Background/Purpose: Rheumatoid arthritis (RA) has an increased prevalence and severity in women compared to men, yet the underlying etiology of this sexual dimorphism is unknown. Similar sex differences in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of RA have been reported. Most notably, female TNF-Tg mice die earlier than males, with the majority dying between 6-7 months of age, while male mice die sporadically between 5-12 months of age. Recent studies have suggested that the gut microbiota significantly contribute to the pathogenesis of RA. This has been supported by the K/BxN mouse model of arthritis, which only develops arthritis when colonized with commensal bacteria. Based on this influence of microbiome on arthritis, we hypothesize that a sexually dimorphic microbiome exists in TNF-Tg mice, which is associated with disease severity.

Methods: An initial pilot study was performed to assess beta-diversity in male vs. female TNF-Tg mice (n=10), by 16S rRNA sequencing of fecal pellets. We also performed a principal coordinate analysis (PCoA) on these data. Based on significant findings, we collected samples from 4 separately housed cohorts of mice at 5.5 months of age, when TNF-Tg females have advanced disease and males have moderate disease. Cohorts were formed for the purpose of comparing TNF-Tg vs. WT and female vs male gut microbiome profiles (n=6 per cohort). 16S rRNA sequencing was performed on all samples.

Results: We found that female TNF-Tg mice had a significantly decreased beta-diversity (p<0.05) compared to their male counterparts. PCoA demonstrated a clear spatial separation between male and female samples, suggesting distinct gut microbiome profiles. Follow up studies demonstrated that female TNF-Tg mice had enriched levels of several Bacteroidetes and Firmicutes species, as well as suppressed levels of Bifidobacterium pseudolongum, a known commensal bacterium with noted immunosuppressive properties.

Conclusion: Here, we have shown for the first time that the TNF-Tg model of RA demonstrates both a disease-associated dysbiosis, as well as a sexually dimorphic microbiome profile within the TNF-Tg population. We have also shown that the female TNF-Tg microbiome was enriched in certain Bacteroidetes and Firmicutes species compared to the male cohort. The greatest disparity was with the bacterium Bifidobacterium pseudolongum, which multiple studies have suggested has an immunosuppressive phenotype and was greatly suppressed in female TNF-Tg mice. Further research is needed to investigate its role in inflammatory environments and whether active manipulation of the gut microbiome with probiotics may alter the disease state.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/female-tumor-necrosis-factor-transgenic-mice-have-more-severe-arthritis-than-males-and-supporessed-levels-of-bifidobacterium-pseudolongum-in-their-gut-microbiome/