title: Safety of probiotic Escherichia coli strain Nissle 1917 depends on intestinal microbiota and adaptive immunity of the host.
abstract: Probiotics 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., Escherichia coli Nissle). 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. coli strain Nissle 1917, strain Nissle 1917 mutants, the commensal strain E. coli mpk, or Bacteroides vulgatus mpk. Additionally, we reconstituted Rag1(-/-) mice with CD4(+) T cells. E. coli translocation 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. coli strain Nissle 1917, but not oral challenge with E. coli mpk, resulted in translocation and dissemination. The mortality rate was significantly higher for E. coli strain Nissle 1917-challenged GF-raised Rag1(-/-) mice (100%; P < 0.001) than for E. coli strain Nissle 1917-challenged SPF-raised Rag1(-/-) mice (0%) and GF-raised C57BL/6J mice (0%). Translocation of and mortality due to strain E. coli Nissle 1917 in GF-raised Rag1(-/-) mice were prevented when mice were reconstituted with T cells prior to strain E. coli Nissle 1917 challenge, but not when mice were reconstituted with T cells after E. coli strain Nissle 1917 challenge. Cocolonization experiments revealed that E. coli mpk could not prevent translocation of strain E. coli Nissle 1917. Moreover, we demonstrated that neither lipopolysaccharide structure nor flagella play a role in E. coli strain 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. coli strain 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.
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gronbach
authors.forename: Ute
authors.initials: U
authors.lastname: Eberle
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Olschläger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dobrindt
authors.forename: Frank
authors.initials: F
authors.lastname: Leithäuser
authors.forename: Jan Hendrik
authors.initials: JH
authors.lastname: Niess
authors.forename: Gerd
authors.initials: G
authors.lastname: Döring
authors.forename: Jörg
authors.initials: J
authors.lastname: Reimann
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Autenrieth
authors.forename: Julia-Stefanie
authors.initials: JS
authors.lastname: Frick
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004926:Escherichia coli / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D005798:Genes, Bacterial / Q000235:genetics / Q000276:immunology; D016654:Genes, RAG-1 / Q000276:immunology; D007422:Intestines / Q000382:microbiology*; D054892:Metagenome / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D019936:Probiotics / Q000009:adverse effects*; D013601:T-Lymphocytes / Q000276:immunology; D014178:Translocation, Genetic / Q000276:immunology
chemical_list: D016207:Cytokines