Jun Miyoshi1, Sawako Miyoshi2, Tom O Delmont3, Candace Cham4, Sonny T M Lee5, Aki Sakatani4, Karen Yang4, Yue Shan4, Megan Kennedy4, Evan Kiefl6, Mahmoud Yousef7, Sean Crosson8, Mitchell Sogin9, Dionysios A Antonopoulos10, A Murat Eren11, Vanessa Leone12, Eugene B Chang13. 1. Department of Medicine, Knapp Center for Biomedical Discovery, The University of Chicago Knapp Center for Biomedical Discovery, Chicago, Illinois; Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan. 2. Department of Medicine, Knapp Center for Biomedical Discovery, The University of Chicago Knapp Center for Biomedical Discovery, Chicago, Illinois; Department of General Medicine, Kyorin University School of Medicine, Tokyo, Japan. 3. Department of Medicine, Knapp Center for Biomedical Discovery, The University of Chicago Knapp Center for Biomedical Discovery, Chicago, Illinois; Génomique Métabolique, Genoscope, Institut François Jacob, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Centre National de la Recherche Scientifique, Université Evry, Université Paris-Saclay, Evry, France. 4. Department of Medicine, Knapp Center for Biomedical Discovery, The University of Chicago Knapp Center for Biomedical Discovery, Chicago, Illinois. 5. Department of Medicine, Knapp Center for Biomedical Discovery, The University of Chicago Knapp Center for Biomedical Discovery, Chicago, Illinois; Division of Biology, Kansas State University, Manhattan, Kansas. 6. Department of Medicine, Knapp Center for Biomedical Discovery, The University of Chicago Knapp Center for Biomedical Discovery, Chicago, Illinois; Graduate Program in Biophysical Sciences, The University of Chicago Gordon Center for Integrative Science, Chicago, Illinois. 7. Undergraduate Program, Department of Computer Science, The University of Chicago John Crerar Library, Chicago, Illinois. 8. Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan. 9. Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Marine Biological Laboratory, Woods Hole, Massachusetts. 10. Biosciences Division, Argonne National Laboratory, Illinois. 11. Department of Medicine, Knapp Center for Biomedical Discovery, The University of Chicago Knapp Center for Biomedical Discovery, Chicago, Illinois; Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Marine Biological Laboratory, Woods Hole, Massachusetts. 12. Department of Medicine, Knapp Center for Biomedical Discovery, The University of Chicago Knapp Center for Biomedical Discovery, Chicago, Illinois; Department of Animal and Dairy Sciences, University of Wisconsin-Madison, Madison, Wisconsin. 13. Department of Medicine, Knapp Center for Biomedical Discovery, The University of Chicago Knapp Center for Biomedical Discovery, Chicago, Illinois. Electronic address: echang@medicine.bsd.uchicago.edu.
Abstract
BACKGROUND & AIMS: Perturbations in the early-life gut microbiome are associated with increased risk for complex immune disorders like inflammatory bowel diseases. We previously showed that maternal antibiotic-induced gut dysbiosis vertically transmitted to offspring increases experimental colitis risk in interleukin (IL) 10 gene deficient (IL10-/-) mice, a finding that may result from the loss/lack of essential microbes needed for appropriate immunologic education early in life. Here, we aimed to identify key microbes required for proper development of the early-life gut microbiome that decrease colitis risk in genetically susceptible animals. METHODS: Metagenomic sequencing followed by reconstruction of metagenome-assembled genomes was performed on fecal samples of IL10-/- mice with and without antibiotic-induced dysbiosis to identify potential missing microbial members needed for immunologic education. One high-value target strain was then engrafted early and/or late into the gut microbiomes of IL10-/- mice with antibiotic-induced dysbiosis. RESULTS: Early-, but not late-, life engraftment of a single dominant Bacteroides strain of non-antibiotic-treated IL10-/- mice was sufficient to restore the development of the gut microbiome, promote immune tolerance, and prevent colitis in IL10-/- mice that had antibiotic-induced dysbiosis. CONCLUSIONS: Restitution of a keystone microbial strain missing in the early-life antibiotic-induced gut dysbiosis results in recovery of the microbiome, proper development of immune tolerance, and reduced risk for colitis in genetically prone hosts.
BACKGROUND & AIMS: Perturbations in the early-life gut microbiome are associated with increased risk for complex immune disorders like inflammatory bowel diseases. We previously showed that maternal antibiotic-induced gut dysbiosis vertically transmitted to offspring increases experimental colitis risk in interleukin (IL) 10 gene deficient (IL10-/-) mice, a finding that may result from the loss/lack of essential microbes needed for appropriate immunologic education early in life. Here, we aimed to identify key microbes required for proper development of the early-life gut microbiome that decrease colitis risk in genetically susceptible animals. METHODS: Metagenomic sequencing followed by reconstruction of metagenome-assembled genomes was performed on fecal samples of IL10-/- mice with and without antibiotic-induced dysbiosis to identify potential missing microbial members needed for immunologic education. One high-value target strain was then engrafted early and/or late into the gut microbiomes of IL10-/- mice with antibiotic-induced dysbiosis. RESULTS: Early-, but not late-, life engraftment of a single dominant Bacteroides strain of non-antibiotic-treated IL10-/- mice was sufficient to restore the development of the gut microbiome, promote immune tolerance, and prevent colitis in IL10-/- mice that had antibiotic-induced dysbiosis. CONCLUSIONS: Restitution of a keystone microbial strain missing in the early-life antibiotic-induced gut dysbiosis results in recovery of the microbiome, proper development of immune tolerance, and reduced risk for colitis in genetically prone hosts.
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