TY - JOUR
T1 - A thermogenic fat-epithelium cell axis regulates intestinal disease tolerance
AU - Man, Kevin
AU - Bowman, Christopher
AU - Braverman, Kristina N.
AU - Escalante, Veronica
AU - Tian, Yuan
AU - Bisanz, Jordan E.
AU - Ganeshan, Kirthana
AU - Wang, Biao
AU - Patterson, Andrew
AU - Bayrer, James R.
AU - Turnbaugh, Peter J.
AU - Chawla, Ajay
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank members of the Chawla laboratory and A. Loh for comments on the manuscript. The authors’ work was supported by an Innovator Award from the Kenneth Rainin Foundation and grants from NIH (DK094641, DK101064) to A.C.; J.R.B. was supported by grants from NIH (R03 DK121061-01 and P30 DK098722) and K.M. was supported by National Health and Medical Research Council (NHMRC) (GNT1142229). The authors acknowledge support from the Pathology & Imaging Core of the University of California, San Francisco (UCSF) Liver Center (P30 DK026743) and the UCSF Gnotobiotics Core.
Funding Information:
19. D. Berry et al., Intestinal microbiota signatures associated with inflammation history in mice experiencing recurring colitis. Front. Microbiol. 6, 1408 (2015). Materials and Methods Experimental details on animals, isolation of colonocytes and intestinal crypts, flow-cytometric analysis of lamina propria lymphocytes, colonization and colitis studies in GF mice, immunoblotting, quantification of colonocyte hypoxia, tissue histology and immunofluorescence, energy expenditure measurements, next-generation sequencing and RNA-seq analysis, 16s rRNA gene sequencing and analysis, metabolomics, and statistical analyses for this study are described in detail in SI Appendix, Materials and Methods. Data Availability. Data generated or analyzed during this study are included in this published article and its SI Appendix files. The RNA-seq data have been deposited in the Gene Expression Omnibus database under ID code GSE158488. The 16S rRNA-seq data have been deposited at the Sequence Read Archive (SRA) repository under BioProject PRJNA667805. ACKNOWLEDGMENTS. We thank members of the Chawla laboratory and A. Loh for comments on the manuscript. The authors’ work was supported by an Innovator Award from the Kenneth Rainin Foundation and grants from NIH (DK094641, DK101064) to A.C.; J.R.B. was supported by grants from NIH (R03 DK121061-01 and P30 DK098722) and K.M. was supported by National Health and Medical Research Council (NHMRC) (GNT1142229). The authors acknowledge support from the Pathology & Imaging Core of the University of California, San Francisco (UCSF) Liver Center (P30 DK026743) and the UCSF Gnotobiotics Core. 20. M. C. Kullberg et al., Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12-and gamma interferon-dependent mechanism. Infect. Immun. 66, 5157–5166 (1998). 21. H. Gehart, H. Clevers, Tales from the crypt: New insights into intestinal stem cells. Nat. Rev. Gastroenterol. Hepatol. 16, 19–34 (2019). 22. T. Valenta et al., Wnt ligands secreted by subepithelial mesenchymal cells are es-sential for the survival of intestinal stem cells and gut homeostasis. Cell Rep. 15, 911–918 (2016). 23. Y. M. Nusse et al., Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature 559, 109–113 (2018). 24. M. X. Byndloss et al., Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enter-obacteriaceae expansion. Science 357, 570–575 (2017). 25. T. Tanaka et al., A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci. 94, 965–973 (2003). 26. S. Moriyama et al., β2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359, 1056–1061 (2018). 27. M. Harms, P. Seale, Brown and beige fat: Development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013). 28. Y. Q. Li et al., Gsα deficiency in adipose tissue improves glucose metabolism and in-sulin sensitivity without an effect on body weight. Proc. Natl. Acad. Sci. U.S.A. 113, 446–451 (2016). 29. U. M. Gundra et al., Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct. Blood 123, e110–e122 (2014). 30. L. Bosurgi et al., Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science 356, 1072–1076 (2017). 31. H. Qing et al., Origin and function of stress-induced IL-6 in murine models. Cell 182, 372–387.e14 (2020). 32. Y. Ge et al., Adipokine apelin ameliorates chronic colitis in Il-10-/- mice by promoting intestinal lymphatic functions. Biochem. Pharmacol. 148, 202–212 (2018). 33. F. Wei et al., PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner. Sci. Rep. 4, 7023 (2014). 34. Y. Zhang, M. Brenner, W. L. Yang, P. Wang, Recombinant human MFG-E8 ameliorates colon damage in DSS-and TNBS-induced colitis in mice. Lab. Invest. 95, 480–490 (2015). 35. L. Santucci et al., Galectin-1 suppresses experimental colitis in mice. Gastroenterology 124, 1381–1394 (2003). 36. J. Nedergaard, B. Cannon, The browning of white adipose tissue: Some burning is-sues. Cell Metab. 20, 396–407 (2014). IMMUNOLOGY AND INFLAMMATION
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/12/15
Y1 - 2020/12/15
N2 - Disease tolerance, the capacity of tissues to withstand damage caused by a stimulus without a decline in host fitness, varies across tissues, environmental conditions, and physiologic states. While disease tolerance is a known strategy of host defense, its role in noninfectious diseases has been understudied. Here, we provide evidence that a thermogenic fat-epithelial cell axis regulates intestinal disease tolerance during experimental colitis. We find that intestinal disease tolerance is a metabolically expensive trait, whose expression is restricted to thermoneutral mice and is not transferable by the microbiota. Instead, disease tolerance is dependent on the adrenergic state of thermogenic adipocytes, which indirectly regulate tolerogenic responses in intestinal epithelial cells. Our work has identified an unexpected mechanism that controls intestinal disease tolerance with implications for colitogenic diseases.
AB - Disease tolerance, the capacity of tissues to withstand damage caused by a stimulus without a decline in host fitness, varies across tissues, environmental conditions, and physiologic states. While disease tolerance is a known strategy of host defense, its role in noninfectious diseases has been understudied. Here, we provide evidence that a thermogenic fat-epithelial cell axis regulates intestinal disease tolerance during experimental colitis. We find that intestinal disease tolerance is a metabolically expensive trait, whose expression is restricted to thermoneutral mice and is not transferable by the microbiota. Instead, disease tolerance is dependent on the adrenergic state of thermogenic adipocytes, which indirectly regulate tolerogenic responses in intestinal epithelial cells. Our work has identified an unexpected mechanism that controls intestinal disease tolerance with implications for colitogenic diseases.
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U2 - 10.1073/pnas.2012003117
DO - 10.1073/pnas.2012003117
M3 - Article
C2 - 33257580
AN - SCOPUS:85098467415
SN - 0027-8424
VL - 117
SP - 32029
EP - 32037
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 50
ER -