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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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.
The authors declare no competing financial interests.
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Frontiers in Immunology (2019)
Food & Function (2019)
Journal of Autoimmunity (2019)
Nature Reviews Nephrology (2019)