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Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut

Nature Medicine volume 17, pages 1585–1593 (2011)Cite this article

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Abstract

Using a systems biology approach, we discovered and dissected a three-way interaction between the immune system, the intestinal epithelium and the microbiota. We found that, in the absence of B cells, or of IgA, and in the presence of the microbiota, the intestinal epithelium launches its own protective mechanisms, upregulating interferon-inducible immune response pathways and simultaneously repressing Gata4-related metabolic functions. This shift in intestinal function leads to lipid malabsorption and decreased deposition of body fat. Network analysis revealed the presence of two interconnected epithelial-cell gene networks, one governing lipid metabolism and another regulating immunity, that were inversely expressed. Gene expression patterns in gut biopsies from individuals with common variable immunodeficiency or with HIV infection and intestinal malabsorption were very similar to those of the B cell–deficient mice, providing a possible explanation for a longstanding enigmatic association between immunodeficiency and defective lipid absorption in humans.

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Figure 1: Dysregulation of gene expression in the small intestine of BcKO mice.
Figure 2: Dysregulation of gene expression is present in the gut of antibody-deficient and IgA-deficient mice.
Figure 3: Microbiota are necessary for intestinal alterations in BcKO mice.
Figure 4: Dysregulation of Gata4-dependent functions in BcKO mice.
Figure 5: Increased immune and decreased metabolic state of epithelium in BcKO mice.
Figure 6: Balance between immune and metabolic processes in vitro and in vivo in mice and humans.

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Sequence Read Archive

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Acknowledgements

This research was supported in part by the Intramural Research Program of the NIAID, NIH. We thank T. Myers, Q. Su and A. Godinez of the NIAID microarray facility for excellent technical support; R. Schwartz for providing funding for germ-free re-derivation; W. Strober for help with human subjects; C. Jones for technical support of bacterial pyrosequencing; T.D. Randall (Trudeau Institute) for AID/μS mice; S. Epstein (US Food and Drug Administration), J. Misplon (US Food and Drug Administration) and D.P. Huston (Texas A&M Health Science Center) for IgAKO mice; D. Kaiserlian (Institut National de la Santé et de la Recherche Médicale) and R. Blumberg (Harvard University) for providing the MODE-K cell line; R. Varma for help in experiments; Laboratory of Cellular and Molecular Immunology members and M. Sterman Dolnikoff, I. Shmulevich and A. Dzutsev for discussions and suggestions; Y. Kotliarov for help with graphics; S. Varma for help finding human gene homologues; J. Coursen for excellent technical support; B. Epstein for assistance with software programming; and the personnel of NIH mouse facilities in buildings 4 and 6B. The Cincinnati Mouse Metabolic Phenotyping Center is supported by NIH grant U24 DK059630 and National Gnotobiotic Rodent Resource Center at the University of North Carolina is supported by grant P40RR018603.

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Author notes

  1. Natalia Shulzhenko & Andrey Morgun

    Present address: Present address: College of Pharmacy, Oregon State University, Corvallis, Oregon, USA.,

  2. Natalia Shulzhenko and Andrey Morgun: These authors contributed equally to this work.

Authors and Affiliations

  1. 'Ghost Lab', T Cell Tolerance and Memory Section, Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), US National Institutes of Health (NIH), Bethesda, Maryland, USA

    Natalia Shulzhenko, Andrey Morgun & Polly Matzinger

  2. Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA

    William Hsiao & Claire Fraser-Liggett

  3. Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Michele Battle

  4. Mucosal Immunology Section, Laboratory of Host Defenses, NIAID, NIH, Bethesda, Maryland, USA

    Michael Yao

  5. Mouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

    Oksana Gavrilova

  6. Comparative Medicine Branch, NIAID, NIH, Bethesda, Maryland, USA

    Marlene Orandle

  7. Immunology Institute, Mount Sinai Medical Center, New York, New York, USA

    Lloyd Mayer

  8. University of Bern, Bern, Switzerland

    Andrew J Macpherson & Kathy D McCoy

  9. Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada

    Kathy D McCoy

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Contributions

N.S. and A.M. conceived the original idea, designed the study, conducted most of the experiments, analyzed the data and wrote the manuscript. W.H. analyzed microbiome data and drafted the related part of the manuscript. M.B. provided Gata4KOvil mice and did some Gata4-related experiments. M.Y. and L.M. collected duodenal biopsies and performed clinical evaluation of human subjects. O.G. performed and analyzed experiments related to lipid metabolism. M.O. performed histological evaluation of mouse samples. A.J.M. and K.D.M. re-derived germ-free JhKO mice and collected organs. C.F.-L. supervised microbiome evaluation and drafted the related part of the manuscript. P.M. supervised the whole study and wrote the manuscript.

Corresponding authors

Correspondence to Natalia Shulzhenko, Andrey Morgun or Polly Matzinger.

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Shulzhenko, N., Morgun, A., Hsiao, W. et al. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat Med 17, 1585–1593 (2011). https://doi.org/10.1038/nm.2505

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