The emerging role of bile acids in white adipose tissue

Trends in Endocrinology & Metabolism - Tập 34 - Trang 718-734 - 2023
Andreas Schmid1, Thomas Karrasch2, Andreas Schäffler2
1Basic Research Laboratory for Molecular Endocrinology, Adipocyte Biology, and Biochemistry, University of Giessen, D 35392 Giessen, Germany
2Department of Internal Medicine III – Endocrinology, Diabetology, and Metabolism, University of Giessen, D 35392 Giessen, Germany

Tài liệu tham khảo

Albaugh, 2017, Bile acids and bariatric surgery, Mol. Aspects Med., 56, 75, 10.1016/j.mam.2017.04.001 Albaugh, 2023, Regulation of body weight: lessons learned from bariatric surgery, Mol. Metab., 68, 10.1016/j.molmet.2022.101517 Frikke-Schmidt, 2016, Does bariatric surgery improve adipose tissue function?, Obes. Rev., 17, 795, 10.1111/obr.12429 Chondronikola, 2016, Bariatric surgery and type 2 diabetes: are there weight loss-independent therapeutic effects of upper gastrointestinal bypass?, J. Intern. Med., 280, 476, 10.1111/joim.12527 Browning, 2019, Changes in bile acid metabolism, transport, and signaling as central drivers for metabolic improvements after bariatric surgery, Curr. Obes. Rep., 8, 175, 10.1007/s13679-019-00334-4 Runkel, 2011, Evidence-based German guidelines for surgery for obesity, Int. J. Colorectal. Dis., 26, 397, 10.1007/s00384-011-1136-5 Runkel, 2011, Bariatric surgery, Dtsch. Arztebl. Int., 108, 341 Albaugh, 2015, Early increases in bile acids post Roux-en-Y gastric bypass are driven by insulin-sensitizing, secondary bile acids, J. Clin. Endocrinol. Metab., 100, E1225, 10.1210/jc.2015-2467 Laferrere, 2016, Bariatric surgery and obesity: influence on the incretins, Int. J. Obes., Suppl. 6, S32, 10.1038/ijosup.2016.8 Webb, 2017, Bariatric surgery – time to replace with GLP-1?, Scand. J. Gastroenterol., 52, 635, 10.1080/00365521.2017.1293154 Hindso, 2021, The role of GLP-1 in postprandial glucose metabolism after bariatric surgery: a narrative review of human GLP-1 receptor antagonist studies, Surg Obes Relat Dis, 17, 1383, 10.1016/j.soard.2021.01.041 Wang, 2019, Role of bile acids in bariatric surgery, Front Physiol, 10, 374, 10.3389/fphys.2019.00374 Xu, 2021, Recent advances in the mechanisms underlying the beneficial effects of bariatric and metabolic surgery, Surg Obes Relat Dis, 17, 231, 10.1016/j.soard.2020.08.028 Penney, 2015, The role of bile acids in reducing the metabolic complications of obesity after bariatric surgery: a systematic review, International journal of obesity, 39, 1565, 10.1038/ijo.2015.115 Schaffler, 2023, Role of metaflammation as a systemic manifestation of metabolic diseases, Inn. Med. (Heidelb.), 64, 313 Itoh, 2022, Developmental origins of metaflammation; a bridge to the future between the DOHaD theory and evolutionary biology, Front Endocrinol (Lausanne), 13, 10.3389/fendo.2022.839436 Hotamisligil, 2006, Inflammation and metabolic disorders, Nature, 444, 860, 10.1038/nature05485 Hotamisligil, 2017, Inflammation, metaflammation and immunometabolic disorders, Nature, 542, 177, 10.1038/nature21363 Prattichizzo, 2018, Inflammageing and metaflammation: the Yin and Yang of type 2 diabetes, Ageing Res Rev, 41, 1, 10.1016/j.arr.2017.10.003 von Stebut, 2019, IL-17A in psoriasis and beyond: cardiovascular and metabolic implications, Front Immunol, 10, 3096, 10.3389/fimmu.2019.03096 Rehman, 2021, Role of macrophages in the endocrine