ESRRA (estrogen related receptor alpha) is a critical regulator of intestinal homeostasis through activation of autophagic flux via gut microbiota

References

• Giguere V, Yang N, Segui P, et al. Identification of a new class of steroid hormone receptors. Nature. 1988;331(6151):91–94.
   PubMed Web of Science ®Google Scholar
• To GV. ERR in the estrogen pathway. Trends Endocrinol Metab. 2002;13(5):220–225.
   PubMed Web of Science ®Google Scholar
• Horard B, Vanacker JM. Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand. J Mol Endocrinol. 2003;31(3):349–357.
   PubMed Web of Science ®Google Scholar
• Giguere V. Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr Rev. 2008;29(6):677–696.
   PubMed Web of Science ®Google Scholar
• Bardet PL, Laudet V, Vanacker JM. Studying non-mammalian models? Not a fool’s ERRand! Trends Endocrinol Metab. 2006;17(4):166–171.
   PubMed Web of Science ®Google Scholar
• Xia H, Dufour CR, Giguere V. ERRalpha as a Bridge Between Transcription and Function: role in Liver Metabolism and Disease. Front Endocrinol. (Lausanne) 2019;10:206.
   PubMed Web of Science ®Google Scholar
• Huss JM, Garbacz WG, Xie W. Constitutive activities of estrogen-related receptors: transcriptional regulation of metabolism by the ERR pathways in health and disease. Biochim Biophys Acta. 2015;1852(9):1912–1927.
   PubMed Web of Science ®Google Scholar
• Kim SY, Yang CS, Lee HM, et al. ESRRA (estrogen-related receptor alpha) is a key coordinator of transcriptional and post-translational activation of autophagy to promote innate host defense. Autophagy. 2018;14(1):152–168.
   PubMed Web of Science ®Google Scholar
• Kim DS, Kwon JE, Lee SH, et al. Attenuation of Rheumatoid Inflammation by Sodium Butyrate Through Reciprocal Targeting of HDAC2 in Osteoclasts and HDAC8 in T Cells. Front Immunol. 2018;9:1525.
   PubMed Web of Science ®Google Scholar
• He X, Ma S, Tian Y, et al. ERRalpha negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction. PLoS Pathog. 2017;13(6):e1006347.
   PubMed Web of Science ®Google Scholar
• Sonoda J, Laganiere J, Mehl IR, et al. Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense. Genes Dev. 2007;21(15):1909–1920.
   PubMed Web of Science ®Google Scholar
• Ke PSB, Xu ZQ1, Chen XW1, et al. Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease. Front Immunol. 2017;7:695.
   PubMed Web of Science ®Google Scholar
• G Tz M, Sipos F. Interplay of autophagy and innate immunity in Crohn’s disease: a key immunobiologic feature. World J Gastroenterol. 2013;19(28):4447–4454.
   PubMed Web of Science ®Google Scholar
• T Nl F, Adolph T, Blumberg RS, et al. Crohn’s disease: NOD2, autophagy and ER stress converge. Gut. 2011;60(11):1580–1588.
   PubMed Web of Science ®Google Scholar
• Williams MA, O’Callaghan A, Corr SCIL. 33 and IL-18 in Inflammatory Bowel Disease Etiology and Microbial Interactions. Front Immunol. 2019;10:1091.
   PubMed Web of Science ®Google Scholar
• Richard ML, Sokol H. The gut mycobiota: insights into analysis, environmental interactions and role in gastrointestinal diseases. Nat Rev Gastroenterol Hepatol. 2019;16(6):331–345.
   PubMed Web of Science ®Google Scholar
• Suh HW, Kim JK, Kim TS, et al. New Insights into Vitamin D and Autophagy in Inflammatory Bowel Diseases. Curr Med Chem. 2017;24(9):898–910.
   PubMed Web of Science ®Google Scholar
• Iida T, Onodera K, Nakase H. Role of autophagy in the pathogenesis of inflammatory bowel disease. World J Gastroenterol. 2017;23(11):1944–1953.
