Foxp3+ regulatory T cells (Tregs) control inflammation. Foxp3 loss-of-function mutations cause a severe multi-organ autoimmune and inflammatory disorder in humans (IPEX syndrome) and in mice (Scurfy, sf). Treg-deficient sf mice generally die of a lymphoproliferative syndrome with severe multi-organ inflammation at 21-28 days old. Lactobacillus reuteri (LR) has beneficial effects in several human diseases such as necrotizing enterocolitis (NEC), rotavirus diarrhea, infant colic and atopic dermatitis. Our preliminary studies demonstrated that feeding LR strain DSM17938 (LR17938) for 3 weeks significantly prolonged the survival of sf mice. Specific Aims are to (1-1) test the effects of 1-,2-, and 3-week LR feeding regimens on the survival of sf mice; (1-2) test whether the therapeutic effect is specific to LR17938 compared with other probiotics; and (2-1) investigate the immunological changes in sf mice produced by LR17938 and another probiotic; (2-2) characterize the fecal microbial community and metabolome of sf mice, and the effects of LR17938. The impact of the proposed studies will (1) provides preclinical data for potential LR treatment of autoimmune diseases, focusing on IPEX syndrome. (In theory, LR treatment could prolong survival prior to bone marrow transplantation); and (2) provide insights into how the probiotic LR modulates the immune system. The studies may lead to future clinical trials for IPEX syndrome and possibly other autoimmune and inflammatory disorders.