Unraveling the GUT-salivary gland axis: microbial and microbial metabolite-based strategies for sjögren's syndrome therapy

The National Institute of Dental and Craniofacial Research awarded The Forsyth Institute $629,029 on September 2, 2026, under the Oral Diseases and Disorders Research program (CFDA 93.121) to investigate therapeutic mechanisms linking the gut microbiome and salivary gland function in Sjögren's syndrome.

The project unravels the gut-salivary gland axis by testing whether healthy gut microbiota and specific bacterial species protect salivary gland integrity and function through production of short-chain fatty acids and other microbial metabolites. The research examines how fecal microbiota transplant and beneficial bacterial species exert protective and therapeutic effects in salivary gland pathology associated with Sjögren's disease by mediating gut-salivary gland communication at cellular and molecular levels in salivary tissues.

Performance occurs in Cambridge, Massachusetts, with work running through May 31, 2031. The award is structured as a Project Grant, the standard NIH research project grant mechanism for investigator-initiated basic and translational research.

Abstract

Salivary gland function is chronically impaired in sjӧgren's disease (SJD), which is a chronic autoimmune exocrine gland disorder with no cure or effective treatment available. Dysregulated innate and adaptive immune responses, including heightened interferon responses, drive the onset and chronic persistence of salivary gland inflammation, damage and functional impairment. There is a pressing need for novel, effective therapies that protect/improve salivary gland function and mitigate SJD. GUT microbiome dysbiosis is closely linked to various autoimmune and inflammatory diseases, including sjӧgren's disease, while healthy fecal microbiota transplant (FMT) shows promise in mitigating inflammatory pathology and preserving/restoring tissue function. In murine models of SJD, transplanting certain GUT bacterial species or their metabolites, such as short-chain fatty acids (scfas) alleviates salivary gland pathology. However, many critical knowledge gaps remain, particularly regarding the tissue protective mechanisms of the GUT-salivary gland axis. The main objective of this project is to define the GUT-salivary gland axis in SJD, focusing on the salivary gland-beneficial effects of healthy FMT and specific GUT bacteria, and unraveling two mechanistic layers underlying these actions: (i) microbial metabolites as key mediators linking the GUT and salivary glands, and (II) cellular targets and molecular changes in salivary tissues. We will test the central hypothesis that healthy GUT microbiota harbor bacterial species that protect/improve salivary gland integrity and function, and transplantation of these healthy GUT microbiota or beneficial bacterial species can exert protective and therapeutic effects in SJD-associated salivary gland pathology by producing scfas and other metabolites, which mediate GUT-salivary gland communication and mitigate interferon-induced detrimental responses in salivary epithelial cells. In aim 1 of the project, we will elucidate key salivary tissue mechanisms underlying the protective effects of healthy FMT in a murine model of SJD observed in our preliminary studies. We will also evaluate the therapeutic potential of healthy FMT on established SJD in this mouse model. In aim 2, we will examine the protective and therapeutic effects of two specific GUT bacterial species, identified in our preliminary studies, on salivary gland function in the murine model of SJD. In aim 3, we will investigate the previously unexplored effects of scfas on human salivary gland cells and peripheral and immune cells from SJD patients, and identify key beneficial microbial metabolites linking GUT microbiome to salivary glands in FMT and SJD in both mice and humans. This project will employ advanced immunological, microbiological and systems biological approaches, including 16S rrna gene sequencing for microbiome profiling, transcriptomic analysis of salivary gland epithelial populations, and metabolomic profiling. The novel and highly translatable findings from this project will significantly advance the development of innovative microbial-based therapies for SJD and other inflammatory salivary gland disorders.