Akkermansia muciniphila inhibits nonalcoholic steatohepatitis by orchestrating TLR2-activated γδT17 cell and macrophage polarization

References

• Yang RX, Zou ZS, Zhong BH, Deng H, He FP, Shi JP, Zhao CY, Mi YQ, Zhou YJ, Di FS, et al. The pathologic relevance of metabolic criteria in patients with biopsy-proven nonalcoholic fatty liver disease and metabolic dysfunction associated fatty liver disease: a multicenter cross-sectional study in China. Hepatobiliary Pancreat Dis Int. 2021;20(5):426–24. doi:10.1016/j.hbpd.2021.06.002.
   PubMed Web of Science ®Google Scholar
• Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastro Hepat. 2018;15:11–20. doi:10.1038/nrgastro.2017.109.
   PubMed Web of Science ®Google Scholar
• Khan RS, Newsome PN. NAFLD in 2017: novel insights into mechanisms of disease progression. Nat Rev Gastroenterol Hepatol. 2018;15(2):71–72. doi:10.1038/nrgastro.2017.181.
   PubMed Web of Science ®Google Scholar
• Cai J, Zhang XJ, Li H. Role of innate immune signaling in non-alcoholic fatty liver disease. Trends Endocrinol Metab. 2018;29(10):712–722. doi:10.1016/j.tem.2018.08.003.
   PubMed Web of Science ®Google Scholar
• Chopyk DM, Grakoui A. Contribution of the intestinal microbiome and gut barrier to hepatic disorders. Gastroenterol. 2020;159(3):849–863. doi:10.1053/j.gastro.2020.04.077.
   PubMed Web of Science ®Google Scholar
• Kazankov K, Jørgensen SMD, Thomsen KL, Møller HJ, Vilstrup H, George J, Schuppan D, Grønbæk H. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastro Hepat. 2019;16:145–159. doi:10.1038/s41575-018-0082-x.
   PubMed Web of Science ®Google Scholar
• Torres‐Hernandez A, Wang W, Nikiforov Y, Tejada K, Torres L, Kalabin A, Adam S. Wu J, Lu L, Chen R et al. γδ T cells promote steatohepatitis by orchestrating innate and adaptive immune programming. Hepatol. 2020;71(2):477–494. doi:10.1002/hep.30952.
   PubMed Web of Science ®Google Scholar
• Racanelli V, Rehermann B. The liver as an immunological organ. Hepatol. 2006;43(S1):S54–62. doi:10.1002/hep.21060.
   PubMedGoogle Scholar
• Hayday AC. γδ T cells and the lymphoid stress-surveillance response. Immunity. 2009;31(2):184–196. doi:10.1016/j.immuni.2009.08.006.
   PubMed Web of Science ®Google Scholar
• Li F, Hao X, Chen Y, Bai L, Gao X, Lian Z, Wei H, Sun R, Tian Z. The microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner. Nat Commun. 2017;8(1):13839. doi:10.1038/ncomms13839.
   Google Scholar
• Postler TS, Ghosh S. Understanding the holobiont: how microbial metabolites affect human health and shape the immune system. Cell Metab. 2017;26(1):110–130. doi:10.1016/j.cmet.2017.05.008.
   PubMed Web of Science ®Google Scholar
• Thaiss CA, Levy M, Suez J, Elinav E. The interplay between the innate immune system and the microbiota. Curr Opin Immunol. 2014;26:41–48. doi:10.1016/j.coi.2013.10.016.
   PubMed Web of Science ®Google Scholar
• Michaudel C, Sokol H. The gut microbiota at the service of immunometabolism. Cell Metab. 2020;32(4):514–523. doi:10.1016/j.cmet.2020.09.004.
   PubMed Web of Science ®Google Scholar
• Hänninen A, Toivonen R, Pöysti S, Belzer C, Plovier H, Ouwerkerk JP, Emani R, Cani PD, De Vos WM. Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice. Gut. 2018;67(8):1445–1453. doi:10.1136/gutjnl-2017-314508.
   PubMed Web of Science ®Google Scholar
• Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA. 2013;110(22):9066–9071. doi:10.1073/pnas.1219451110.
   PubMed Web of Science ®Google Scholar
• Li J, Lin S, Vanhoutte PM, Woo CW, Xu A. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in Apoe −/− Mice. Circulation. 2016;133(24):2434–2446. doi:10.1161/circulationaha.115.019645.
