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

Abstract

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 play a role in the pathogenesis of celiac disease and inflammatory bowel disease (IBD). While the immunological roles of IL-15 have been largely studied, its potential impact on the microbiota remains unexplored. Analysis of 16S rRNA-based inventories of bacterial communities in mice overexpressing IL-15 in the intestinal epithelium (v-IL-15tg mice) shows distinct changes in the composition of the intestinal bacteria. While 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 inducedmore » 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.« less

Authors:
; ; ; ; ; ; ; ORCiD logo; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
University of Chicago; National Institutes of Health (NIH)
OSTI Identifier:
1429905
DOE Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article
Journal Name:
The ISME Journal
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 1751-7362
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
autoimmunity; butyrate; dysbiosis; dysbiosis, interleukin-15, butyrate, inflammatory bowel disease, autoimmunity; inflammatory bowel disease; interleukin-­15

Citation Formats

Meisel, Marlies, Mayassi, Toufic, Fehlner-Peach, Hannah, Koval, Jason C., O'Brien, Sarah L., Hinterleitner, Reinhard, Lesko, Kathryn, Kim, Sangman, Bouziat, Romain, Chen, Li, Weber, Christopher R., Mazmanian, Sarkis K., Jabri, Bana, and Antonopoulos, Dionysios A. Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis. United States: N. p., 2016. Web. doi:10.1038/ismej.2016.114.
Meisel, Marlies, Mayassi, Toufic, Fehlner-Peach, Hannah, Koval, Jason C., O'Brien, Sarah L., Hinterleitner, Reinhard, Lesko, Kathryn, Kim, Sangman, Bouziat, Romain, Chen, Li, Weber, Christopher R., Mazmanian, Sarkis K., Jabri, Bana, & Antonopoulos, Dionysios A. Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis. United States. doi:10.1038/ismej.2016.114.
Meisel, Marlies, Mayassi, Toufic, Fehlner-Peach, Hannah, Koval, Jason C., O'Brien, Sarah L., Hinterleitner, Reinhard, Lesko, Kathryn, Kim, Sangman, Bouziat, Romain, Chen, Li, Weber, Christopher R., Mazmanian, Sarkis K., Jabri, Bana, and Antonopoulos, Dionysios A. Tue . "Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis". United States. doi:10.1038/ismej.2016.114.
@article{osti_1429905,
title = {Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis},
author = {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.},
abstractNote = {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 play a role in the pathogenesis of celiac disease and inflammatory bowel disease (IBD). While the immunological roles of IL-15 have been largely studied, its potential impact on the microbiota remains unexplored. Analysis of 16S rRNA-based inventories of bacterial communities in mice overexpressing IL-15 in the intestinal epithelium (v-IL-15tg mice) shows distinct changes in the composition of the intestinal bacteria. While 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.},
doi = {10.1038/ismej.2016.114},
journal = {The ISME Journal},
issn = {1751-7362},
number = 1,
volume = 11,
place = {United States},
year = {2016},
month = {9}
}

Works referenced in this record:

Inflammatory Bowel Disease
journal, November 2009

  • Abraham, Clara; Cho, Judy H.
  • New England Journal of Medicine, Vol. 361, Issue 21
  • DOI: 10.1056/NEJMra0804647

A microbial symbiosis factor prevents intestinal inflammatory disease
journal, May 2008

  • Mazmanian, Sarkis K.; Round, June L.; Kasper, Dennis L.
  • Nature, Vol. 453, Issue 7195
  • DOI: 10.1038/nature07008

Biphenyl-utilizing bacteria and their functional genes in a pine root zone contaminated with polychlorinated biphenyls (PCBs)
journal, May 2007

  • Leigh, Mary Beth; Pellizari, Vivian H.; Uhlík, Ondřej
  • The ISME Journal, Vol. 1, Issue 2
  • DOI: 10.1038/ismej.2007.26

IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction
journal, November 2015

  • Jabri, Bana; Abadie, Valérie
  • Nature Reviews Immunology, Vol. 15, Issue 12
  • DOI: 10.1038/nri3919

PyNAST: a flexible tool for aligning sequences to a template alignment
journal, November 2009