system, Trends in endocrinology and metabolism: TEM, 32, 238, 10.1016/j.tem.2020.12.001 Hotamisligil, 1993, Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance, Science, 259, 87, 10.1126/science.7678183 Yao, 2022, Adipose tissue macrophage in obesity-associated metabolic diseases, Front Immunol, 13, 10.3389/fimmu.2022.977485 Ouchi, 2011, Adipokines in inflammation and metabolic disease, Nature reviews. Immunology, 11, 85, 10.1038/nri2921 Chavez-Talavera, 2017, Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease, Gastroenterology, 152, 1679, 10.1053/j.gastro.2017.01.055 Machado, 2022, Browning of the white adipose tissue regulation: new insights into nutritional and metabolic relevance in health and diseases, Nutr Metab (Lond), 19, 61, 10.1186/s12986-022-00694-0 Bargut, 2017, Browning of white adipose tissue: lessons from experimental models, Horm. Mol. Biol. Clin. Invest., 31 Watanabe, 2006, Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation, Nature, 439, 484, 10.1038/nature04330 Straniero, 2020, Of mice and men: murine bile acids explain species differences in the regulation of bile acid and cholesterol metabolism, Journal of lipid research, 61, 480, 10.1194/jlr.RA119000307 Dreyfuss, 2021, High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control, Nature communications, 12, 6951, 10.1038/s41467-021-27289-2 Myronovych, 2020, Assessment of the role of FGF15 in mediating the metabolic outcomes of murine vertical sleeve gastrectomy (VSG), Am J Physiol Gastrointest Liver Physiol, 319, G669, 10.1152/ajpgi.00175.2020 McGavigan, 2017, TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice, Gut, 66, 226, 10.1136/gutjnl-2015-309871 Tian, 2017, Bile acid signaling and bariatric surgery, Liver Res, 1, 208, 10.1016/j.livres.2017.12.007 Ding, 2019, Targeting bile acid-activated receptors in bariatric surgery, Handb Exp Pharmacol, 256, 359, 10.1007/164_2019_229 Flynn, 2019, Metabolic effects of bile acids: potential role in bariatric surgery, Cell Mol Gastroenterol Hepatol, 8, 235, 10.1016/j.jcmgh.2019.04.014 Houten, 2006, Endocrine functions of bile acids, The EMBO journal, 25, 1419, 10.1038/sj.emboj.7601049 Frommherz, 2016, Age-related changes of plasma bile acid concentrations in healthy adults – results from the cross-sectional KarMeN study, PloS one, 11, 10.1371/journal.pone.0153959 Schmid, 2016, Bile acid metabolome after an oral lipid tolerance test by liquid chromatography–tandem mass spectrometry (LC-MS/MS), PloS one, 11, 10.1371/journal.pone.0148869 Matysik, 2011, Bile acid signaling after an oral glucose tolerance test, Chem Phys Lipids, 164, 525, 10.1016/j.chemphyslip.2011.05.003 Ahmad, 2013, Roux-en-Y gastric bypass normalizes the blunted postprandial bile acid excursion associated with obesity, International journal of obesity, 37, 1553, 10.1038/ijo.2013.38 Jahansouz, 2016, Bile acids increase independently from hypocaloric restriction after bariatric surgery, Ann Surg, 264, 1022, 10.1097/SLA.0000000000001552 Jørgensen, 2015, Improvements in glucose metabolism early after gastric bypass surgery are not explained by increases in total bile acids and fibroblast growth factor 19 concentrations, J Clin Endocrinol Metab, 100, E396, 10.1210/jc.2014-1658 Nakatani, 2009, Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery, Metabolism, 58, 1400, 10.1016/j.metabol.2009.05.006 Patti, 2009, Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism, Obesity, 