Taurodeoxycholic acid and valine reverse obesity-associated augmented alloimmune responses and prolong allograft survival.
Authors:
Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Tr
Publication Type: Journal Article
Date: 2022
DOI: NIHMS1938160
ID: 34551205
Abstract
Obesity initiates a chronic inflammatory network linked to perioperative complications and increased acute rejection rates in organ transplantation. Bariatric surgery is the most effective treatment of obesity recommended for morbidly obese transplant recipients. Here, we delineated the effects of obesity and bariatric surgery on alloimmunity and transplant outcomes in diet-induced obese (DIO) mice. Allograft survival was significantly shorter in DIO-mice. When performing sleeve gastrectomies (SGx) prior to transplantation, we found attenuated T cell-derived alloimmune responses resulting in prolonged allograft survival. Administering taurodeoxycholic acid (TDCA) and valine, metabolites depleted in DIO-mice and restored through SGx, prolonged graft survival in DIO-mice comparable with SGx an dampened Th1 and Th17 alloimmune responses while Treg frequencies and CD4 T cell-derived IL-10 production were augmented. Moreover, in recipient animals treated with TDCA/valine, levels of donor-specific antibodies had been reduced. Mechanistically, TDCA/valine restrained inflammatory M1-macrophage polarization through TGR5 that compromised cAMP signaling and inhibited macrophage-derived T cell activation. Consistently, administering a TGR5 agonist to DIO-mice prolonged allograft survival. Overall, we provide novel insights into obesity-induced inflammation and its impact on alloimmunity. Furthermore, we introduce TDCA/valine as a noninvasive alternative treatment for obese transplant patients.
Chemical List
- Taurodeoxycholic Acid|||Valine
Reference List
- Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001;414(6865):799–806.|||Khandekar MJ, Cohen P, Spiegelman BM. Molecular mechanisms of cancer development in obesity. Nat Rev Cancer 2011;11(12):886–895.|||Kwan JM, Hajjiri Z, Metwally A, Finn PW, Perkins DL. Effect of the Obesity Epidemic on Kidney Transplantation: Obesity Is Independent of Diabetes as a Risk Factor for Adverse Renal Transplant Outcomes. PLoS One 2016;11(11):e0165712.|||Weissenbacher A, Jara M, Ulmer H, Biebl M, Bösmüller C, Schneeberger S et al. Recipient and donor body mass index as important risk factors for delayed kidney graft function. Transplantation 2012;93(5):524–529.|||Cannon RM, Jones CM, Hughes MG, Eng M, Marvin MR. The impact of recipient obesity on outcomes after renal transplantation. Ann Surg 2013;257(5):978–984.|||Yamamoto S, Hanley E, Hahn AB, Isenberg A, Singh TP, Cohen D et al. The impact of obesity in renal transplantation: an analysis of paired cadaver kidneys. Clin Transplant 2002;16(4):252–256.|||Gore JL, Pham PT, Danovitch GM, Wilkinson AH, Rosenthal JT, Lipshutz GS et al. Obesity and outcome following renal transplantation. Am J Transplant 2006;6(2):357–363.|||Curran SP, Famure O, Li Y, Kim SJ. Increased recipient body mass index is associated with acute rejection and other adverse outcomes after kidney transplantation. Transplantation 2014;97(1):64–70.|||Lentine KL, Rocca-Rey LA, Bacchi G, Wasi N, Schmitz L, Salvalaggio PR et al. Obesity and cardiac risk after kidney transplantation: experience at one center and comprehensive literature review. Transplantation 2008;86(2):303–312.|||Kilic A, Conte JV, Shah AS, Yuh DD. Orthotopic heart transplantation in patients with metabolic risk factors. Ann Thorac Surg 2012;93(3):718–724.|||Hoogeveen EK, Aalten J, Rothman KJ, Roodnat JI, Mallat MJ, Borm G et al. Effect of obesity on the outcome of kidney transplantation: a 20-year follow-up. Transplantation 2011;91(8):869–874.