Mechanisms of Immunomodulation by Probiotic L. reuteri in Acute Gastroenteritis

产品描述（申请人提供）：益生菌或有益微生物在预防和治疗多种胃肠道疾病方面显示出前景，但对益生菌如何改善急性胃肠炎知之甚少。长期目标是揭示肠道中益生菌调节宿主免疫系统的机制，从而促进肠道感染的更快恢复。益生菌罗伊氏乳杆菌是人类和小鼠胃肠道固有的，通常被认为是安全的微生物，改善人类和小鼠的轮状病毒胃肠炎，并通过尚不清楚的机制增加伊加，IgA是对许多肠道病原体的免疫应答中的关键因素。共生细菌可以上调肠上皮细胞（IEC）中多聚IG受体（plgR）的表达，导致伊加向肠腔的转运增加。此外，多种肠道细菌刺激IEC分泌APRIL（增殖诱导配体），其促进B细胞中的类别转换重组为伊加。因此，主要假设是益生菌罗伊氏乳杆菌通过上调pIgR（其增加管腔伊加转运）和通过诱导肠上皮细胞分泌细胞因子APRIL（其增强伊加产生）来增强对轮状病毒感染的粘膜伊加应答。这一假设将以两个具体目标进行检验。1)确定pIgR在益生菌L介导的增强轮状病毒特异性伊加应答中的作用。reuteri。将使用体外伊加转运测定、定量实时PCR阵列以及野生型和pIgR缺陷型益生菌处理的小鼠。2)确定益生菌L.感染lEC的罗伊氏杆菌诱导APRIL增强轮状病毒特异性伊加反应。将使用液体珠阵列平台、IEC和B细胞的共培养物以及野生型和APRIL缺陷型小鼠。这些研究将确定在益生菌增强对病毒感染的粘膜免疫中发挥作用的分子机制。 公共卫生相关性：感染性腹泻是美国发病的主要原因，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的主要原因之一。揭示益生菌在急性胃肠炎中的免疫调节机制对改善人类健康具有巨大的潜力，因为对有益微生物的深入了解将有助于益生菌工程和合理选择天然菌株，以促进感染后更快的恢复。在严重疾病和长期并发症发展之前预防或治疗急性胃肠炎将大大减少住院治疗，医疗费用和残疾调整生命年。

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.