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Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis

Meisel, Marlies and Mayassi, Toufic and Fehlner-Peach, Hannah and Koval, Jason C. and O'Brien, Sarah L. and Hinterleitner, Reinhard and Lesko, Kathryn and Kim, Sangman and Bouziat, Romain and Chen, Li and Weber, Christopher R. and Mazmanian, Sarkis K. and Jabri, Bana and Antonopoulos, Dionysios A. (2017) Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis. ISME Journal, 11 (1). pp. 15-30. ISSN 1751-7362. PMCID PMC5315477.

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Dysbiosis resulting in gut-microbiome alterations with reduced butyrate production are thought to disrupt intestinal immune homeostasis and promote complex immune disorders. However, whether and how dysbiosis develops before the onset of overt pathology remains poorly defined. Interleukin-15 (IL-15) is upregulated in distressed tissue and its overexpression is thought to predispose susceptible individuals to and have a role in the pathogenesis of celiac disease and inflammatory bowel disease (IBD). Although the immunological roles of IL-15 have been largely studied, its potential impact on the microbiota remains unexplored. Analysis of 16S ribosomal RNA-based inventories of bacterial communities in mice overexpressing IL-15 in the intestinal epithelium (villin-IL-15 transgenic (v-IL-15tg) mice) shows distinct changes in the composition of the intestinal bacteria. Although some alterations are specific to individual intestinal compartments, others are found across the ileum, cecum and feces. In particular, IL-15 overexpression restructures the composition of the microbiota with a decrease in butyrate-producing bacteria that is associated with a reduction in luminal butyrate levels across all intestinal compartments. Fecal microbiota transplant experiments of wild-type and v-IL-15tg microbiota into germ-free mice further indicate that diminishing butyrate concentration observed in the intestinal lumen of v-IL-15tg mice is the result of intrinsic alterations in the microbiota induced by IL-15. This reconfiguration of the microbiota is associated with increased susceptibility to dextran sodium sulfate-induced colitis. Altogether, this study reveals that IL-15 impacts butyrate-producing bacteria and lowers butyrate levels in the absence of overt pathology, which represent events that precede and promote intestinal inflammatory diseases.

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Mazmanian, Sarkis K.0000-0003-2713-1513
Additional Information:© 2016 International Society for Microbial Ecology. Received 10 January 2016; Revised 17 June 2016; Accepted 27 June 2016. Advance online publication 20 September 2016. This work was supported by grants from the Digestive Diseases Research Core Center (DK42086) at the University of Chicago to DAA and BJ, the US National Institutes of Health (R01DK078938) to SKM, (RO1DK67180) to BJ, and FWF Austrian Science Fund (project no.: J 3418-B19) to MM. The submitted manuscript has been created by UChicago Argonne, LLC, Operator of Argonne National Laboratory (‘Argonne’). Argonne, a US Department of Energy Office of Science laboratory, is operated under contract no. DE-AC02-06CH11357. The US Government retains for itself, and others acting on its behalf, a paid-up nonexclusive, irrevocable worldwide license in said article to reproduce, prepare derivative works, distribute copies to the public, and perform publicly and display publicly, by or on behalf of the Government. Author contributions: MM, TM, HF-P, JCK, SLO, RH, KL, SK, RB, and LC performed the studies. CRW performed the histological analysis and scoring. MM, TM, BJ and DAA analyzed the data. SKM helped with the generation of germ free mice, and the design of germ-free experiments. MM, DAA and BJ wrote the manuscript. DAA, and BJ coordinated and supervised the project. DAA designed and performed analysis of the microbiota. BJ conceived and designed the overall project. [Bana Jabri and Dionysios A Antonopoulos] These authors are joint senior authors on this work. The authors declare no conflict of interest.
Funding AgencyGrant Number
Digestive Disease Research CenterDK42086
FWF Der WissenschaftsfondsJ 3418-B19
Department of Energy (DOE)DE-AC02-06CH11357
Issue or Number:1
PubMed Central ID:PMC5315477
Record Number:CaltechAUTHORS:20161003-163706860
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:70778
Deposited By: George Porter
Deposited On:04 Oct 2016 14:43
Last Modified:24 Feb 2020 22:23

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