Summary Western lifestyle is linked to autoimmune and metabolic diseases, driven by changes in diet and gut microbiota composition. Using a Toll-like receptor 7 (TLR7)-dependent mouse models of lupus, we dissect dietary effects on the gut microbiota and find that Lactobacillus reuteri can drive autoimmunity but is ameliorated via dietary resistant starch (RS). Culture of internal organs and 16S rDNA sequencing revealed TLR7-dependent translocation of Lactobacillus reuteri in mice and fecal enrichment of Lactobacillus in a subset of lupus patients. L. reuteri colonization worsened autoimmune manifestations under specific-pathogen-free and gnotobiotic conditions, notably increasing plasmacytoid dendritic cells (pDCs) and interferon signaling. However, RS suppressed the abundance and translocation of L. reuteri via short-chain fatty acids, which inhibited its growth. Additionally, RS decreased pDCs, interferon pathways, organ involvement and mortality. Thus, RS exerts beneficial effects in lupus-prone hosts through suppressing a pathobiont that mediates interferon pathways implicated in the pathogenesis of human autoimmunity.

The earliest autoantibodies in lupus are directed against the RNA binding autoantigen Ro60, but the triggers against this evolutionarily conserved antigen remain elusive. We identified Ro60 orthologs in a subset of human skin, oral, and gut commensal bacterial species and confirmed the presence of these orthologs in patients with lupus and healthy controls. Thus, we hypothesized that commensal Ro60 orthologs may trigger autoimmunity via cross- reactivity in genetically susceptible individuals. Sera from human anti-Ro60–positive lupus patients immunoprecipi-tated commensal Ro60 ribonucleoproteins. Human Ro60 autoantigen–specific CD4 memory T cell clones from lupus patients were activated by skin and mucosal Ro60-containing bacteria, supporting T cell cross-reactivity in humans. Further, germ-free mice spontaneously initiated anti-human Ro60 T and B cell responses and developed glomerular immune complex deposits after monocolonization with a Ro60 ortholog–containing gut commensal, linking anti- Ro60 commensal responses in vivo with the production of human Ro60 autoantibodies and signs of autoimmunity. Together, these data support that colonization with autoantigen ortholog-producing commensal species may initiate and sustain chronic autoimmunity in genetically predisposed individuals. The concept of commensal ortholog cross-reactivity may apply more broadly to autoimmune diseases and lead to novel treatment approaches aimed at defined commensal species.

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Diet-induced modulation of host immune-microbiota interactions could be an attractive way to ameliorate autoimmunity. Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with no cure. We used resistant starch (RS) as a novel approach to prevent SLE. We fed RS to a spontaneous TLR7 Tg and TLR7 agonist (Imiquimod, IMQ)-inducible lupus model to modulate gut microbial communities and lupus pathogenesis. Depletion of the gut microbiota with antibiotics reduced mortality in TLR7 Tg mice. Also, IMQ-induced lupus was ameliorated in GF compared to SPF B6 mice, supporting a role for the microbiota in the pathogenesis. In both models, RS reduced mortality, kidney involvement, hepatosplenomegaly, and type I interferons. Plasmacytoid dendritic cell (pDC) accumulation and type I interferon signaling in spleen and Peyer’s patches was also reduced. Fecal 16S rDNA sequencing and culture of internal organs revealed that Lactobacillus reuteri translocates to MLN, liver and spleen in TLR7 Tg mice, and that fecal loads and translocation were suppressed by RS. Lupus induction by IMQ in GF B6 mice was exacerbated by L. reuteri monocolonization. In addition, L. reuteri gavage in the IMQ-inducible model worsened lupus manifestations, which were prevented by RS feeding before onset of disease. RS induced short-chain fatty acids (SCFA) in ileum and blood of TLR7 Tg mice, which suppressed growth of L. reuteri in vitro. In summary, RS exerts beneficial effects in lupus-prone hosts through suppression of pathobionts and type I interferon pathways, which are known to contribute to human SLE. This study provides novel insights into diet-host-microbiota interactions and may aid in the development of functional foods to treat autoimmune diseases.