17, 1671, 10.1038/oby.2009.102 Spinelli, 2016, Influence of Roux-en-Y gastric bypass on plasma bile acid profiles: a comparative study between rats, pigs and humans, International journal of obesity, 40, 1260, 10.1038/ijo.2016.46 Myronovych, 2014, The role of small heterodimer partner in nonalcoholic fatty liver disease improvement after sleeve gastrectomy in mice, Obesity, 22, 2301, 10.1002/oby.20890 Yang, 2021, Serum glucagon, bile acids, and FGF-19: metabolic behavior patterns after Roux-en-Y gastric bypass and vertical sleeve gastrectomy, Obes Surg, 31, 4939, 10.1007/s11695-021-05677-3 Kohli, 2013, Weight loss induced by Roux-en-Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids, J Clin Endocrinol Metab, 98, E708, 10.1210/jc.2012-3736 Werling, 2013, Enhanced fasting and post-prandial plasma bile acid responses after Roux-en-Y gastric bypass surgery, Scand J Gastroenterol, 48, 1257, 10.3109/00365521.2013.833647 Ding, 2016, Vertical sleeve gastrectomy activates GPBAR-1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice, Hepatology, 64, 760, 10.1002/hep.28689 Quante, 2021, Restored TDCA and valine levels imitate the effects of bariatric surgery, Elife, 10, 10.7554/eLife.62928 Schmid, 2019, Evidence of functional bile acid signaling pathways in adipocytes, Molecular and cellular endocrinology, 483, 1, 10.1016/j.mce.2018.12.006 Shinohara, 2020, Promotion of lipogenesis by PPARgamma-activated FXR expression in adipocytes, Biochem Biophys Res Commun, 527, 49, 10.1016/j.bbrc.2020.04.075 Velazquez-Villegas, 2018, TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue, Nature communications, 9, 245, 10.1038/s41467-017-02068-0 Rizzo, 2006, The farnesoid X receptor promotes adipocyte differentiation and regulates adipose cell function in vivo, Mol Pharmacol, 70, 1164, 10.1124/mol.106.023820 Svensson, 2013, The TGR5 gene is expressed in human subcutaneous adipose tissue and is associated with obesity, weight loss and resting metabolic rate, Biochem Biophys Res Commun, 433, 563, 10.1016/j.bbrc.2013.03.031 Cariou, 2006, The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice, The Journal of biological chemistry, 281, 11039, 10.1074/jbc.M510258200 Dehondt, 2023, Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis, Molecular metabolism, 69, 10.1016/j.molmet.2023.101686 van Zutphen, 2019, FXR overexpression alters adipose tissue architecture in mice and limits its storage capacity leading to metabolic derangements, Journal of lipid research, 60, 1547, 10.1194/jlr.M094508 Teodoro, 2021, Chenodeoxycholic acid has non-thermogenic, mitodynamic anti-obesity effects in an in vitro CRISPR/Cas9 model of bile acid receptor TGR5 knockdown, Int J Mol Sci, 22, 10.3390/ijms222111738 Broeders, 2015, The bile acid chenodeoxycholic acid increases human brown adipose tissue activity, Cell metabolism, 22, 418, 10.1016/j.cmet.2015.07.002 Heeren, 2018, Brown adipose tissue and lipid metabolism, Curr Opin Lipidol, 29, 180, 10.1097/MOL.0000000000000504 Teodoro, 2016, The bile acid chenodeoxycholic acid directly modulates metabolic pathways in white adipose tissue in vitro: insight into how bile acids decrease obesity, NMR in biomedicine, 29, 1391, 10.1002/nbm.3583 Lefebvre, 2009, Role of bile acids and bile acid receptors in metabolic regulation, Physiol Rev, 89, 147, 10.1152/physrev.00010.2008 Ryan, 2014, FXR is a molecular target