Altered Mucosal Microbiome Diversity and Disease Severity in Sjögren Syndrome

Abstract

There is mounting evidence that the microbiome has potent immunoregulatory functions. We assessed the effects of intestinal dysbiosis in a model of Sjögren syndrome (SS) by subjecting mice to desiccating stress (DS) and antibiotics (ABX). We characterized the conjunctival, tongue and fecal microbiome profiles of patients with SS. Severity of ocular surface and systemic disease was graded. 16S ribosomal RNA gene sequencing characterized the microbiota. ABX + DS mice had a significantly worse dry eye phenotype compared to controls, a decrease in Clostridium and an increase in Enterobacter, Escherichia/Shigella, and Pseudomonas in stool after ABX + DS for 10 days. Goblet cell density was significantly lower in ABX treated groups compared to controls. Stool from SS subjects had greater relative abundances of Pseudobutyrivibrio, Escherichia/Shigella, Blautia, and Streptococcus, while relative abundance of Bacteroides, Parabacteroides, Faecalibacterium, and Prevotella was reduced compared to controls. The severity of SS ocular and systemic disease was inversely correlated with microbial diversity. These findings suggest that SS is marked by a dysbiotic intestinal microbiome driven by low relative abundance of commensal bacteria and high relative abundance of potentially pathogenic genera that is associated with worse ocular mucosal disease in a mouse model of SS and in SS patients.

Oral microbiota in autoimmune polyendocrine syndrome type 1

“…Using animal models of experimental colitis [34] and arthritis [35] it was shown that Gram-negative bacteria, possibly through the TLR2/IL-10 axis, reduced inflammation [34], whereas Gram-positive bacteria contributed to a more severe disease [35]. In a mouse model of Sjögren’s disease, depletion of the intestinal microbiome worsened the ocular response to desiccation, while the overall severity of disease correlated with intestinal microbiome diversity [36]. Two recent characterizations of the oral microbiota in primary Sjögren’s syndrome demonstrated a significant shift in the oral microbiota of patients and reduced numbers of genera [20,37], suggesting a role of the oral microbiota in the pathogenesis.…”

The Pathophysiology of Dry Eye Disease

“…17, 167 This is in sharp contrast to cultures of the lid margin and periocular skin which often grow bacteria. 168, 169 Studies using 16S genomic sequencing have demonstrated an ocular surface microbiome that may have the lowest biomass of any tissue in the body 16, 170, 171 No difference in the quantity and diversity of the ocular microbiome was noted between SS and control subjects; 16 however, significant alterations of the intestinal microbiome were noted in the same cohort with a significant decrease in commensal genera and an increase in pathogenic genera, such as Escherichia/Shigella and Proteobacteria. Mice that had an antibiotic-induced depletion of the microbiome with a cocktail of five oral antibiotics prior to experimental desiccating stress developed significantly worse dry eye than control mice that did not receive antibiotics, suggesting that the intestinal microbiome can modulate ocular surface inflammation and severity of dry eye disease.…”

“…Mice that had an antibiotic-induced depletion of the microbiome with a cocktail of five oral antibiotics prior to experimental desiccating stress developed significantly worse dry eye than control mice that did not receive antibiotics, suggesting that the intestinal microbiome can modulate ocular surface inflammation and severity of dry eye disease. 16 …”

“…190, 191 Intestinal dysbiosis has been found as a risk factor for SS dry eye and mice with antibiotic-induced depletion of their microbiome developed significantly worse ocular surface disease in response to desiccating stress. 16 Supplementation with commensal microbiota have shown anti-inflammatory effects in autoimmune conditions such as inflammatory bowel disease and diabetes mellitus. 192–196 It is possible that probiotics or metabolites of commensal bacteria could have future therapeutic potential for dry eye disease.…”

Intestinal dysbiosis is common in systemic sclerosis and associated with gastrointestinal and extraintestinal features of disease

“…In the field of rheumatology, intestinal dysbiosis has been associated with rheumatoid arthritis (RA), systemic lupus erythematosus, Sjögren’s syndrome and ankylosing spondylitis [7–11]. A randomised double-blind placebo-controlled clinical trial in RA patients indicated that disease activity may be sensitive to modulation of gut microbiota through ingestion of probiotics [12].…”