   PubMed Web of Science ®Google Scholar
• Novak EA, Mollen KP. Mitochondrial dysfunction in inflammatory bowel disease. Front Cell Dev Biol. 2015;3:62.
   PubMed Web of Science ®Google Scholar
• Yu T, Guo F, Yu Y, et al. Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy. Cell. 2017;170(3):548–563 e16.
   PubMed Web of Science ®Google Scholar
• Chu H, Khosravi A, Kusumawardhani IP, et al. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science. 2016;352(6289):1116–1120.
   PubMed Web of Science ®Google Scholar
• Modica S, Gofflot F, Murzilli S, et al. The intestinal nuclear receptor signature with epithelial localization patterns and expression modulation in tumors. Gastroenterology. 2010;138(2):636–648. 648 e1–12
   PubMed Web of Science ®Google Scholar
• Boismenu R, Chen Y. Insights from mouse models of colitis. J Leukoc Biol. 2000;67(3):267–278.
   PubMed Web of Science ®Google Scholar
• Deguchi Y, Andoh A, Yagi Y, et al. The S1P receptor modulator FTY720 prevents the development of experimental colitis in mice. Oncol Rep. 2006;16(4):699–703.
   PubMed Web of Science ®Google Scholar
• Sladek R, Beatty B, Squire J, et al. Chromosomal mapping of the human and murine orphan receptors ERRalpha (ESRRA) and ERRbeta (ESRRB) and identification of a novel human ERRalpha-related pseudogene. Genomics. 1997;45(2):320–326.
   PubMed Web of Science ®Google Scholar
• Li F, Zhu YT. HGF-activated colonic fibroblasts mediates carcinogenesis of colonic epithelial cancer cells via PKC-cMET-ERK1/2-COX-2 signaling. Cell Signal. 2015;27(4):860–866.
   PubMed Web of Science ®Google Scholar
• Kim S, Eun HS, Jo EK. Roles of Autophagy-Related Genes in the Pathogenesis of Inflammatory Bowel Disease. Cells. 2019;8(1):1.
   Web of Science ®Google Scholar
• Palmieri M, Impey S, Kang H, et al. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet. 2011;20(19):3852–3866.
   PubMed Web of Science ®Google Scholar
• Pavel M, Renna M, Park SJ, et al. Contact inhibition controls cell survival and proliferation via YAP/TAZ-autophagy axis. Nat Commun. 2018;9(1):2961.
   PubMed Web of Science ®Google Scholar
• Scarpulla RC, Vega RB, Kelly DP. Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol Metab. 2012;23(9):459–466.
   PubMed Web of Science ®Google Scholar
• Salatino S, Kupr B, Baresic M, et al. The Genomic Context and Corecruitment of SP1 Affect ERRalpha Coactivation by PGC-1alpha in Muscle Cells. Mol Endocrinol. 2016;30(7):809–825.
   PubMedGoogle Scholar
• Willy PJ, Murray IR, Qian J, et al. Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand. Proc Natl Acad Sci U S A. 2004;101(24):8912–8917.
   PubMed Web of Science ®Google Scholar
• Sun X, Sun L, Zhao Y, et al. MAVS maintains mitochondrial homeostasis via autophagy. Cell Discov. 2016;2:16024.
   PubMed Web of Science ®Google Scholar
• Eichele DD, Kharbanda KK. Dextran sodium sulfate colitis murine model: an indispensable tool for advancing our understanding of inflammatory bowel diseases pathogenesis. World J Gastroenterol. 2017;23(33):6016.
   PubMed Web of Science ®Google Scholar
• De Fazio L, Cavazza E, Spisni E, et al. Longitudinal analysis of inflammation and microbiota dynamics in a model of mild chronic dextran sulfate sodium-induced colitis in mice. World J Gastroenterol. 2014;20(8):2051.
   PubMed Web of Science ®Google Scholar
• Schwab C, Berry D, Rauch I, et al. Longitudinal study of murine microbiota activity and interactions with the host during acute inflammation and recovery. Isme J. 2014;8(5):1101–1114.