for the effects of vertical sleeve gastrectomy, Nature, 509, 183, 10.1038/nature13135 Albaugh, 2019, Role of bile acids and GLP-1 in mediating the metabolic improvements of bariatric surgery, Gastroenterology, 156, 1041, 10.1053/j.gastro.2018.11.017 Li, 2020, Farnesoid X receptor contributes to body weight-independent improvements in glycemic control after Roux-en-Y gastric bypass surgery in diet-induced obese mice, Molecular metabolism, 37, 10.1016/j.molmet.2020.100980 Hao, 2018, Roux-en-Y gastric bypass surgery-induced weight loss and metabolic improvements are similar in TGR5-deficient and wildtype mice, Obes Surg, 28, 3227, 10.1007/s11695-018-3297-6 Schmid, 2020, Downregulation of CTRP-3 by weight loss in vivo and by bile acids and incretins in adipocytes in vitro, Int. J. Mol. Sci., 21, 8168, 10.3390/ijms21218168 Zhang, 2015, Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection, Science, 347, 67, 10.1126/science.1260972 Hopfinger, 2021, Regulation of CAMP (cathelicidin antimicrobial peptide) expression in adipocytes by TLR 2 and 4, Innate Immun, 27, 184, 10.1177/1753425920988167 Hochberg, 2021, Serum levels and adipose tissue gene expression of cathelicidin antimicrobial peptide (CAMP) in obesity and during weight loss, Horm. Metab. Res., 53, 169, 10.1055/a-1323-3050 Hochberg, 2021, Serum levels and adipose tissue gene expression of cathelicidin antimicrobial peptide (CAMP) in obesity and during weight loss, Horm Metab Res, 53, 169, 10.1055/a-1323-3050 Guo, 2017, Fibroblast growth factor 21 reverses suppression of adiponectin expression via inhibiting endoplasmic reticulum stress in adipose tissue of obese mice, Exp Biol Med (Maywood), 242, 441, 10.1177/1535370216677354 Zhou, 2010, DsbA-L alleviates endoplasmic reticulum stress-induced adiponectin downregulation, Diabetes, 59, 2809, 10.2337/db10-0412 Xia, 2017, Tauroursodeoxycholic acid inhibits TNF-alpha-induced lipolysis in 3T3-L1 adipocytes via the IRE–JNK–perilipin-A signaling pathway, Mol Med Rep, 15, 1753, 10.3892/mmr.2017.6209 Karrasch, 2014, Short-term regulation of visfatin release in vivo by oral lipid ingestion and in vitro by fatty acid stimulation, Exp Clin Endocrinol Diabetes, 122, 126, 10.1055/s-0033-1363262 Schmid, 2015, Short-term regulation of resistin in vivo by oral lipid ingestion and in vitro by fatty acid stimulation, Exp Clin Endocrinol Diabetes, 123, 553, 10.1055/s-0035-1555942 Schmid, 2013, Regulation and function of C1Q/TNF-related protein-5 (CTRP-5) in the context of adipocyte biology, Exp Clin Endocrinol Diabetes, 121, 310, 10.1055/s-0032-1333299 Jiao, 2011, FFA-induced adipocyte inflammation and insulin resistance: involvement of ER stress and IKKbeta pathways, Obesity, 19, 483, 10.1038/oby.2010.200 Kawasaki, 2012, Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue, Scientific reports, 2, 799, 10.1038/srep00799 Freitas, 2023, Insights by which TUDCA is a potential therapy against adiposity, Front Endocrinol (Lausanne), 14, 10.3389/fendo.2023.1090039 Lee, 2015, Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in InsrP1195L/+ mice fed high-fat-diet, Scientific reports, 5, 17565, 10.1038/srep17565 Younce, 2012, MCP-1 induced protein promotes adipogenesis via oxidative stress, endoplasmic reticulum stress and autophagy, Cell Physiol Biochem, 30, 307, 10.1159/000339066 Shihabudeen, 2015, Chenodeoxycholic acid, an endogenous FXR ligand alters adipokines