Alanyl-glutamine supplementation of standard treatment for C. difficile infection

补充丙氨酰谷氨酰胺作为艰难梭菌感染的标准治疗方法

• 批准号: 10670117
• 负责人: Cirle Alcantara Warren
• 金额: $ 79.58万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-13 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670117
• 关键词: Adult; Aftercare; Age; Animals; Antibiotic Therapy; Antibiotics; Apoptosis; Body Weight decreased; CASP8 gene; Cell Line; Cell Proliferation; Cells; Cessation of life; Child; Clinical Trials; Clostridium; Clostridium difficile; Comparative Effectiveness Research; Data; Death Rate; Diarrhea; Dipeptides; Disease; Dose; Double-Blind Method; Ensure; Epidemiology; Gastroenterology; Geriatrics; Glutamine; Growth; Histopathology; Hospitalization; Human; Immunocompromised Host; Impairment; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Intestinal Secretions; Intestines; Mediating; Monoclonal Antibodies; Mus; Nosocomial Infections; Oral; Oryctolagus cuniculus; Outcome Study; Pathogenesis; Patients; Performance; Persons; Phase II Clinical Trials; Pilot Projects; Placebo Control; Population; Production; Productivity; Public Health; Publishing; Randomized; Rattus; Reaction; Recovery; Recurrence; Recurrent disease; Relapse; Research Personnel; Research Proposals; Safety; Supplementation; Testing; Time; Tissues; Toxin; Treatment outcome; Vancomycin; Virulence Factors; Work; aged; antibiotic-associated diarrhea; antimicrobial; cell motility; comparison control; cost; double-blind placebo controlled trial; dysbiosis; gut inflammation; gut microbiota; healthcare-associated infections; human disease; human old age (65+); improved; improved outcome; in vivo; innovation; intestinal barrier; intestinal epithelium; metabolic profile; metabolomics; microbiome; microbiota; mortality; mouse model; novel; novel strategies; nutritional supplementation; parenteral administration; pharmacologic; prevent; primary outcome; rho; secondary outcome; standard care; standard of care; systemic inflammatory response

PROJECT SUMMARY C. difficile is the leading cause of antibiotic-associated diarrhea and nosocomial infection. Antibiotic treatment is the standard approach in managing C. difficile infection (CDI) and is associated with high recurrence rates of up to 65% depending on the number of previous disease. Alanyl-glutamine prevents C. difficile toxin-induced impairment of cell migration and proliferation in intestinal cell lines, secretion and histopathology in animal ileal tissues, and increased apoptosis in vitro and in vivo. We have shown that in the mouse model of CDI, alanyl- glutamine supplementation significantly reduced diarrhea, weight loss, histopathology, relapse and deaths in vancomycin-treated mice. A small pilot study in human suggests that alanyl-glutamine may prevent recurrent disease up to 6 months after CDI treatment. We hypothesize that supplementation with alanyl-glutamine will improve outcomes of treatment of CDI in humans. To prove this hypothesis, we plan to conduct a randomized, double-blinded, placebo-controlled trial. The specific aims of this project are 3-fold. First, we shall determine the optimal dose of oral alanyl-glutamine on preventing recurrence and deaths in patients treated with standard anti-C.difficile agents. Secondly, we shall demonstrate the safety of oral alanyl- glutamine supplementation. And thirdly, we shall test the effect of alanyl-glutamine on intestinal inflammation, barrier function and gut flora in patients undergoing standard treatment for CDI. This research proposal will allow for a rigorous, safe and productive performance of the clinical trial to prove the benefit of alanyl-glutamine in human disease, potentially introducing a novel approach to treatment of CDI.

项目摘要 艰难梭菌是抗生素相关腹泻和医院感染的主要原因。抗生素治疗是 管理艰难梭菌感染（CDI）的标准方法，并与UP的高复发率有关 根据先前疾病的数量，至65％。丙酰谷氨酰胺可防止艰难梭菌诱导的 肠道细胞系中细胞迁移和增殖的损害，动物回肠的分泌和组织病理学 组织，体外和体内凋亡增加。我们已经表明，在CDI的小鼠模型中 补充谷氨酰胺可显着减少腹泻，体重减轻，组织病理学，复发和死亡 万古霉素治疗的小鼠。人类的一项小型试点研究表明，丙氨酸 - 谷氨酰胺可能会预防复发 CDI治疗后长达6个月的疾病。我们假设补充丙氨酸 - 谷氨酰胺将 改善人类CDI治疗的结果。为了证明这一假设，我们计划进行 随机，双盲，安慰剂对照试验。该项目的具体目标是3倍。首先，我们将 确定口服丙烷 - 谷氨酰胺的最佳剂量在预防患者复发和死亡方面的最佳剂量 用标准抗C.缺陷剂处理。其次，我们将证明口服丙烷的安全性 补充谷氨酰胺。第三，我们将测试丙酰基谷氨酰胺对肠道的影响 接受标准治疗CDI的患者的炎症，屏障功能和肠道菌群。这 研究建议将允许对临床试验进行严格，安全和富有成效的表现，以证明 丙酰谷氨酰胺在人类疾病中的益处，有可能引入一种新型的CDI治疗方法。

项目成果

Interaction of Clostridioides difficile infection with frailty and cognition in the elderly: a narrative review.

• DOI: 10.1186/s40001-023-01432-9
• 发表时间: 2023-10-17
• 期刊: EUROPEAN JOURNAL OF MEDICAL RESEARCH
• 影响因子: 4.2
• 作者: Fernandez-Cotarelo, Maria-Jose;Jackson-Akers, Jasmine Y.;Nagy-Agren, Stephanie E.;Warren, Cirle A.
• 通讯作者: Warren, Cirle A.

Hospitalized Older Patients with Clostridioides difficile Infection Refractory to Conventional Antibiotic Therapy Benefit from Fecal Microbiota Transplant.

传统抗生素治疗难治的艰难梭菌感染住院老年患者可受益于粪便微生物群移植。

• DOI: 10.20900/agmr20210012
• 发表时间: 2021
• 期刊: Advances in geriatric medicine and research
• 作者: Shin,JaeHyun;Hays,RachelAnn;Warren,CirleAlcantara
• 通讯作者: Warren,CirleAlcantara

Teaching old mice new tricks: the utility of aged mouse models of C. difficile infection to study pathogenesis and rejuvenate immune response.

• DOI: 10.1080/19490976.2021.1966255
• 发表时间: 2021-01
• 期刊: Gut microbes
• 影响因子: 12.2
• 作者: Shin JH;Pawlowski SW;Warren CA
• 通讯作者: Warren CA

Clostridioides difficile colonization among very young children in resource-limited settings.

• DOI: 10.1016/j.cmi.2022.01.022
• 发表时间: 2022-07
• 期刊: CLINICAL MICROBIOLOGY AND INFECTION
• 影响因子: 14.2
• 作者: Brennhofer, Stephanie A.;McQuade, Elizabeth T. Rogawski;Liu, Jie;Guerrant, Richard L.;Platts-Mills, James A.;Warren, Cirle A.
• 通讯作者: Warren, Cirle A.

Alanyl-glutamine supplementation for Clostridioides difficile infection treatment (ACT): a double-blind randomised controlled trial study protocol.

• DOI: 10.1136/bmjopen-2023-075721
• 发表时间: 2023-07-19
• 期刊: BMJ open
• 影响因子: 2.9