   PubMed Web of Science ®Google Scholar
• Parada Venegas D, De la Fuente MK, Landskron G, et al. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases. Front Immunol. 2019;10:277.
   PubMed Web of Science ®Google Scholar
• Basso PJ, Camara NOS, Microbial-Based S-CH. Therapies in the Treatment of Inflammatory Bowel Disease - An Overview of Human Studies. Front Pharmacol. 2018;9:1571.
   PubMed Web of Science ®Google Scholar
• Fritz T, Niederreiter L, Adolph T, et al. Crohn’s disease: NOD2, autophagy and ER stress converge. Gut. 2011;60(11):1580–1588.
   PubMed Web of Science ®Google Scholar
• Yuk JM, Kim TS, Kim SY, et al. Orphan Nuclear Receptor ERRalpha Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation. Immunity. 2015;43(1):80–91.
   PubMed Web of Science ®Google Scholar
• Casaburi I, Chimento A, De Luca A, et al. Cholesterol as an Endogenous ERRalpha Agonist: A New Perspective to Cancer Treatment. Front Endocrinol. (Lausanne). 2018;9:525.
   PubMed Web of Science ®Google Scholar
• Mehto S, Jena KK, Nath P, et al. The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy. Mol Cell. 2019;73(3):429–445 e7.
   PubMed Web of Science ®Google Scholar
• Xia Y, Liu N, Xie X, et al. The macrophage-specific V-ATPase subunit ATP6V0D2 restricts inflammasome activation and bacterial infection by facilitating autophagosome-lysosome fusion. Autophagy. 2019;15(6):960–975.
   PubMed Web of Science ®Google Scholar
• Lee HY, Kim J, Quan W, et al. Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis. Autophagy. 2016;12(8):1390–1403.
   PubMed Web of Science ®Google Scholar
• Murano T, Najibi M, Paulus GLC, et al. Transcription factor TFEB cell-autonomously modulates susceptibility to intestinal epithelial cell injury in vivo. Sci Rep. 2017;7(1):13938.
   PubMedGoogle Scholar
• Han J, Theiss AL. Stat3: friend or foe in colitis and colitis-associated cancer? Inflamm Bowel Dis. 2014;20(12):2405–2411.
   PubMed Web of Science ®Google Scholar
• Xu Y, Shen J, Ran Z. Emerging views of mitophagy in immunity and autoimmune diseases. Autophagy. 2020;16(1):3–17.
   PubMed Web of Science ®Google Scholar
• Haberman Y, Karns R, Dexheimer PJ, et al. Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response. Nat Commun. 2019;10(1):38.
   PubMedGoogle Scholar
• Boyapati RK, Dorward DA, Tamborska A, et al. Mitochondrial DNA Is a Pro-Inflammatory Damage-Associated Molecular Pattern Released During Active IBD. Inflamm Bowel Dis. 2018;24(10):2113–2122.
   PubMed Web of Science ®Google Scholar
• Woo CY, Jang JE, Lee SE, et al. Mitochondrial Dysfunction in Adipocytes as a Primary Cause of Adipose Tissue Inflammation. Diabetes Metab J. 2019;43(3):247–256.
   PubMed Web of Science ®Google Scholar
• Li Y, Tinoco R, Elmén L, et al. Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5−/− mice. Nat Commun. 2019;10(1):1492.
   PubMedGoogle Scholar
• EJC G, Iljazovic A, Gronow A, et al. Shaping of Intestinal Microbiota in Nlrp6- and Rag2-Deficient Mice Depends on Community Structure. Cell Rep. 2017;21(13):3914–3926.
   PubMed Web of Science ®Google Scholar
• Nunberg M, Werbner N, Neuman H, et al. Interleukin 1α-Deficient Mice Have an Altered Gut Microbiota Leading to Protection from Dextran Sodium Sulfate-Induced Colitis. mSystems. 2018;3(3):e00213–17.
