Gut dysbiosis is prevailing in Sjögren's syndrome and is related to dry eye severity

Abstract

Objective: To investigate gut dysbiosis in patients with Sjögren's syndrome (SS) or dry eye syndrome (DES) compared to normal subjects and to evaluate the association of dysbiosis with dry eye severity.

Methods: 10 subjects with SS, 14 subjects with DES and 12 controls were enrolled. Corneal staining, tear break up time (TBUT) and tear secretion were evaluated. Bacterial genomic 16s rRNA from stool samples were analyzed. Main outcomes were microbiome compositional differences among groups and their correlation to dry eye signs.

Results: Gut microbiome analysis revealed significant compositional differences in SS compared to controls and DES. In phylum, Bacteriodetes increased, while Firmicutes/Bacteroidetes ratio and Actinobacteria decreased (p<0.05). In genus, Bifidobacterium was reduced (vs controls; p = 0.025, vs DES; p = 0.026). Beta diversity of SS also showed significant distances from controls and DES (p = 0.007 and 0.019, respectively). SS showed decreased genus of Blautia (p = 0.041), Dorea (p = 0.025) and Agathobacter (p = 0.035) compared to controls and increased genus of Prevotella (p = 0.026), Odoribacter (p = 0.028) and Alistipes (p = 0.46) compared to DES. On the other hand, DES only had increased genus Veillonella (p = 0.045) and reduced Subdoligranulum (p = 0.035) compared to controls. Bacteroidetes, Actinobacteria and Bifidobacterium were significantly related with dry eye signs (p<0.05). After adjustment of age, gender and group classification, multivariate linear regression analysis revealed tear secretion was strongly affected by Prevotella (p = 0.025). With additional adjustment of hydroxychloroquine use, TBUT was markedly affected by Prevotella (p = 0.037) and Actinobacteria (p = 0.001).

Conclusions: Sjögren's syndrome showed significant gut dysbiosis compared to controls and environmental dry eye syndrome, while dry eye patients showed compositional changes of gut microbiome somewhere in between Sjögren's syndrome and controls. Dysbiosis of the gut microbiota was partly correlated to dry eye severity.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Dry eye indices in controls, DES, and SS groups.

NEI score was significantly higher in SS than in both controls and DES (p

Fig 2. Species richness and Shannon diversity analysis of Controls, DES and SS groups.

Species richness analyzed by Chao 1 did not show any differences among groups (controls vs. DES; p = 0.877, controls vs. SS; p = 0.553, SS vs. DES; p = 0.447, Wilcoxon rank-sum test) (A). Shannon diversity index also did not reveal any differences among groups (controls vs. DES; p = 0.918, controls vs. SS; p = 0.792, SS vs. DES; p = 0.907, Wilcoxon rank-sum test) (B). DES: dry eye syndrome group, SS: Sjogren’s syndrome group Bars indicate maximum and minimum values.

Fig 3. Taxonomic proportions according to compositions in phylum and genus of Controls, DES, and SS groups.

Overall, taxonomic relative abundance in phylum (A) and genus (B) is shown for all groups. DES: dry eye syndrome group, SS: Sjogren’s syndrome group.

Fig 4. Taxonomic relative abundance according to Phylum, Family and Genus, and principle coordinates analysis of Controls, DES, and SS groups.

In phylum, significantly abundant Bacteroidetes (p

Fig 5. Univariate linear regression analysis between dry eye indices and intestinal microbiome.

NEI score showed significant positive relation with Bacteroidetes (p = 0.036, R2 = 0.123) and negative relation with Bifidobacterium (p = 0.035, R2 = 0.124), while there was no significance with Actinobacteria (p = 0.062, R2 = 0.099) (A). Tear secretion showed positive relation with both Actinobacteria (p < 0.001, R2 = 0.331) and Bifidobacterium (p = 0.001, R2 = 0.263), while there was no significance with Bacteroidetes (p = 0.084, R2 = 0.085) (B). TBUT showed negative relation with Bacteroidetes (p = 0.018, R2 = 0.154), and positive relation with both Actinobacteria (p < 0.001, R2 = 0.534) and Bifidobacterium (p < 0.001, R2 = 0.401) (C). DES: dry eye syndrome group, SS: Sjogren’s syndrome group, NEI: National Eye Institute, TBUT: Tear break up time, mm: millimeters, sec: seconds.