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: 7031596
• 负责人: AMMON B PECK
• 金额: $ 21.31万
• 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 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031596
• 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）：草酸杆菌是一种革兰氏阴性菌，厌氧细菌，居住在大多数胃肠道中，并非全部，包括人，包括人。通过调节肠中草酸的吸收性和分泌途径，该细菌与宿主具有重要的共生关系，从而在血浆中保持稳态水平。肠道中没有这种细菌与高黄油尿症相关，并且首次和草酸钙肾脏肾结石的频率增加。因此，缺失O.型孔似乎是尿石症的危险因素。人类孔基烯殖民化的流行病学研究指出了几种重要的观察：人类通常是幼儿殖民的；几乎所有孩子都可以自然地殖民。成人人口的定殖率在全球范围内仅在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O. fulmigenes治疗原发性高氧确实核酸甲状腺尿尿充血的临床试验提供了令人鼓舞的结果，从而提高了幽灵，即该细菌可能有效地将阿氧酸钙肾脏疾病与肠肠尿中尿尿症作为根本原因。这样的人群是肠易激疾病（IBD）患者的亚组，这些患者患有肾结石。在本探索性R21赠款应用中提出的研究是对NIDDK计划公告PA-03-065的回应，其中一个目标是开发新的动物模型，这些模型可能有助于阐明肠病患者中草种石材疾病的病因学因素，并确定改善的预防和治疗选择。为此，我们建议确定（a）与人类克罗恩病共享许多特征的IL-10基因KO小鼠是否代表了一种适当的动物模型，用于研究与IBD相关的高氧和草酸钙肾脏疾病，以及（b）O.甲酸造成的造成型的有效治疗均具有降低的牛氧化型，或者是降低了牛的疾病。与IBD。通过定义O.型甲素和宿主之间的相互关系，当宿主患有IBD时，我们将能够定义局限性和/或在“益生菌样”疗法中使用该细菌治疗IBD患者中尿尿症的可能风险。