   PubMed Web of Science ®Google Scholar
• Contijoch EJ, Britton GJ, Yang C, et al. Gut microbiota density influences host physiology and is shaped by host and microbial factors. Elife. 2019;8:e40553.
   PubMed Web of Science ®Google Scholar
• Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146(6):1489–1499.
   PubMed Web of Science ®Google Scholar
• Arthur JC, Perez-Chanona E, Muhlbauer M, et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science. 2012;338(6103):120–123.
   PubMed Web of Science ®Google Scholar
• Yang Y, Weng W, Peng J, et al. Fusobacterium nucleatum Increases Proliferation of Colorectal Cancer Cells and Tumor Development in Mice by Activating Toll-Like Receptor 4 Signaling to Nuclear Factor-kappaB, and Up-regulating Expression of MicroRNA-21. Gastroenterology. 2017;152(4):851–866 e24.
   PubMed Web of Science ®Google Scholar
• Wu M, Wu Y, Li J, et al. The Dynamic Changes of Gut Microbiota in Muc2 Deficient Mice. Int J Mol Sci. 2018;19:9.
   Web of Science ®Google Scholar
• Tang C, Kakuta S, Shimizu K, et al. Suppression of IL-17F, but not of IL-17A, provides protection against colitis by inducing Treg cells through modification of the intestinal microbiota. Nat Immunol. 2018;19(7):755–765.
   PubMed Web of Science ®Google Scholar
• Roy U, EJC G, Iljazovic A, et al. Distinct Microbial Communities Trigger Colitis Development upon Intestinal Barrier Damage via Innate or Adaptive Immune Cells. Cell Rep. 2017;21(4):994–1008.
   PubMed Web of Science ®Google Scholar
• Yoshida N, Emoto T, Yamashita T, et al. Bacteroides vulgatus and Bacteroides dorei Reduce Gut Microbial Lipopolysaccharide Production and Inhibit Atherosclerosis. Circulation. 2018;138(22):2486–2498.
   PubMed Web of Science ®Google Scholar
• Santoru ML, Piras C, Murgia A, et al. Cross sectional evaluation of the gut-microbiome metabolome axis in an Italian cohort of IBD patients. Sci Rep. 2017;7(1):9523.
   PubMedGoogle Scholar
• Khan I, Ullah N, Zha L, et al. Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): cause or Consequence? IBD Treatment Targeting the Gut Microbiome. Pathogens. 2019;8(3):126.
   Web of Science ®Google Scholar
• Delday M, Mulder I, Logan ET, et al. Bacteroides thetaiotaomicron Ameliorates Colon Inflammation in Preclinical Models of Crohn’s Disease. Inflamm Bowel Dis. 2018;25(1):85–96.
   Web of Science ®Google Scholar
• Neff CP, Rhodes Matthew E, Arnolds Kathleen L, et al. Diverse Intestinal Bacteria Contain Putative Zwitterionic Capsular Polysaccharides with Anti-inflammatory Properties. Cell Host Microbe. 2016;20(4):535–547.
   PubMed Web of Science ®Google Scholar
• Waidmann M, Bechtold O, Frick J-S, et al. Bacteroides vulgatus protects against escherichia coli-induced colitis in gnotobiotic interleukin-2-deficient mice. Gastroenterology. 2003;125(1):162–177.
   PubMed Web of Science ®Google Scholar
• Aidy SE, Derrien M, Aardema R, et al. Transient inflammatory-like state and microbial dysbiosis are pivotal in establishment of mucosal homeostasis during colonisation of germ-free mice. Benef Microbes. 2014;5(1):67–77.
   PubMed Web of Science ®Google Scholar
• Bordon Y. A microbial trigger for colitis. Nat Rev Immunol. 2019;19(6):350–351.
   PubMed Web of Science ®Google Scholar
• Berry D, Schwab C, Milinovich G, et al. Phylotype-level 16S rRNA analysis reveals new bacterial indicators of health state in acute murine colitis. Isme J. 2012;6(11):2091–2106.