   PubMed Web of Science ®Google Scholar
• Grander C, Adolph TE, Wieser V, Lowe P, Wrzosek L, Gyongyosi B, Ward DV, Grabherr F, Gerner RR, Pfister A, et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut. 2018;67(5):891–901. doi:10.1136/gutjnl-2016-313432.
   PubMed Web of Science ®Google Scholar
• Yoon HS, Cho CH, Yun MS, Jang SJ, You HJ, Kim JH, Han D, Cha KH, Moon SH, Lee K, et al. Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice. Nature microbiol. 2021;6(5):563–573. doi:10.1038/s41564-021-00880-5.
   PubMed Web of Science ®Google Scholar
• Depommier C, Everard A, Druart C, Plovier H, Van Hul M, Vieira-Silva S, Falony G, Raes J, Maiter D, Delzenne NM, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med. 2019;25(7):1096–1103. doi:10.1038/s41591-019-0495-2.
   PubMed Web of Science ®Google Scholar
• Llopis M, Cassard AM, Wrzosek L, Boschat L, Bruneau A, Ferrere G, Puchois V, Martin JC, Lepage P, Le Roy T, et al. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut. 2016;65(5):830–839. doi:10.1136/gutjnl-2015-310585.
   PubMed Web of Science ®Google Scholar
• Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends in Endocrinol Metab. 2013;24(11):537–545. doi:10.1016/j.tem.2013.05.009.
   PubMed Web of Science ®Google Scholar
• MacParland SA, Liu JC, Ma XZ, Innes BT, Bartczak AM, Gage BK, Manuel J, Khuu N, Echeverri J, Linares I, et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun. 2018;9(1):4383. doi:10.1038/s41467-018-06318-7.
   PubMed Web of Science ®Google Scholar
• Wang L, E FD, Stärkel P, Hartmann P, Chen P, Llorente C, DePew J, Moncera K, B HS, A BD, Hooper, L, et al. Intestinal REG3 lectins protect against alcoholic steatohepatitis by reducing mucosa-associated microbiota and preventing bacterial translocation. Cell Host & Microbe. 2016;19(2):227–239. doi:10.1016/j.chom.2016.01.003.
   PubMed Web of Science ®Google Scholar
• Nguyen MT, Götz F. Lipoproteins of gram-positive bacteria: key players in the immune response and virulence. Microbiol Mol Biol Rev. 2016;80(3):891–903. doi:10.1128/mmbr.00028-16.
   PubMed Web of Science ®Google Scholar
• Alam A, Leoni G, Quiros M, Wu H, Desai C, Nishio H, Jones RM, Nusrat A, Neish AS. The microenvironment of injured murine gut elicits a local pro-restitutive microbiota. Nature microbiol. 2016;1(2):15021. doi:10.1038/nmicrobiol.2015.21.
   PubMed Web of Science ®Google Scholar
• Derrien M, Vaughan EE, Plugge CM, de Vos WM. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol. 2004;54(5):1469–1476. doi:10.1099/ijs.0.02873-0.
   PubMed Web of Science ®Google Scholar
• Kimura I, Ichimura A, Ohue-Kitano R, Igarashi M. Free fatty acid receptors in health and disease. Physiol Rev. 2020;100(1):171–210. doi:10.1152/physrev.00041.2018.
   PubMed Web of Science ®Google Scholar
• Sun M, Wu W, Chen L, Yang W, Huang X, Ma C, Chen F, Xiao Y, Zhao Y, Ma C, et al. Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis. Nat Commun. 2018;9(1):3555. doi:10.1038/s41467-018-05901-2.
   PubMed Web of Science ®Google Scholar
• Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host & Microbe. 2018;23(6):716–724. doi:10.1016/j.chom.2018.05.003.
   PubMed Web of Science ®Google Scholar
• Chelakkot C, Choi Y, Kim DK, Park HT, Ghim J, Kwon Y, Jeon J, Kim MS, Jee YK, Gho YS, et al. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Exp Mol Med. 2018;50(2):e450. doi:10.1038/emm.2017.282.
   PubMed Web of Science ®Google Scholar
• Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, Bae JW. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014;63(5):727–735. doi:10.1136/gutjnl-2012-303839.
   PubMed Web of Science ®Google Scholar
• Kim S, Lee Y, Kim Y, Seo Y, Lee H, Ha J, Lee J, Choi Y, Oh H, Yoon Y, et al. Akkermansia muciniphila prevents fatty liver disease, decreases serum triglycerides, and maintains gut homeostasis. Appl Environ Microb. 2020;86(7). doi:10.1128/aem.03004-19.