and reverses insulin resistance, Molecular and cellular endocrinology, 414, 19, 10.1016/j.mce.2015.07.012 Oh, 2016, Ursodeoxycholic acid decreases age-related adiposity and inflammation in mice, BMB Rep, 49, 105, 10.5483/BMBRep.2016.49.2.173 Axling, 2020, Increased whole body energy expenditure and protection against diet-induced obesity in Cyp8b1-deficient mice is accompanied by altered adipose tissue features, Adipocyte, 9, 587, 10.1080/21623945.2020.1827519 Chen, 2017, Chenodeoxycholic acid attenuates high-fat diet-induced obesity and hyperglycemia via the G protein-coupled bile acid receptor 1 and proliferator-activated receptor gamma pathway, Exp Ther Med, 14, 5305 Carino, 2017, Gpbar1 agonism promotes a Pgc-1alpha-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice, Scientific reports, 7, 13689, 10.1038/s41598-017-13102-y Dufer, 2012, Bile acids acutely stimulate insulin secretion of mouse beta-cells via farnesoid X receptor activation and K(ATP) channel inhibition, Diabetes, 61, 1479, 10.2337/db11-0815 Chen, 2023, Glycoursodeoxycholic acid regulates bile acids level and alters gut microbiota and glycolipid metabolism to attenuate diabetes, Gut Microbes, 15, 10.1080/19490976.2023.2192155 Schmid, 2020, Role of progranulin in adipose tissue innate immunity, Cytokine, 125, 10.1016/j.cyto.2019.154796 Zhang, 2021, Obeticholic acid ameliorates obesity and hepatic steatosis by activating brown fat, Exp Ther Med, 22, 991, 10.3892/etm.2021.10423 Haczeyni, 2017, Obeticholic acid improves adipose morphometry and inflammation and reduces steatosis in dietary but not metabolic obesity in mice, Obesity, 25, 155, 10.1002/oby.21701 Maneschi, 2013, FXR activation normalizes insulin sensitivity in visceral preadipocytes of a rabbit model of MetS, J Endocrinol, 218, 215, 10.1530/JOE-13-0109 Rizzo, 2010, Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist, Mol Pharmacol, 78, 617, 10.1124/mol.110.064501 Qiu, 2018, Lipid accumulation inhibitory activities of novel isoxazole-based chenodeoxycholic acids: design, synthesis and preliminary mechanism study, Bioorg Med Chem Lett, 28, 2879, 10.1016/j.bmcl.2018.07.026 de Oliveira, 2016, Bile acid receptor agonists INT747 and INT777 decrease oestrogen deficiency-related postmenopausal obesity and hepatic steatosis in mice, Biochim Biophys Acta, 1862, 2054, 10.1016/j.bbadis.2016.07.012 Bouillon, 2014, Vitamin D and energy homeostasis: of mice and men, Nat Rev Endocrinol, 10, 79, 10.1038/nrendo.2013.226 Carazo, 2017, Acetylated deoxycholic (DCA) and cholic (CA) acids are potent ligands of pregnane X (PXR) receptor, Toxicol Lett, 265, 86, 10.1016/j.toxlet.2016.11.013 Zhuang, 2017, Chemoproteomic profiling of bile acid interacting proteins, ACS Cent Sci, 3, 501, 10.1021/acscentsci.7b00134 Shulman, 2014, Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease, N Engl J Med, 371, 2237, 10.1056/NEJMra1011035 Després, 2006, Abdominal obesity and metabolic syndrome, Nature, 444, 881, 10.1038/nature05488 Gregor, 2011, Inflammatory mechanisms in obesity, Annu Rev Immunol, 29, 415, 10.1146/annurev-immunol-031210-101322 McLaughlin, 2017, Role of innate and adaptive immunity in obesity-associated metabolic disease, J Clin Invest, 127, 5, 10.1172/JCI88876 Hirosumi, 2002, A central role for JNK in obesity and insulin resistance, Nature, 420, 333, 10.1038/nature01137 Wang, 2019, An evolutionary perspective on immunometabolism, Science, 