and differentially affect gut microbes and metabolites in mice with Treg deficiency.

Treg deficiency causes a lethal, CD4 T cell-driven autoimmune disease called IPEX syndrome (immunodysregulation, polyendocrinopathy, and enteropathy, with X-linked inheritance) in humans and in the scurfy (SF) mouse, a mouse model of the disease. Feeding DSM 17938 (LR 17938, LR) to SF mice reprograms the gut microbiota, reduces disease progression, and prolongs lifespan. However, the efficacy and mechanism of LR, compared with other probiotics, in producing these effects is unknown. We compared LR with (LGG), an extensively investigated probiotic. LR was more effective than LGG in prolonging survival. Both probiotics restored the fecal microbial alpha diversity, but they produced distinct fecal bacterial clusters and differentially modulated microbial relative abundance (RA). LR increased the RA of phylum_Firmicutes, whereas LR reduced phylum_Bacteroidetes, and , reversing changes attributed to the SF phenotype. LGG primarily reduced the RA of . Both LR and LGG reduced the potentially pathogenic taxon . Plasma metabolomics revealed substantial differences among 696 metabolites. We observed similar changes of many clusters of metabolites in SF mice associated with treatment with either LR or LGG. However, a unique effect of LR was to increase the abundance of plasma adenosine metabolites such as inosine, which we previously showed had immune modulatory effects. In conclusion: ) different probiotics produce distinct signatures in the fecal microbial community in mice with Treg deficiency; and ) when comparing different probiotics, there are strain-specific microbial products with different anti-inflammatory properties, reinforcing the concept that "one size does not fit all" in the treatment of autoimmune disease. In the treatment of Treg-deficiency-induced autoimmunity, DSM 17938 (LR) showed greater efficacy than (LGG). The study demonstrated that two different probiotics produce distinct signatures in the fecal microbial community in mice with Treg deficiency, but with many similarities in global plasma metabolites in general. However, there are strain-specific microbial products with different anti-inflammatory properties, reinforcing the concept that "one size does not fit all" in the treatment of autoimmune disease.