Background/Purpose: The etiology of lupus-associated antiphospholipid syndrome (APS) is unknown but microbial triggers have been implicated in transient antiphospholipid antibody production in both mice and humans. We hypothesize that a constant trigger of autoreactivity lies within the gut microbiome and tested if persistent reactivity to β₂-glycoprotein I (β₂GPI) and mortality in the spontaneous (NZWxBXSB)F₁ model of lupus-associated APS are sustained by specific members of the gut microbiota.

Methods: (NZWxBXSB)F₁ hybrid male mice were treated orally with combined or single antibiotics (vancomycin, metronidazole, neomycin and ampicillin) targeting different microbial community structures starting at 6 weeks of age. Female TLR7 transgenic C57BL/6 mice were similarly treated with broad-spectrum antibiotics. Sera, urine and fecal pellets were collected longitudinally and analysed for anti-β₂GPI titers, proteinuria from lupus nephritis and eubacterial 16S rDNA load by real-time PCR. H&E slides were prepared from tissues for histologic analysis. Splenocyte proliferation was assessed by [³H]-thymidine incorporation.

Results: Not only broad-spectrum antibiotics but also vancomycin or ampicillin alone lowered anti-β₂GPI antibodies at 4 months of age (n=5 each; p=0.014) and protected mice from deaths due to coronary microthrombi, pulmonary emboli or strokes (n=5 each; p=0.005). Proliferation of splenocytes to the autoantigen (using recombinant β₂GPI) was diminished compared to anti-CD3-induced proliferation (n=8 each; p=0.0012). Proteinuria due to lupus nephritis was also suppressed in microbiota-depleted mice (n=8 each; p=0.026). Furthermore, mortality from systemic lupus-like disease was significantly reduced in lupus-prone TLR7 transgenic C57BL/6 mice treated with antibiotics (n=9-10 each; p=0.0154).

Conclusion: Vancomycin-sensitive gut commensals are necessary for anti-β₂GPI-antibody-induced thrombembolic deaths. Broad-spectrum antibiotics selectively reduced T cell proliferation to β₂GPI but not anti-CD3, suggesting antigen-specific effects of the gut microbiota. These results support that gram-positive members of the gut microbiota are fundamentally involved in the pathogenesis of APS. The gut microbiota modulate also lupus pathogenesis in two spontaneous models, suggesting that not only APS but also SLE is dependent on the gut microbial community composition we are currently defining to identify novel biomarkers and treatment targets.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-pathogenic-role-for-the-gut-microbiota-in-murine-antiphospholipid-syndrome-and-lupus/