NOD mouse colonies around the world- recent facts and figures
journal, May 1993


Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon
journal, September 2008

  • Waldecker, Markus; Kautenburger, Tanja; Daumann, Heike
  • The Journal of Nutritional Biochemistry, Vol. 19, Issue 9
  • DOI: 10.1016/j.jnutbio.2007.08.002

Expression of colonic antigens by goblet and columnar epithelial cells in ileal pouch mucosa: their association with inflammatory change and faecal stasis.
journal, September 1994

  • Campbell, A. P.; Merrett, M. N.; Kettlewell, M.
  • Journal of Clinical Pathology, Vol. 47, Issue 9
  • DOI: 10.1136/jcp.47.9.834

Protein Kinase C θ Regulates the Phenotype of Murine CD4+ Th17 Cells
journal, May 2014


An improved Greengenes taxonomy with explicit ranks for ecological and evolutionary analyses of bacteria and archaea
journal, December 2011

  • McDonald, Daniel; Price, Morgan N.; Goodrich, Julia
  • The ISME Journal, Vol. 6, Issue 3
  • DOI: 10.1038/ismej.2011.139

Intestinal Bacteria and the Regulation of Immune Cell Homeostasis
journal, March 2010


Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis
journal, July 2010

  • Lee, Y. K.; Menezes, J. S.; Umesaki, Y.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue Supplement_1
  • DOI: 10.1073/pnas.1000082107

Evolution of Mammals and Their Gut Microbes
journal, June 2008


Innate immunity and intestinal microbiota in the development of Type 1 diabetes
journal, September 2008

  • Wen, Li; Ley, Ruth E.; Volchkov, Pavel Yu.
  • Nature, Vol. 455, Issue 7216
  • DOI: 10.1038/nature07336

The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease
journal, April 2002

  • Cuthbert, Andrew P.; Fisher, Sheila A.; Mirza, Muddassar M.
  • Gastroenterology, Vol. 122, Issue 4
  • DOI: 10.1053/gast.2002.32415

An ecological and evolutionary perspective on human–microbe mutualism and disease
journal, October 2007

  • Dethlefsen, Les; McFall-Ngai, Margaret; Relman, David A.
  • Nature, Vol. 449, Issue 7164
  • DOI: 10.1038/nature06245

Review article: the role of butyrate on colonic function: REVIEW: ROLE OF BUTYRATE ON COLONIC FUNCTION
journal, October 2007


IL-15 Is Highly Expressed in Inflammatory Bowel Disease and Regulates Local T Cell-Dependent Cytokine Production
journal, April 2000


Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis
journal, July 1992


Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation
journal, November 2013

  • Arpaia, Nicholas; Campbell, Clarissa; Fan, Xiying
  • Nature, Vol. 504, Issue 7480
  • DOI: 10.1038/nature12726

Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample
journal, June 2010

  • Caporaso, J. G.; Lauber, C. L.; Walters, W. A.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue Supplement_1
  • DOI: 10.1073/pnas.1000080107

Diversity of the Human Intestinal Microbial Flora
journal, June 2005


FastTree 2 – Approximately Maximum-Likelihood Trees for Large Alignments
journal, March 2010


IL-15: a central regulator of celiac disease immunopathology
journal, June 2014

  • Abadie, Valérie; Jabri, Bana
  • Immunological Reviews, Vol. 260, Issue 1
  • DOI: 10.1111/imr.12191

UniFrac: an effective distance metric for microbial community comparison
journal, September 2010

  • Lozupone, Catherine; Lladser, Manuel E.; Knights, Dan
  • The ISME Journal, Vol. 5, Issue 2
  • DOI: 10.1038/ismej.2010.133

Effects of dietary fiber on inflammatory bowel disease
journal, June 2005

  • Galvez, Julio; Rodríguez-Cabezas, M. Elena; Zarzuelo, Antonio
  • Molecular Nutrition & Food Research, Vol. 49, Issue 6
  • DOI: 10.1002/mnfr.200500013

Gut-Residing Segmented Filamentous Bacteria Drive Autoimmune Arthritis via T Helper 17 Cells
journal, June 2010