   Web of Science ®Google Scholar
• Lorenzo PM, Sajoux I, Izquierdo AG, Gomez-Arbelaez D, Zulet MA, Abete I, Castro AI, Baltar J, Portillo MP, Tinahones FJ, et al. Immunomodulatory effect of a very-low-calorie ketogenic diet compared with bariatric surgery and a low-calorie diet in patients with excessive body weight. Clin Nutr. 2022;41(7):1566–1577. doi:10.1016/j.clnu.2022.05.007.
   PubMed Web of Science ®Google Scholar
• Koutoukidis DA, Astbury NM, Tudor KE, Morris E, Henry JA, Noreik M, Jebb SA, Aveyard P. Association of weight loss interventions with changes in biomarkers of nonalcoholic fatty liver disease: a systematic review and meta-analysis. JAMA Intern Med. 2019;179(9):1262–1271. doi:10.1001/jamainternmed.2019.2248.
   PubMed Web of Science ®Google Scholar
• Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, Scott DK, O’Doherty RM. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes. 2010;59(2):347–357. doi:10.2337/db09-0016.
   PubMed Web of Science ®Google Scholar
• Wang L, Tang L, Feng Y, Zhao S, Han M, Zhang C, Yuan G, Zhu J, Cao S, Wu Q, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8 + T cells in mice. Gut. 2020;69(11):1988–1997. doi:10.1136/gutjnl-2019-320105.
   PubMed Web of Science ®Google Scholar
• Keshavarz Azizi Raftar S, Ashrafian F, Yadegar A, Lari A, Moradi HR, Shahriary A, Azimirad M, Alavifard H, Mohsenifar Z, Davari M, et al. The protective effects of live and pasteurized akkermansia muciniphila and its extracellular vesicles against HFD/CCl4-induced liver injury. Microbiol Spectr. 2021;9(2):e0048421. doi:10.1128/Spectrum.00484-21.
   PubMed Web of Science ®Google Scholar
• Miura K, Yang L, van Rooijen N, Brenner DA, Ohnishi H, Seki E. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatol. 2013;57(2):577–589. doi:10.1002/hep.26081.
   PubMed Web of Science ®Google Scholar
• Zhang H, Carnevale G, Polese B, Simard M, Thurairajah B, Khan N, Gentile ME, Fontes G, Vinh DC, Pouliot R, et al. CD109 restrains activation of cutaneous IL-17-producing γδ T cells by commensal microbiota. Cell Reports. 2019;29(2):391–405.e5. doi:10.1016/j.celrep.2019.09.003.
   PubMed Web of Science ®Google Scholar
• Wu P, Wu D, Ni C, Ye J, Chen W, Hu G, Wang Z, Wang C, Zhang Z, Xia W, et al. γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity. 2014;40(5):785–800. doi:10.1016/j.immuni.2014.03.013.
   PubMed Web of Science ®Google Scholar
• Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity. 2009;31(2):321–330. doi:10.1016/j.immuni.2009.06.020.
   PubMed Web of Science ®Google Scholar
• Ma HY, Yamamoto G, Xu J, Liu X, Karin D, Kim JY, Alexandrov LB, Koyama Y, Nishio T, Benner C, et al. IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. J Hepatol. 2020;72(5):946–959. doi:10.1016/j.jhep.2019.12.016.
   PubMed Web of Science ®Google Scholar
• Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, Cong M, Iwaisako K, Liu X, Zhang M, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterol. 2012;143(3):765–776.e3. doi:10.1053/j.gastro.2012.05.049.
   PubMed Web of Science ®Google Scholar
• Pérez MM, Martins LMS, Dias MS, Pereira CA, Leite JA, Gonçalves ECS, de Almeida PZ, de Freitas EN, Tostes RC, Ramos SG, et al. Interleukin-17/interleukin-17 receptor axis elicits intestinal neutrophil migration, restrains gut dysbiosis and lipopolysaccharide translocation in high-fat diet-induced metabolic syndrome model. Immunol. 2019;156(4):339–355. doi:10.1111/imm.13028.
