Dysbiotic oral microbiota and infected salivary glands in Sjögren’s syndrome

Abstract

Key events in the pathogenesis of Sjӧgren syndrome (SS) include the change of salivary gland epithelial cells into antigen-presenting cell-like phenotypes and focal lymphocytic sialadenitis (FLS). However, what triggers these features in SS is unknown. Dysbiosis of the gut and oral microbiomes is a potential environmental factor in SS, but its connection to the etiopathogenesis of SS remains unclear. This study aimed to characterize the oral microbiota in SS and to investigate its potential role in the pathogenesis of SS. Oral bacterial communities were collected by whole mouthwash from control subjects (14 without oral dryness and 11 with dryness) and primary SS patients (8 without oral dryness and 17 with dryness) and were analyzed by pyrosequencing. The SS oral microbiota was characterized by an increased bacterial load and Shannon diversity. Through comparisons of control and SS in combined samples and then separately in non-dry and dry conditions, SS-associated taxa independent of dryness were identified. Three SS-associated species and 2 control species were selected and used to challenge human submandibular gland tumor (HSG) cells. Among the selected SS-associated bacterial species, Prevotella melaninogenica uniquely upregulated the expression of MHC molecules, CD80, and IFNλ in HSG cells. Concomitantly, P. melaninogenica efficiently invaded HSG cells. Sections of labial salivary gland (LSG) biopsies from 8 non-SS subjects and 15 SS patients were subjected to in situ hybridization using universal and P. melaninogenica-specific probes. Ductal cells and the areas of infiltration were heavily infected with bacteria in the LSGs with FLS. Collectively, dysbiotic oral microbiota may initiate the deregulation of SGECs and the IFN signature through bacterial invasion into ductal cells. These findings may provide new insights into the etiopathogenesis of SS.

Salivary dysbiosis in Sjögren’s syndrome and a commensal-mediated immunomodulatory effect of salivary gland epithelial cells

“…The tendency of Proteobacteria to be enriched mostly in healthy controls may indicate the shared biological properties of the taxa within this phylum. Further, this observation is in agreement with the decreased abundance of oral Proteobacteria reported for Sjögren’s syndrome patients 26 , 28 , 29 , 31 , 32 . Similarly, phylum Actinobacteria, comprised of four out of the six taxa belonging to the final set, were enriched in pSS patients.…”

“…In recent years, studies based on saliva, oral washing, and buccal and tongue mucosa have suggested the involvement of oral dysbiosis in Sjögren's syndrome [25][26][27][28][29][30][31][32] , with some researchers further suggesting it may have an active role in the pathogenesis of Sjögren's syndrome. Given the proximity of the oral cavity to the SGECs microenvironment, the present study hypothesized that oral microbiota may modulate the antigen presentation of SGECs to regulate CD4 T cell function.…”

Association of a dysbiotic oral microbiota with the development of focal lymphocytic sialadenitis in IκB-ζ-deficient mice

“…1d ), as reported in SS 19 . We previously reported infection of ductal cells and the area of FLS with bacteria in the labial salivary glands obtained from SS patients 20 . In situ hybridization using a 16S rRNA-targeted probe revealed the presence of infected ducts not only near the area of FLS but also at the area without infiltration in both genotypes (Fig.…”

“…The S. danieliae -predominated oral microbiota, which was lost in the noncohoused Nfkbiz −/− mice, may be specialized in a tolerant coexistence with the host. Induction of the antigen-presenting cell-like phenotype in human submandibular gland tumor cells by SS-associated bacterial species and infection of ductal cells with bacteria in the labial salivary glands obtained from SS patients have been presented as potential mechanisms for driving FLS 20 . Bacterial infection of the salivary glands was observed in both Nfkbiz +/+ and Nfkbiz −/− mice.…”

“…Bacterial infection of the salivary glands was observed in both Nfkbiz +/+ and Nfkbiz −/− mice. The ability of bacteria to induce cytokines and chemokines from the host cells varies depending on the species 20 , 35 , which may be also accounted for. Mitigation of FLS in the cohoused Nfkbiz −/− mice that harbored the Nfkbiz +/+ -type oral microbiota supports the role of the dysbiotic oral microbiota in the development of FLS.…”