Mechanisms of Immunomodulation by Probiotic L. reuteri in Acute Gastroenteritis

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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.