Antibiotic treatment for Tuberculosis induces a profound dysbiosis of the microbiome that persists long after therapy is completed
Matthew F Wipperman, Daniel W Fitzgerald, Marc Antoine Jean Juste, Ying Taur, Sivaranjani Namasivayam, Alan Sher, James M Bean, Vanni Bucci, Michael S Glickman, Matthew F Wipperman, Daniel W Fitzgerald, Marc Antoine Jean Juste, Ying Taur, Sivaranjani Namasivayam, Alan Sher, James M Bean, Vanni Bucci, Michael S Glickman
Abstract
Mycobacterium tuberculosis, the cause of Tuberculosis (TB), infects one third of the world's population and causes substantial mortality worldwide. In its shortest format, treatment of TB requires six months of multidrug therapy with a mixture of broad spectrum and mycobacterial specific antibiotics, and treatment of multidrug resistant TB is longer. The widespread use of this regimen makes this one of the largest exposures of humans to antimicrobials, yet the effects of TB treatment on intestinal microbiome composition and long-term stability are unknown. We compared the microbiome composition, assessed by both 16S rDNA and metagenomic DNA sequencing, of TB cases during antimycobacterial treatment and following cure by 6 months of antibiotics. TB treatment does not perturb overall diversity, but nonetheless dramatically depletes multiple immunologically significant commensal bacteria. The microbiomic perturbation of TB therapy can persist for at least 1.2 years, indicating that the effects of TB treatment are long lasting. These results demonstrate that TB treatment has dramatic effects on the intestinal microbiome and highlight unexpected durable consequences of treatment for the world's most common infection on human ecology.
Conflict of interest statement
The authors declare that they have no competing interests.
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References
- Global Tuberculosis Report (World Health Organization, 2016).
- Nathan C. What can immunology contribute to the control of the world’s leading cause of death from bacterial infection? Immunol Rev. 2015;264:2–5. doi: 10.1111/imr.12277.
- Abel L, El-Baghdadi J, Bousfiha AA, Casanova JL, Schurr E. Human genetics of tuberculosis: a long and winding road. Philos Trans R Soc Lond B Biol Sci. 2014;369:20130428. doi: 10.1098/rstb.2013.0428.
- Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature. 2016;535:75–84. doi: 10.1038/nature18848.
- Furusawa Y, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504:446–450. doi: 10.1038/nature12721.
- Arpaia N, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504:451–455. doi: 10.1038/nature12726.
- Trompette A, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med. 2014;20:159–166. doi: 10.1038/nm.3444.
- Arrieta MC, et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med. 2015;7:307ra152. doi: 10.1126/scitranslmed.aab2271.
- Segal, L. N. et al. Anaerobic Bacterial Fermentation Products Increase Tuberculosis Risk in Antiretroviral-Drug-Treated HIV Patients. Cell Host Microbe21, 530–537, e534, doi:10.1016/j.chom.2017.03.003 (2017).
- Moya A, Ferrer M. Functional Redundancy-Induced Stability of Gut Microbiota Subjected to Disturbance. Trends Microbiol. 2016;24:402–413. doi: 10.1016/j.tim.2016.02.002.
- Becattini S, Taur Y, Pamer EG. Antibiotic-Induced Changes in the Intestinal Microbiota and Disease. Trends Mol Med. 2016;22:458–478. doi: 10.1016/j.molmed.2016.04.003.
- Brismar B, Edlund C, Malmborg AS, Nord CE. Ciprofloxacin concentrations and impact of the colon microflora in patients undergoing colorectal surgery. Antimicrob Agents Chemother. 1990;34:481–483. doi: 10.1128/AAC.34.3.481.
- Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008;6:e280. doi: 10.1371/journal.pbio.0060280.
- Hernandez E, et al. Functional consequences of microbial shifts in the human gastrointestinal tract linked to antibiotic treatment and obesity. Gut Microbes. 2013;4:306–315. doi: 10.4161/gmic.25321.
- Theriot CM, et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection. Nat Commun. 2014;5:3114. doi: 10.1038/ncomms4114.
