Mechanisms of Immunomodulation by Probiotic L. reuteri in Acute Gastroenteritis

益生菌罗伊氏乳杆菌对急性胃肠炎的免疫调节机制

• 批准号: 8078111
• 负责人: Geoffrey A Preidis
• 金额: $ 3.53万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078111
• 关键词: Accounting; Acute; Adverse effects; B-Lymphocytes; Bacteria; Biological Assay; Caring; Child; Childhood; Clinical; Coculture Techniques; Complex; Diarrhea; Disease; Economic Burden; Engineering; Enteral; Enterocytes; Epithelial Cells; Future; Gastroenteritis; Gastroenterology; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression; Health; Histopathology; Hospitalization; Human; Immune response; Immune system; Immunocompromised Host; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; In Vitro; Incidence; Incubated; Indigenous; Indium; Infection; Infectious Agent; International; Intestines; Lactobacillus reuteri; Life; Ligands; Liquid substance; Mediating; Medical; Microbe; Modeling; Molecular; Morbidity - disease rate; Mucosal Immunity; Mus; Natural Selections; Neonatal; Outcome; Play; Polymeric Immunoglobulin Receptors; Prevention; Preventive; Probiotics; Production; Property; Recovery; Reporting; Role; Rotavirus; Rotavirus Infections; Severity of illness; Testing; Therapeutic; Time; Underserved Population; United States; Virus Diseases; Work; base; commensal microbes; cost; cytokine; disability; disability-adjusted life years; enteric pathogen; human disease; immunoregulation; improved; in vivo; intestinal epithelium; microorganism; mortality; novel therapeutic intervention; pathogen; prevent; public health relevance; receptor expression; response; success; transcytosis

DESCRIPTION (provided by applicant): Probiotics, or beneficial microbes, show promise in the prevention and treatment of multiple gastrointestinal diseases, but little is known about how probiotics ameliorate acute gastroenteritis. The long-term objective is to uncover mechanisms by which probiotic bacteria in the intestine modulate the host immune system and thus facilitate more rapid recovery from enteric infections. Probiotic Lactobacillus reuteri is indigenous to the human and mouse gastrointestinal tracts, is generally recognized as a safe microorganism, ameliorates rotaviral gastroenteritis in humans and mice, and increases IgA, a key element in the immune response to many enteric pathogens, by mechanisms that are still unknown. Commensal bacteria can upregulate expression of the polymeric Ig receptor (plgR) in intestinal epithelial cells (lECs), leading to increased transport of IgA to the intestinal lumen. Furthermore, a variety of intestinal bacteria stimulate I ECs to secrete APRIL (a proliferation-inducing ligand), which facilitates class-switch recombination in B cells to IgA. Therefore, the primary hypothesis is that probiotic Lactobacillus reuteri enhances the mucosal IgA response to rotavirus infection by upregulating pIgR, which increases luminal IgA transport, and by inducing intestinal epithelial cells to secrete the cytokine APRIL, which enhances IgA production. This hypothesis will be tested with two specific aims. 1) Establish the role of pIgR in the enhanced rotavirus-specific IgA response mediated by probiotic L. reuteri. An in vitro IgA transport assay, quantitative real-time PCR arrays, and both wild type and pIgR-deficient probiotic-treated mice will be used. 2) Determine whether interaction of probiotic L. reuteri with infected lECs induces APRIL to enhance the rotavirus-specific IgA response. A liquid bead array platform, co-cultures of lECs and B cells, and both wild type and APRIL-deficient mice will be utilized. These studies will identify molecular mechanisms that play a role in probiotic enhancement of mucosal immunity to viral infections. PUBLIC HEALTH RELEVANCE: Infectious diarrhea is a leading cause of morbidity in the United States, especially among children, international travelers, and immunocompromised patients, and is one of the leading causes of global childhood mortality. Uncovering the mechanisms of immunomodulation by probiotic bacteria in acute gastroenteritis has enormous potential to improve human health, in that an enhanced understanding of beneficial microbes will facilitate probiotic engineering and rational selection of natural strains to promote more rapid recovery following infection. Preventing or treating acute gastroenteritis before severe disease and long-term complications develop would dramatically reduce hospitalizations, medical costs, and disability-adjusted life years.

描述（由申请人提供）：益生菌或有益的微生物在预防和治疗多种胃肠道疾病方面表现出希望，但对益生菌如何缓解急性胃肠炎的方式知之甚少。长期目标是揭示肠中益生菌细菌调节宿主免疫系统的机制，从而促进从肠道感染中更快地恢复。 Reuteri益生菌是人类和小鼠胃肠道的土著，通常被认为是一种安全的微生物，可以改善人类和小鼠中的Rotaviral Gastroenteritis，并增加IGA，并增加对许多机械性病原体的免疫反应的关键元素。共生细菌可以上调肠上皮细胞（LEC）中聚合物Ig受体（PLGR）的表达，从而导致IgA向肠腔的转运增加。此外，各种肠道细菌刺激了ICS分泌April（一种增殖的诱导配体），这促进了B细胞中的类别切换重组到IgA。因此，主要的假设是，益生菌乳酸杆菌REUTERI通过上调PIGR来增强对轮状病毒感染的粘膜IgA反应，从而增加了腔内IgA转运，并通过诱导肠上皮细胞来促进细胞因子四月，从而增强了IGA的产生。该假设将以两个具体的目的进行检验。 1）确定PIGR在由益生菌L. reuteri介导的增强轮状病毒特异性IgA反应中的作用。将使用体外IGA转运测定，定量实时PCR阵列以及野生型和缺乏益生菌治疗的小鼠。 2）确定益生菌L. reuteri与感染的LEC的相互作用是否诱导四月以增强轮状病毒特异性IgA反应。将使用液态珠阵列平台，LEC和B细胞的共同培养物以及野生型和四月缺乏的小鼠。这些研究将确定分子机制，这些机制在益生菌对病毒感染的粘膜免疫增强中发挥作用。 公共卫生相关性：传染性腹泻是美国发病率的主要原因，尤其是在儿童，国际旅行者和免疫功能低下的患者中，并且是全球儿童死亡率的主要原因之一。探索益生菌在急性胃肠炎中通过益生菌调节的机制具有改善人类健康的巨大潜力，因为对有益的微生物的理解增强将促进益生菌工程和自然菌株的合理选择，以促进感染后更快地恢复。在严重疾病和长期并发症发生之前，预防或治疗急性胃肠炎将大大减少住院，医疗费用和残疾调整的生活年。