Gut Microbiome and Salivary Gland Function: Protective Actions & Key Players - PROJECT SUMMARY Salivary gland function is chronically impaired in Sjӧgren’s syndrome, an autoimmune exocrine gland disease with no cure or effective treatment available. Aberrantly activated innate immune cells, autoreactive T- and B cells, and proinflammatory cytokines collectively cause Sjogren’s-characteristic salivary gland inflammation and dysfunction. There is an urgent need for novel, effective therapies that protect/improve salivary gland function and ameliorate salivary gland inflammation. The importance of host gut microbiome in health and disease is increasingly recognized, yet very little is known about the impact of gut microbiome on salivary glands, especially the protective bacteria and their actions. Hence, the main objective of this project is to address this knowledge gap, with a particular focus on identifying the potentially salivary gland-protective gut bacteria and revealing their precise actions using both murine models and cells and samples from Sjӧgren’s disease patients. Our preliminary studies showed that transplant of fecal bacteria from healthy C57BL/6 mice to the non-obese diabetic mice, a spontaneous model of Sjӧgren’s syndrome, exerted a protective effect on salivary glands. The protection was accompanied by reduced inflammatory responses and diminished expression of bromodomain containing 2, an epigenetic reader/modulator, in salivary gland epithelial cells. We also identified multiple specific bacterial species with salivary gland-protective potentials based on our preliminary microbiome analyses and the pertinent evidence from human studies in the literature. We formed the central hypothesis that healthy gut microbiota contains bacterial species that, acting through their metabolites, protect salivary gland function by mitigating inflammatory responses and dysfunction of salivary gland epithelial cells through mechanisms including downregulating the expression of epigenetic reader of bromodomain containing 2. Aim 1 of this project will define and discover the mechanisms underlying the protective effects of healthy C57BL/6 fecal microbiota transplant on salivary glands in the non-obese diabetic mice and a second, induced model of Sjӧgren’s syndrome. Aim 2 will explore the protective impact of specific gut bacterial species on salivary gland function in the two mouse models. Aim 3 will identify and test microbial metabolites that may mediate the salivary gland- protective impact of gut microbiota using both mouse SS models and cells/samples from human Sjӧgren’s disease patients. The project will employ a combination of sophisticated immunological, microbiological and systemic biological methodologies, including 16S rRNA gene sequencing analysis of microbiome, RNA- sequencing analysis of host cells, and metabolomic assays. Knowledge generated will have direct relevance to and impact on human health, and will advance the development of novel, gut microbe/microbial metabolite- based therapies to combat autoimmune Sjӧgren’s disease as well as other salivary gland inflammatory disorders.