|||Ducloux D, Kazory A, Simula-Faivre D, Chalopin JM. One-year post-transplant weight gain is a risk factor for graft loss. Am J Transplant 2005;5(12):2922–2928.|||Nicoletto BB, Fonseca NK, Manfro RC, Gonçalves LF, Leitão CB, Souza GC. Effects of obesity on kidney transplantation outcomes: a systematic review and meta-analysis. Transplantation 2014;98(2):167–176.|||Afaneh C, Rich B, Aull MJ, Hartono C, Kapur S, Leeser DB. Pancreas transplantation considering the spectrum of body mass indices. Clin Transplant 2011;25(5):E520–529.|||Molina Raya A, García Navarro A, San Miguel Méndez C, Domínguez Bastante M, Villegas Herrera MT, Granero K et al. Influence of Obesity on Liver Transplantation Outcomes. Transplant Proc 2016;48(7):2503–2505.|||Flabouris K, Chadban S, Ladhani M, Cervelli M, Clayton P. Body mass index, weight-adjusted immunosuppression and the risk of acute rejection and infection after kidney transplantation: a cohort study. Nephrol Dial Transplant 2019;34(12):2132–2143.|||Heinbokel T, Floerchinger B, Schmiderer A, Edtinger K, Liu G, Elkhal A et al. Obesity and its impact on transplantation and alloimmunity. Transplantation 2013;96(1):10–16.|||Molinero LL, Yin D, Lei YM, Chen L, Wang Y, Chong AS et al. High-Fat Diet-Induced Obesity Enhances Allograft Rejection. Transplantation 2016;100(5):1015–1021.|||Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr., Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112(12):1796–1808.|||Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112(12):1821–1830.|||Xu H. Obesity and metabolic inflammation. Drug Discov Today Dis Mech 2013;10(1–2).|||Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010;2010.|||Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006;444(7121):860–867.|||Nandipati KC, Subramanian S, Agrawal DK. Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance. Mol Cell Biochem 2017;426(1–2):27–45.|||Gloire G, Legrand-Poels S, Piette J. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 2006;72(11):1493–1505.|||Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 2006;281(36):26602–26614.|||Bai Y, Sun Q. Macrophage recruitment in obese adipose tissue. Obes Rev 2015;16(2):127–136.|||Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 2009;15(8):914–920.|||Wang Q, Wu H. T Cells in Adipose Tissue: Critical Players in Immunometabolism. Front Immunol 2018;9:2509.|||Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009;15(8):930–939.|||Rocha VZ, Folco EJ, Sukhova G, Shimizu K, Gotsman I, Vernon AH et al. Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ Res 2008;103(5):467–476.|||Deng T, Lyon CJ, Minze LJ, Lin J, Zou J, Liu JZ et al. Class II major histocompatibility complex plays an essential role in obesity-induced adipose inflammation. Cell Metab 2013;17(3):411–422.|||Morris DL, Cho KW, Delproposto JL, Oatmen KE, Geletka LM, Martinez-Santibanez G et al. Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice. Diabetes 2013;62(8):2762–2772.|||Li J, Li C, Zhuang Q, Peng B, Zhu Y, Ye Q et al. The Evolving Roles of Macrophages in Organ Transplantation. J Immunol Res 2019;2019:5763430.|||Wu D, Dawson NA, Levings MK. Obesity-Associated Adipose Tissue Inflammation and Transplantation. Am J Transplant 2016;16(3):743–750.|||Mori DN, Kreisel D, Fullerton JN, Gilroy DW, Goldstein DR. Inflammatory triggers of acute rejection of organ allografts. Immunol Rev 2014;258(1):132–144.|||Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 2009;15(8):921–929.|||McLaughlin T, Ackerman SE, Shen L, Engleman E. Role of innate and adaptive immunity in obesity-associated metabolic disease. J Clin Invest 2017;127(1):5–13.|||Chatzigeorgiou A, Karalis KP, Bornstein SR, Chavakis T. Lymphocytes in obesity-related adipose tissue inflammation. Diabetologia 2012;55(10):2583–2592.|||Han JM, Patterson SJ, Speck M, Ehses JA, Levings MK. Insulin inhibits IL-10-mediated regulatory T cell function: implications for obesity. J Immunol 2014;192(2):623–629.