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ABSTRACTProbiotics are viable microorganisms that are increasingly used for treatment of a variety of diseases. Occasionally, however, probiotics may have adverse clinical effects, including septicemia. Here we examined the role of the intestinal microbiota and the adaptive immune system in preventing translocation of probiotics (e.g., EscherichiacoliNissle). We challenged C57BL/6J mice raised under germfree conditions (GF-raised C57BL/6J mice) and Rag1−/−mice raised under germfree conditions (GF-raised Rag1−/−mice) and under specific-pathogen-free conditions (SPF-raised Rag1−/−mice) with probiotic E. colistrain Nissle 1917, strain Nissle 1917 mutants, the commensal strain E. colimpk, or Bacteroides vulgatusmpk. Additionally, we reconstituted Rag1−/−mice with CD4+T cells. E. colitranslocation and dissemination and the mortality of mice were assessed. In GF-raised Rag1−/−mice, but not in SPF-raised Rag1−/−mice or GF-raised C57BL/6J mice, oral challenge with E. colistrain Nissle 1917, but not oral challenge with E. colimpk, resulted in translocation and dissemination. The mortality rate was significantly higher for E. colistrain Nissle 1917-challenged GF-raised Rag1−/−mice (100%; P< 0.001) than for E. colistrain Nissle 1917-challenged SPF-raised Rag1−/−mice (0%) and GF-raised C57BL/6J mice (0%). Translocation of and mortality due to strain E. coliNissle 1917 in GF-raised Rag1−/−mice were prevented when mice were reconstituted with T cells prior to strain E. coliNissle 1917 challenge, but not when mice were reconstituted with T cells after E. colistrain Nissle 1917 challenge. Cocolonization experiments revealed that E. colimpk could not prevent translocation of strain E. coliNissle 1917. Moreover, we demonstrated that neither lipopolysaccharide structure nor flagella play a role in E. colistrain Nissle 1917 translocation and dissemination. Our results suggest that if both the microbiota and adaptive immunity are defective, translocation across the intestinal epithelium and dissemination of the probiotic E. colistrain Nissle 1917 may occur and have potentially severe adverse effects. Future work should define the possibly related molecular factors that promote probiotic functions, fitness, and facultative pathogenicity.