Multiomics-guided discovery of protective microbiome signatures in lupus-prone mice treated with Faecalibacterium prausnitzii

Gut microbiome dysbiosis has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). However, microbiota-targeted therapeutic strategies have been lacking. Here, we report the potential of Faecalibacterium prausnitzii (strain UT1) to ameliorate gut dysbiosis and alleviate disease progression in the B6.Sle1.Yaa male mouse model of SLE. Fecal metagenomes of patients with SLE shifted carbohydrate catabolism from dietary fibers to host glycans, coinciding with depletion of F. prausnitzii. Oral administration of UT1 partially reversed lupus-associated microbiome alterations and rescued carbohydrate metabolic deficiency in lupus-prone mice. Using correlative metatranscriptomics and metabolomics, we observed restricted expression of bacterial genes related to mucin degradation, elevated pentose phosphate pathway and bile acid-modifying activities, and redirected tryptophan catabolism toward indoleacetic and indoleacrylic acids. Further host cell profiling showed that UT1 rebalanced colonic regulatory T (Treg) and T helper 17 (Th17) cell responses, suppressed systemic autoimmune activation and autoantibody production, and reduced renal pathology. Thus, our findings identify SLE-associated active microbiome signatures and provide a probiotic candidate for the treatment of lupus disease.