|||Chang SH, Stoll CR, Song J, Varela JE, Eagon CJ, Colditz GA. The effectiveness and risks of bariatric surgery: an updated systematic review and meta-analysis, 2003-2012. JAMA Surg 2014;149(3):275–287.|||Gloy VL, Briel M, Bhatt DL, Kashyap SR, Schauer PR, Mingrone G et al. Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials. BMJ 2013;347:f5934.|||Sjostrom L Review of the key results from the Swedish Obese Subjects (SOS) trial - a prospective controlled intervention study of bariatric surgery. J Intern Med 2013;273(3):219–234.|||Viscido G, Gorodner V, Signorini FJ, Campazzo M, Navarro L, Obeide LR et al. Sleeve Gastrectomy after Renal Transplantation. Obes Surg 2018;28(6):1587–1594.|||Tullius SG, Quante M, Iske J, Heinbokel T, Desai BN, Biefer HRC et al. Restored TDCA and Valine Levels Imitate the Effects of Bariatric Surgery. bioRxiv 2021:2021.2001.2011.425291.|||Winzell MS, Ahren B. The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes 2004;53 Suppl 3:S215–219.|||Wang CY, Liao JK. A mouse model of diet-induced obesity and insulin resistance. Methods Mol Biol 2012;821:421–433.|||Chang SH, Coates PT, McDonald SP. Effects of body mass index at transplant on outcomes of kidney transplantation. Transplantation 2007;84(8):981–987.|||Bagley J, Yuan J, Chandrakar A, Iacomini J. Hyperlipidemia Alters Regulatory T Cell Function and Promotes Resistance to Tolerance Induction Through Costimulatory Molecule Blockade. Am J Transplant 2015;15(9):2324–2335.|||Yang H, Youm YH, Vandanmagsar B, Ravussin A, Gimble JM, Greenway F et al. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. J Immunol 2010;185(3):1836–1845.|||Hara M, Kingsley CI, Niimi M, Read S, Turvey SE, Bushell AR et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol 2001;166(6):3789–3796.|||Fischbein MP, Yun J, Laks H, Irie Y, Oslund-Pinderski L, Fishbein MC et al. Regulated interleukin-10 expression prevents chronic rejection of transplanted hearts. J Thorac Cardiovasc Surg 2003;126(1):216–223.|||McGillicuddy FC, Chiquoine EH, Hinkle CC, Kim RJ, Shah R, Roche HM et al. Interferon gamma attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. J Biol Chem 2009;284(46):31936–31944.|||Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A 1994;91(11):4854–4858.|||Wammers M, Schupp AK, Bode JG, Ehlting C, Wolf S, Deenen R et al. Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids. Sci Rep 2018;8(1):255.|||Choy JC. Granzymes and perforin in solid organ transplant rejection. Cell Death & Differentiation 2010;17(4):567–576.|||Petty M Antibody-Mediated Rejection in Solid Organ Transplant. AACN Adv Crit Care 2016;27(3):316–323.|||Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006;116(6):1494–1505.|||Uehara H, Minami K, Quante M, Nian Y, Heinbokel T, Azuma H et al. Recall features and allorecognition in innate immunity. Transpl Int 2018;31(1):6–13.|||Hambleton J, Weinstein SL, Lem L, DeFranco AL. Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc Natl Acad Sci U S A 1996;93(7):2774–2778.|||Antonios JK, Yao Z, Li C, Rao AJ, Goodman SB. Macrophage polarization in response to wear particles in vitro. Cell Mol Immunol 2013;10(6):471–482.|||Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007;117(1):175–184.|||Penney NC, Kinross J, Newton RC, Purkayastha S. The role of bile acids in reducing the metabolic complications of obesity after bariatric surgery: a systematic review. Int J Obes (Lond) 2015.|||Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003;278(11):9435–9440.|||Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Haussinger D. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 2009;50(3):861–870.|||Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 2011;14(6):747–757.