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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.