- Taur Y, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012;55:905–914. doi: 10.1093/cid/cis580.
- Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci USA. 2011;108(Suppl 1):4554–4561. doi: 10.1073/pnas.1000087107.
- Namasivayam S, et al. Longitudinal profiling reveals a persistent intestinal dysbiosis triggered by conventional anti-tuberculosis therapy. Microbiome. 2017;5:71. doi: 10.1186/s40168-017-0286-2.
- Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq. 2. Genome Biol. 2014;15:550. doi: 10.1186/s13059-014-0550-8.
- Segata N, et al. Metagenomic biomarker discovery and explanation. Genome Biol. 2011;12:R60. doi: 10.1186/gb-2011-12-6-r60.
- Zaborin A, et al. Membership and behavior of ultra-low-diversity pathogen communities present in the gut of humans during prolonged critical illness. MBio. 2014;5:e01361–01314. doi: 10.1128/mBio.01361-14.
- Abubucker S, et al. Metabolic reconstruction for metagenomic data and its application to the human microbiome. PLoS Comput Biol. 2012;8:e1002358. doi: 10.1371/journal.pcbi.1002358.
- Jernberg C, Lofmark S, Edlund C, Jansson JK. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J. 2007;1:56–66. doi: 10.1038/ismej.2007.3.
- Taur Y, Pamer EG. Harnessing microbiota to kill a pathogen: Fixing the microbiota to treat Clostridium difficile infections. Nat Med. 2014;20:246–247. doi: 10.1038/nm.3492.
- Shen Y, et al. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe. 2012;12:509–520. doi: 10.1016/j.chom.2012.08.004.
- Schirmer M, et al. Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity. Cell. 2016;167:1897. doi: 10.1016/j.cell.2016.11.046.
- Tan TG, et al. Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice. Proc Natl Acad Sci USA. 2016;113:E8141–E8150. doi: 10.1073/pnas.1617460113.
- Verver S, et al. Rate of reinfection tuberculosis after successful treatment is higher than rate of new tuberculosis. Am J Respir Crit Care Med. 2005;171:1430–1435. doi: 10.1164/rccm.200409-1200OC.
- Glynn JR, et al. High rates of recurrence in HIV-infected and HIV-uninfected patients with tuberculosis. J Infect Dis. 2010;201:704–711. doi: 10.1086/650529.
- United, S. Health Insurance Portability and Accountability Act of 1996. Public Law 104-191. US Statut Large110, 1936–2103 (1996).
- Harris PA, et al. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–381. doi: 10.1016/j.jbi.2008.08.010.
- Yatsunenko T, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486:222–227.
- Edgar RC. UPARSE: highly accurate OTU sequences from microbial amplicon reads. Nat Methods. 2013;10:996–998. doi: 10.1038/nmeth.2604.
- Haas BJ, et al. Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons. Genome Res. 2011;21:494–504. doi: 10.1101/gr.112730.110.
- Camacho C, et al. BLAST+: architecture and applications. BMC Bioinformatics. 2009;10:421. doi: 10.1186/1471-2105-10-421.
- Geer LY, et al. The NCBI BioSystems database. Nucleic Acids Res. 2010;38:D492–496. doi: 10.1093/nar/gkp858.
- McDonald D, et al. The Biological Observation Matrix (BIOM) format or: how I learned to stop worrying and love the ome-ome. Gigascience. 2012;1:7. doi: 10.1186/2047-217X-1-7.
- R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, Vienna, Austria, 2016).
- McMurdie PJ, Holmes S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One. 2013;8:e61217. doi: 10.1371/journal.pone.0061217.
- Wickham, H. ggplot2: Elegant Graphics for Data Analysis. (Springer Publishing Company, Incorporated, 2009).
- Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–2120. doi: 10.1093/bioinformatics/btu170.
- Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357–359. doi: 10.1038/nmeth.1923.
- Truong DT, et al. MetaPhlAn2 for enhanced metagenomic taxonomic profiling. Nat Methods. 2015;12:902–903. doi: 10.1038/nmeth.3589.
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