Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans

• Type of Material: Article
• Authors: Thomas Hagan, Stanford University; Mario Cortese, Stanford University; Nadine Rouphael, Emory University; Carolyn Boudreau, Ragon Institute of MGH, MIT and Harvard; Caitlin Linde, Ragon Institute of MGH, MIT and Harvard; Mohan S. Maddur, Emory Vaccine Center; Jishnu Das, Ragon Institute of MGH, MIT and Harvard; Hong Wang, Emory Vaccine Center; Jenna Guthmiller, University of Chicago; Nai-Ying Zheng, University of Chicago; Min Huang, University of Chicago; Amit A. Uphadhyay, Emory Vaccine Center; Luiz Gardinassi, Emory University; Caroline Petitdemange, Emory Vaccine Center; Michele Paine McCullough, Emory Vaccine Center; Sara Jo Johnson, Emory Vaccine Center; Kiran Gill, Emory Vaccine Center; Barbara Cervasi, Emory Vaccine Center; Jun Zou, Georgia State University; Alexis Bretin, Georgia State University; Megan Hahn, US Food and Drug Administration; Andrew Gewirtz, Emory University; Steven Bosinger, Emory University; Patrick C. Wilson, University of Chicago; Shuzhao Li, Emory University; Galit Alter, Ragon Institute of MGH, MIT and Harvard; Surender Khurana, US Food and Drug Administration; Hana Golding, US Food and Drug Administration; Bali Pulendran, Emory University
• Language: English
• Date: 2019-09-05
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2019.08.010
• Title of Journal or Parent Work: CELL
• Volume: 178
• Issue: 6
• Start Page: 1313
• End Page: +
• Grant/Funding Information: NIH grants HIPC U19AI090023 (to B.P.), U19AI057266 (to B.P., P.I. Rafi Ahmed),; UH2AI132345 (to S.L.), U24AI120134 (S.E.B.); T32AI07290 (to T.H.),; This work was supported by Emory-UGA CEIRS Contract HHSN272201400004C (to B.P., P.I. Walt Orenstein),; Sean Parker Cancer Institute, the Soffer endowment (B.P), and the Violetta Horton endowment (B.P).
• Keywords: Inhibition; Vaccination; Expression; Biochemistry & Molecular Biology; Monoclonal antibodies; Activation; Bile-acids; Systems; Receptors; Science & Technology; Inflammatory bowel disease; Cell Biology; Life Sciences & Biomedicine; Seasonal influenza
• Research Categories: Chemistry, Pharmaceutical; Health Sciences, Immunology; Health Sciences, Pathology; Biology, Microbiology; Biology, Cell

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.