|||Darzynkiewicz Z, Pozarowski P, Lee BW, Johnson GL. Fluorochrome-labeled inhibitors of caspases: convenient in vitro and in vivo markers of apoptotic cells for cytometric analysis. Methods Mol Biol 2011;682:103–114.|||Quante M, Iske J, Heinbokel T, Desai BN, Cetina Biefer HR, Nian Y et al. Restored TDCA and valine levels imitate the effects of bariatric surgery. Elife 2021;10.|||Han JM, Levings MK. Immune regulation in obesity-associated adipose inflammation. J Immunol 2013;191(2):527–532.|||Strissel KJ, Denis GV, Nikolajczyk BS. Immune regulators of inflammation in obesity-associated type 2 diabetes and coronary artery disease. Curr Opin Endocrinol Diabetes Obes 2014;21(5):330–338.|||Grandaliano G, Gesualdo L, Ranieri E, Monno R, Stallone G, Schena FP. Monocyte chemotactic peptide-1 expression and monocyte infiltration in acute renal transplant rejection. Transplantation 1997;63(3):414–420.|||Grau V, Gemsa D, Steiniger B, Garn H. Chemokine expression during acute rejection of rat kidneys. Scand J Immunol 2000;51(5):435–440.|||Salehi S, Reed EF. The divergent roles of macrophages in solid organ transplantation. Curr Opin Organ Transplant 2015;20(4):446–453.|||Schaefer N, Tahara K, von Websky M, Wehner S, Pech T, Tolba R et al. Role of resident macrophages in the immunologic response and smooth muscle dysfunction during acute allograft rejection after intestinal transplantation. Transpl Int 2008;21(8):778–791.|||Gartlan KH, Markey KA, Varelias A, Bunting MD, Koyama M, Kuns RD et al. Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that induce GVHD without antileukemic effects. Blood 2015;126(13):1609–1620.|||Zhang R, Fang H, Chen R, Ochando JC, Ding Y, Xu J. IL-17A Is Critical for CD8+ T Effector Response in Airway Epithelial Injury After Transplantation. Transplantation 2018;102(12):e483–e493.|||Laparra A, Tricot S, Le Van M, Damouche A, Gorwood J, Vaslin B et al. The Frequencies of Immunosuppressive Cells in Adipose Tissue Differ in Human, Non-human Primate, and Mouse Models. Front Immunol 2019;10:117.|||Forsythe LK, Wallace JM, Livingstone MB. Obesity and inflammation: the effects of weight loss. Nutr Res Rev 2008;21(2):117–133.|||Kakazu E, Ueno Y, Kondo Y, Fukushima K, Shiina M, Inoue J et al. Branched chain amino acids enhance the maturation and function of myeloid dendritic cells ex vivo in patients with advanced cirrhosis. Hepatology 2009;50(6):1936–1945.|||Nunes EA, Lomax AR, Noakes PS, Miles EA, Fernandes LC, Calder PC. β-Hydroxy-β-methylbutyrate modifies human peripheral blood mononuclear cell proliferation and cytokine production in vitro. Nutrition 2011;27(1):92–99.|||Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008;320(5882):1496–1501.|||Lo YC, Lee CF, Powell JD. Insight into the role of mTOR and metabolism in T cells reveals new potential approaches to preventing graft rejection. Curr Opin Organ Transplant 2014;19(4):363–371.|||Sheldon KE, Shandilya H, Kepka-Lenhart D, Poljakovic M, Ghosh A, Morris SM, Jr. Shaping the murine macrophage phenotype: IL-4 and cyclic AMP synergistically activate the arginase I promoter. J Immunol 2013;191(5):2290–2298.|||Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y et al. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 2009;58(11):2574–2582.|||Charo IF. Macrophage polarization and insulin resistance: PPARgamma in control. Cell Metab 2007;6(2):96–98.|||Fu D, Wakabayashi Y, Lippincott-Schwartz J, Arias IM. Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway. Proc Natl Acad Sci U S A 2011;108(4):1403–1408.|||Conde P, Rodriguez M, van der Touw W, Jimenez A, Burns M, Miller J et al. DC-SIGN(+) Macrophages Control the Induction of Transplantation Tolerance. Immunity 2015;42(6):1143–1158.|||Scalea JR, Tomita Y, Lindholm CR, Burlingham W. Transplantation Tolerance Induction: Cell Therapies and Their Mechanisms. Front Immunol 2016;7:87.