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Antibiotic Treatment Induces Long-lasting Changes in the Fecal Microbiota that Protect Against Colitis

Ward, Naomi L. PhD; Phillips, Caleb D. PhD; Nguyen, Deanna D. MD; Shanmugam, Nanda Kumar N. PhD; Song, Yan PhD; Hodin, Richard MD; Shi, Hai Ning DVM, PhD; Cherayil, Bobby J. MD; Goldstein, Allan M. MD

doi: 10.1097/MIB.0000000000000914
Original Basic Science Articles

Background: The interplay between host genetics, immunity, and microbiota is central to the pathogenesis of inflammatory bowel disease. Previous population-based studies suggested a link between antibiotic use and increased inflammatory bowel disease risk, but the mechanisms are unknown. The purpose of this study was to determine the long-term effects of antibiotic administration on microbiota composition, innate immunity, and susceptibility to colitis, as well as the mechanism by which antibiotics alter host colitogenicity.

Methods: Wild-type mice were given broad-spectrum antibiotics or no antibiotics for 2 weeks, and subsequent immunophenotyping and 16S rRNA gene sequencing–based analysis of the fecal microbiome were performed 6 weeks later. In a separate experiment, control and antibiotic-treated mice were given 7 days of dextran sulfate sodium, 6 weeks after completing antibiotic treatment, and the severity of colitis scored histologically. Fecal transfer was performed from control or antibiotic-treated mice to recipient mice whose endogenous microbiota had been cleared with antibiotics, and the susceptibility of the recipients to dextran sulfate sodium–induced colitis was analyzed. Naive CD4+ T cells were transferred from control and antibiotic-treated mice to immunodeficient Rag-1−/− recipients and the severity of colitis compared.

Results: Antibiotics led to sustained dysbiosis and changes in T-cell subpopulations, including reductions in colonic lamina propria total T cells and CD4+ T cells. Antibiotics conferred protection against dextran sulfate sodium colitis, and this effect was transferable by fecal transplant but not by naive T cells.

Conclusions: Antibiotic exposure protects against colitis, and this effect is transferable with fecal microbiota from antibiotic-treated mice, supporting a protective effect of the microbial community.

Supplemental Digital Content Is Available in the Text.Article first published online 8 September 2016.

*Department of Molecular Biology, University of Wyoming, Laramie, Wyoming;

Research and Testing Laboratory, Lubbock, Texas;

Department of Biological Sciences, Texas Tech University, Lubbock, Texas;

§Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts;

Mucosal Immunology and Biology Research Center, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts;

Departments of Surgery, and

**Pediatric Surgery, Massachusetts General Hospital, Boston, Massachusetts.

Address correspondence to: Allan M. Goldstein, MD, Department of Pediatric Surgery, Massachusetts General Hospital, 55 Fruit Street, Warren 1153, Boston, MA 02114 (e-mail: agoldstein@partners.org).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

N. K. N. Shanmugam and B. J. Cherayil were supported by NIH Grant R01 AI089700. D. D. Nguyen was supported by NIH Grant K08DK083430. A. M. Goldstein was supported by a grant from the CSIBD (Center for the Study of Inflammatory Bowel Disease) at Massachusetts General Hospital.

The authors have no conflict of interest to disclose.

Received June 26, 2016

Accepted July 12, 2016

© Crohn's & Colitis Foundation of America, Inc.
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