363, 10.1126/science.aar3932 Shaukat, 2015, Sterile inflammation in Drosophila, Mediators of inflammation, 2015, 10.1155/2015/369286 Schaffler, 2007, Adipose tissue as an immunological organ: Toll-like receptors, C1q/TNFs and CTRPs, Trends Immunol, 28, 393, 10.1016/j.it.2007.07.003 Schaffler, 2012, CTRP family: linking immunity to metabolism, Trends in endocrinology and metabolism: TEM, 23, 194, 10.1016/j.tem.2011.12.003 Shapiro, 1998, The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor, Curr Biol, 8, 335, 10.1016/S0960-9822(98)70133-2 Straub, 2011, Concepts of evolutionary medicine and energy regulation contribute to the etiology of systemic chronic inflammatory diseases, Brain, behavior, and immunity, 25, 1, 10.1016/j.bbi.2010.08.002 Straub, 2014, Interaction of the endocrine system with inflammation: a function of energy and volume regulation, Arthritis research & therapy, 16, 203, 10.1186/ar4484 Straub, 2011, Alterations of the hypothalamic–pituitary–adrenal axis in systemic immune diseases – a role for misguided energy regulation, Clinical and experimental rheumatology, 29, S23 Straub, 2010, Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases, Journal of internal medicine, 267, 543, 10.1111/j.1365-2796.2010.02218.x Straub, 2015, Evolutionary medicine and bone loss in chronic inflammatory diseases – a theory of inflammation-related osteopenia, Seminars in arthritis and rheumatism, 45, 220, 10.1016/j.semarthrit.2015.04.014 Donath, 2014, Targeting inflammation in the treatment of type 2 diabetes: time to start, Nat Rev Drug Discov, 13, 465, 10.1038/nrd4275 Goldfine, 2017, Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk, J Clin Invest, 127, 83, 10.1172/JCI88884 Ridker, 2017, Antiinflammatory therapy with canakinumab for atherosclerotic disease, N Engl J Med, 377, 1119, 10.1056/NEJMoa1707914 Schaffler, 2006, Role of adipose tissue as an inflammatory organ in human diseases, Endocr Rev, 27, 449, 10.1210/er.2005-0022 Zhang, 2018, Targeting autophagy in obesity: from pathophysiology to management, Nat Rev Endocrinol, 14, 356, 10.1038/s41574-018-0009-1 Schaeffler, 2009, Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity, Immunology, 126, 233, 10.1111/j.1365-2567.2008.02892.x Shi, 2006, TLR4 links innate immunity and fatty acid-induced insulin resistance, J Clin Invest, 116, 3015, 10.1172/JCI28898 Lehrke, 2004, Inflamed about obesity, Nat Med, 10, 126, 10.1038/nm0204-126 Xu, 2003, Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance, J Clin Invest, 112, 1821, 10.1172/JCI200319451 Schaffler, 2010, Innate immunity and adipose tissue biology, Trends Immunol., 31, 228, 10.1016/j.it.2010.03.001 Barthelemy, 2023, Beyond energy balance regulation: the underestimated role of adipose tissues in host defense against pathogens, Front Immunol, 14, 10.3389/fimmu.2023.1083191 Alcorn, 2015, Killer fat, Science, 347, 26, 10.1126/science.aaa4567 Lee, 2014, Nutrient-sensing nuclear receptors coordinate autophagy, Nature, 516, 112, 10.1038/nature13961 Sayin, 2013, Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist, Cell metabolism, 17, 225, 10.1016/j.cmet.2013.01.003 Maruyama, 2002, Identification of membrane-type receptor for bile acids (M-BAR), Biochem Biophys Res Commun, 298, 714, 10.1016/S0006-291X(02)02550-0 Yoneno, 2013, TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease, Immunology, 139, 19, 10.1111/imm.12045