。为此，我们建议确定 (a) IL-10 基因 KO 小鼠（已知与人类克罗恩病具有许多共同特征）是否代表了研究与 IBD 相关的高草酸尿症和草酸钙肾结石疾病的适当动物模型(b) O. formigenes 是一种有效的干预治疗方法，可在 IBD 人类患者群体中可能存在的情况下减少高草酸尿和/或草酸钙结晶尿。当宿主患有 IBD 时，通过定义 O. formigenes 与宿主之间的相互关系，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 患者高草酸尿症的局限性和/或可能的风险。