Interleukin 15: biology and relevance to human disease
journal, January 2001


Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells
journal, November 2013

  • Furusawa, Yukihiro; Obata, Yuuki; Fukuda, Shinji
  • Nature, Vol. 504, Issue 7480
  • DOI: 10.1038/nature12721

Reciprocal interactions of the intestinal microbiota and immune system
journal, September 2012

  • Maynard, Craig L.; Elson, Charles O.; Hatton, Robin D.
  • Nature, Vol. 489, Issue 7415
  • DOI: 10.1038/nature11551

Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases
journal, August 2007

  • Frank, D. N.; St. Amand, A. L.; Feldman, R. A.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 34, p. 13780-13785
  • DOI: 10.1073/pnas.0706625104

Ribosomal Database Project: data and tools for high throughput rRNA analysis
journal, November 2013

  • Cole, James R.; Wang, Qiong; Fish, Jordan A.
  • Nucleic Acids Research, Vol. 42, Issue D1
  • DOI: 10.1093/nar/gkt1244

Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15R 
journal, July 2013

  • Chen, J.; Feigenbaum, L.; Awasthi, P.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 33
  • DOI: 10.1073/pnas.1312911110

Search and clustering orders of magnitude faster than BLAST
journal, August 2010


Butyrate acts as a survival factor for colonic epithelial cells: Further fuel for the in vivo versus in vitro debate
journal, March 1997


Introducing GUt Low-Density Array (GULDA) - a validated approach for qPCR-based intestinal microbial community analysis
journal, October 2012

  • Bergström, Anders; Licht, Tine R.; Wilcks, Andrea
  • FEMS Microbiology Letters, Vol. 337, Issue 1
  • DOI: 10.1111/1574-6968.12004

phyloseq: An R Package for Reproducible Interactive Analysis and Graphics of Microbiome Census Data
journal, April 2013


Novel players in coeliac disease pathogenesis: role of the gut microbiota
journal, June 2015

  • Verdu, Elena F.; Galipeau, Heather J.; Jabri, Bana
  • Nature Reviews Gastroenterology & Hepatology, Vol. 12, Issue 9
  • DOI: 10.1038/nrgastro.2015.90

Fermentation of 4-aminobutyrate by Clostridium aminobutyricum : cloning of two genes involved in the formation and dehydration of 4-hydroxybutyryl-CoA
journal, August 2000

  • Gerhardt, Astrid; Çinkaya, Irfan; Linder, Dietmar
  • Archives of Microbiology, Vol. 174, Issue 3, p. 189-199
  • DOI: 10.1007/s002030000195

Regional specialization within the intestinal immune system
journal, September 2014

  • Mowat, Allan M.; Agace, William W.
  • Nature Reviews Immunology, Vol. 14, Issue 10
  • DOI: 10.1038/nri3738

Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens
journal, February 2011


Simple Gas Chromatography Analysis of Faecal Butyrate: Application to Patients at Risk of Pouchitis
journal, January 2001

  • Renom, Gilles; Bulois, Philippe; Hafraoui, Samira
  • Clinical Chemistry and Laboratory Medicine, Vol. 39, Issue 1
  • DOI: 10.1515/CCLM.2001.005

Human Intestinal Microbiota and Type 1 Diabetes
journal, August 2013


High Levels of Proinflammatory Cytokines, but Not Markers of Tissue Injury, in Unaffected Intestinal Areas from Patients with IBD
journal, January 2009

  • León, Alberto J.; Gómez, Emma; Garrote, Jose A.
  • Mediators of Inflammation, Vol. 2009
  • DOI: 10.1155/2009/580450

The microbiology of butyrate formation in the human colon
journal, December 2002


Small-sample estimation of negative binomial dispersion, with applications to SAGE data
journal, July 2007


Diet, gut microbiota and immune responses
journal, December 2010

  • Maslowski, Kendle M.; Mackay, Charles R.
  • Nature Immunology, Vol. 12, Issue 1
  • DOI: 10.1038/ni0111-5