   PubMed Web of Science ®Google Scholar
• Caruso R, Mathes T, Martens EC, et al. A specific gene-microbe interaction drives the development of Crohn’s disease–like colitis in mice. Sci Immunol. 2019;4(34):eaaw 4341.
   Web of Science ®Google Scholar
• Zhang Y, Tian L, Sleiman P, et al. Bayesian analysis of genome-wide inflammatory bowel disease data sets reveals new risk loci. Eur J Hum Genet. 2018;26(2):265–274.
   PubMed Web of Science ®Google Scholar
• Anderson CA, Boucher G, Lees CW, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43(3):246–252.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Li X, Luo Z, et al. ECM1 is an essential factor for the determination of M1 macrophage polarization in IBD in response to LPS stimulation. Proc Natl Acad Sci U S A. 2020;117(6):3083–3092.
   PubMed Web of Science ®Google Scholar
• Liu M, Sun T, Li N, et al. BRG1 attenuates colonic inflammation and tumorigenesis through autophagy-dependent oxidative stress sequestration. Nat Commun. 2019;10(1):4614.
   PubMedGoogle Scholar
• West NR, Hegazy AN, Owens BMJ, et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med. 2017;23(5):579–589.
   PubMed Web of Science ®Google Scholar
• Planell N, Lozano JJ, Mora-Buch R, et al. Transcriptional analysis of the intestinal mucosa of patients with ulcerative colitis in remission reveals lasting epithelial cell alterations. Gut. 2013;62(7):967–976.
   PubMed Web of Science ®Google Scholar
• Angelidou I, Chrysanthopoulou A, Mitsios A, et al. REDD1/Autophagy Pathway Is Associated with Neutrophil-Driven IL-1beta Inflammatory Response in Active Ulcerative Colitis. J Immunol. 2018;200(12):3950–3961.
   PubMed Web of Science ®Google Scholar
• Toubai T, Fujiwara H, Rossi C, et al. Host NLRP6 exacerbates graft-versus-host disease independent of gut microbial composition. Nat Microbiol. 2019;4(5):800–812.
   PubMed Web of Science ®Google Scholar
• Danese S, Sans M, Spencer DM, et al. Angiogenesis blockade as a new therapeutic approach to experimental colitis. Gut. 2007;56(6):855–862.
   PubMed Web of Science ®Google Scholar
• Berg DJ, Davidson N, Kuhn R, et al. Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest. 1996;98(4):1010–1020.
   PubMed Web of Science ®Google Scholar
• Kim JK, Lee HM, Park KS, et al. MIR144* inhibits antimicrobial responses against Mycobacterium tuberculosis in human monocytes and macrophages by targeting the autophagy protein DRAM2. Autophagy. 2017;13(2):423–441.
   PubMed Web of Science ®Google Scholar
• Gupta J, Nebreda AR. Analysis of intestinal permeability in mice. Bio-protocol. 2014;4(22):e1289.
   Google Scholar
• Kim JK, Kim YS, Lee HM, et al. GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections. Nat Commun. 2018;9(1):4184.
   PubMedGoogle Scholar
• Cole JR, Wang Q, Fish JA, et al. Ribosomal Database Project: data and tools for high throughput rRNA analysis. Nucleic Acids Res. 2013;42(D1):D633–D642.
   PubMed Web of Science ®Google Scholar
• Wang Q, Garrity GM, Tiedje JM, et al. Naïve Bayesian Classifier for Rapid Assignment of rRNA Sequences into the New Bacterial Taxonomy. Appl Environ Microbiol. 2007;73(16):5261–5267.
   PubMed Web of Science ®Google Scholar
• Ma X, Sun Q, Sun X, et al. Activation of GABAA Receptors in Colon Epithelium Exacerbates Acute Colitis. Front Immunol. 2018;9:987.
   PubMed Web of Science ®Google Scholar
• Motulsky HJ, Brown RE. Detecting outliers when fitting data with nonlinear regression – a new method based on robust nonlinear regression and the false discovery rate. BMC Bioinformatics. 2006;7(1):123.
   PubMed Web of Science ®Google Scholar