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Cell. 2019 Sep 5;178(6):1313-1328.e13. doi: 10.1016/j.cell.2019.08.010.
Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans.
Hagan T1, Cortese M1, Rouphael N2, Boudreau C3, Linde C3, Maddur MS4, Das J3, Wang H4, Guthmiller J5, Zheng NY5, Huang M5, Uphadhyay AA4, Gardinassi L6, Petitdemange C4, McCullough MP2, Johnson SJ2, Gill K4, Cervasi B4, Zou J7, Bretin A7, Hahn M8, Gewirtz AT7, Bosinger SE4, Wilson PC5, Li S6, Alter G3, Khurana S8, Golding H8, Pulendran B9.
Author information
1 Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA. 2 Hope Clinic of the Emory Vaccine Center, Decatur, GA 30030, USA. 3 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. 4 Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, GA 30329, USA. 5 Department of Medicine, Section of Rheumatology, Knapp Center for Lupus and Immunology, University of Chicago, Chicago, IL 60637, USA. 6 Department of Medicine, Emory University, Atlanta, GA 30303, USA. 7 Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA. 8 Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. 9 Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: bpulend@stanford.edu.
Abstract
Emerging evidence indicates a central role for the microbiome in immunity. However, causal evidence in humans is sparse. Here, we administered broad-spectrum antibiotics to healthy adults prior and subsequent to seasonal influenza vaccination. Despite a 10,000-fold reduction in gut bacterial load and long-lasting diminution in bacterial diversity, antibody responses were not significantly affected. However, in a second trial of subjects with low pre-existing antibody titers, there was significant impairment in H1N1-specific neutralization and binding IgG1 and IgA responses. In addition, in both studies antibiotics treatment resulted in (1) enhanced inflammatory signatures (including AP-1/NR4A expression), observed previously in the elderly, and increased dendritic cell activation; (2) divergent metabolic trajectories, with a 1,000-fold reduction in serum secondary bile acids, which was highly correlated with AP-1/NR4A signaling and inflammasome activation. Multi-omics integration revealed significant associations between bacterial species and metabolic phenotypes, highlighting a key role for the microbiome in modulating human immunity.
Copyright ? 2019 Elsevier Inc. All rights reserved.
KEYWORDS:
antibodies; bile acids; gene expression profiling; immunology; influenza; metabolomics; microbiota; systems biology; systems vaccinology; vaccines
PMID: 31491384 DOI: 10.1016/j.cell.2019.08.010
Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans.
Hagan T1, Cortese M1, Rouphael N2, Boudreau C3, Linde C3, Maddur MS4, Das J3, Wang H4, Guthmiller J5, Zheng NY5, Huang M5, Uphadhyay AA4, Gardinassi L6, Petitdemange C4, McCullough MP2, Johnson SJ2, Gill K4, Cervasi B4, Zou J7, Bretin A7, Hahn M8, Gewirtz AT7, Bosinger SE4, Wilson PC5, Li S6, Alter G3, Khurana S8, Golding H8, Pulendran B9.
Author information
1 Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA. 2 Hope Clinic of the Emory Vaccine Center, Decatur, GA 30030, USA. 3 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA. 4 Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, GA 30329, USA. 5 Department of Medicine, Section of Rheumatology, Knapp Center for Lupus and Immunology, University of Chicago, Chicago, IL 60637, USA. 6 Department of Medicine, Emory University, Atlanta, GA 30303, USA. 7 Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA. 8 Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. 9 Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: bpulend@stanford.edu.
Abstract
Emerging evidence indicates a central role for the microbiome in immunity. However, causal evidence in humans is sparse. Here, we administered broad-spectrum antibiotics to healthy adults prior and subsequent to seasonal influenza vaccination. Despite a 10,000-fold reduction in gut bacterial load and long-lasting diminution in bacterial diversity, antibody responses were not significantly affected. However, in a second trial of subjects with low pre-existing antibody titers, there was significant impairment in H1N1-specific neutralization and binding IgG1 and IgA responses. In addition, in both studies antibiotics treatment resulted in (1) enhanced inflammatory signatures (including AP-1/NR4A expression), observed previously in the elderly, and increased dendritic cell activation; (2) divergent metabolic trajectories, with a 1,000-fold reduction in serum secondary bile acids, which was highly correlated with AP-1/NR4A signaling and inflammasome activation. Multi-omics integration revealed significant associations between bacterial species and metabolic phenotypes, highlighting a key role for the microbiome in modulating human immunity.
Copyright ? 2019 Elsevier Inc. All rights reserved.
KEYWORDS:
antibodies; bile acids; gene expression profiling; immunology; influenza; metabolomics; microbiota; systems biology; systems vaccinology; vaccines
PMID: 31491384 DOI: 10.1016/j.cell.2019.08.010