Treatment of Diversion Colitis with Short-Chain-Fatty Acid Irrigation
journal, January 1989

  • Harig, James M.; Soergel, Konrad H.; Komorowski, Richard A.
  • New England Journal of Medicine, Vol. 320, Issue 1
  • DOI: 10.1056/NEJM198901053200105

Intraepithelial lymphocytes in celiac disease immunopathology
journal, June 2012

  • Abadie, Valérie; Discepolo, Valentina; Jabri, Bana
  • Seminars in Immunopathology, Vol. 34, Issue 4
  • DOI: 10.1007/s00281-012-0316-x

A gene-targeted approach to investigate the intestinal butyrate-producing bacterial community
journal, January 2013

  • Vital, Marius; Penton, Christopher R.; Wang, Qiong
  • Microbiome, Vol. 1, Issue 1
  • DOI: 10.1186/2049-2618-1-8

Regional Mucosa-Associated Microbiota Determine Physiological Expression of TLR2 and TLR4 in Murine Colon
journal, October 2010


QIIME allows analysis of high-throughput community sequencing data
journal, April 2010

  • Caporaso, J. Gregory; Kuczynski, Justin; Stombaugh, Jesse
  • Nature Methods, Vol. 7, Issue 5
  • DOI: 10.1038/nmeth.f.303

Targeting interleukin-15 in patients with rheumatoid arthritis: A proof-of-concept study
journal, January 2005

  • Baslund, Bo; Tvede, Niels; Danneskiold-Samsoe, Bente
  • Arthritis & Rheumatism, Vol. 52, Issue 9
  • DOI: 10.1002/art.21249

Fast UniFrac: facilitating high-throughput phylogenetic analyses of microbial communities including analysis of pyrosequencing and PhyloChip data
journal, August 2009

  • Hamady, Micah; Lozupone, Catherine; Knight, Rob
  • The ISME Journal, Vol. 4, Issue 1
  • DOI: 10.1038/ismej.2009.97

The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design
journal, August 2006

  • Waldmann, Thomas A.
  • Nature Reviews Immunology, Vol. 6, Issue 8
  • DOI: 10.1038/nri1901

Genetics and pathogenesis of inflammatory bowel disease
journal, June 2011

  • Khor, Bernard; Gardet, Agnès; Xavier, Ramnik J.
  • Nature, Vol. 474, Issue 7351
  • DOI: 10.1038/nature10209

Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease
journal, September 2015


Regulatory Sequences of the Mouse Villin Gene That Efficiently Drive Transgenic Expression in Immature and Differentiated Epithelial Cells of Small and Large Intestines
journal, March 1999

  • Pinto, Daniel; Robine, Sylvie; Jaisser, Frédéric
  • Journal of Biological Chemistry, Vol. 274, Issue 10
  • DOI: 10.1074/jbc.274.10.6476

The gut microbiota shapes intestinal immune responses during health and disease
journal, May 2009

  • Round, June L.; Mazmanian, Sarkis K.
  • Nature Reviews Immunology, Vol. 9, Issue 5
  • DOI: 10.1038/nri2515

Cysteinyl leukotrienes mediate lymphokine killer activity induced by NKG2D and IL-15 in cytotoxic T cells during celiac disease
journal, August 2015

  • Tang, Fangming; Sally, Benjamin; Lesko, Kathryn
  • The Journal of Experimental Medicine, Vol. 212, Issue 10
  • DOI: 10.1084/jem.20150303

The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice
journal, November 2009


Diet is a major factor governing the fecal butyrate-producing community structure across Mammalia, Aves and Reptilia
journal, October 2014


Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms
journal, March 2012

  • Caporaso, J. Gregory; Lauber, Christian L.; Walters, William A.
  • The ISME Journal, Vol. 6, Issue 8
  • DOI: 10.1038/ismej.2012.8

The Microbiome in Inflammatory Bowel Disease: Current Status and the Future Ahead
journal, May 2014


The Microbiome in Infectious Disease and Inflammation
journal, April 2012


Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
journal, December 2014


A model for the role of gut bacteria in the development of autoimmunity for type 1 diabetes
journal, May 2015