   PubMed Web of Science ®Google Scholar
• Gil-Pulido J, Amézaga N, Jorgacevic I, Manthey HD, Rösch M, Brand T, Cidlinsky P, Schäfer S, Beilhack A, Saliba AE, et al. Interleukin-23 receptor expressing γδ T cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice. Cardiovascular Res. 2021;118(14):2932–2945. doi:10.1093/cvr/cvab359.
   Web of Science ®Google Scholar
• Lages CS, Simmons J, Maddox A, Jones K, Karns R, Sheridan R, Shanmukhappa SK, Mohanty S, Kofron M, Russo P, et al. The dendritic cell–T helper 17–macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia. Hepatol. 2017;65(1):174–188. doi:10.1002/hep.28851.
   PubMed Web of Science ®Google Scholar
• Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, Kayser BD, Levenez F, Chilloux J, Hoyles L, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016;65(3):426–436. doi:10.1136/gutjnl-2014-308778.
   PubMed Web of Science ®Google Scholar
• Ponziani FR, Bhoori S, Castelli C, Putignani L, Rivoltini L, Del CF, Sanguinetti M, Morelli D, Paroni SF, Petito V, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatol. 2019;69(1):107–120. doi:10.1002/hep.30036.
   PubMed Web of Science ®Google Scholar
• Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell. 2016;165(6):1332–1345. doi:10.1016/j.cell.2016.05.041.
   PubMed Web of Science ®Google Scholar
• Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Sci. 2013;341(6145):569–573. doi:10.1126/science.1241165.
   PubMed Web of Science ®Google Scholar
• Gu Z, Pei W, Shen Y, Wang L, Zhu J, Zhang Y, Fan S, Wu Q, Li L, Zhang Z. Akkermansia muciniphila and its outer protein Amuc_1100 regulates tryptophan metabolism in colitis. Food Funct. 2021;12(20):10184–10195. doi:10.1039/d1fo02172a.
   PubMed Web of Science ®Google Scholar
• Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: tryptophan’s metabolites in exercise, inflammation, and mental health. Sci. 2017;357(6349):357. doi:10.1126/science.aaf9794.
   Web of Science ®Google Scholar
• Stockinger B, Shah K, Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function. Nat Rev Gastro Hepat. 2021;18(8):559–570. doi:10.1038/s41575-021-00430-8.
   PubMed Web of Science ®Google Scholar
• Wu L, Han Y, Zheng Z, Zhu S, Chen J, Yao Y, Yue S, Teufel A, Weng H, Li L, et al. Obeticholic acid inhibits anxiety via alleviating gut microbiota-mediated microglia accumulation in the brain of high-fat high-sugar diet mice. Nutr. 2021;13(3):940. doi:10.3390/nu13030940.
   Google Scholar
• Ling Q, Huang H, Han Y, Zhang C, Zhang X, Chen K, Wu L, Tang R, Zheng Z, Zheng S, et al. The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: from bench to bedside. Am J Transplant. 2020;20(3):701–713. doi:10.1111/ajt.15665.
   PubMed Web of Science ®Google Scholar
• Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet–induced obesity and diabetes in mice. Diabetes. 2008;57(6):1470–1481. doi:10.2337/db07-1403.
   PubMed Web of Science ®Google Scholar
• Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatol. 2005;41(6):1313–1321. doi:10.1002/hep.20701.
   PubMed Web of Science ®Google Scholar
• Gomes AL, Teijeiro A, Burén S, Tummala KS, Yilmaz M, Waisman A, Theurillat JP, Perna C, Djouder N. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2016;30(1):161–175. doi:10.1016/j.ccell.2016.05.020.
   PubMed Web of Science ®Google Scholar
• Cha JY, Kim DH, Chun KH. The role of hepatic macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Lab Anim Res. 2018;34(4):133–139. doi:10.5625/lar.2018.34.4.133.
   PubMedGoogle Scholar
• Wu L, Han Y, Zheng Z, Peng G, Liu P, Yue S, Zhu S, Jun C, Lv H, Shao L, et al. Altered gut microbial metabolites in amnestic mild cognitive impairment and Alzheimer’s disease: signals in host–microbe interplay. Nutr. 2021;13(1):228. doi:10.3390/nu13010228.
   Google Scholar
• Furuhashi T, Sugitate K, Nakai T, Jikumaru Y, Ishihara G. Rapid profiling method for mammalian feces short chain fatty acids by GC-MS. Anal Biochem. 2018;543:51–54. doi:10.1016/j.ab.2017.12.001.
   PubMed Web of Science ®Google Scholar
• Wang B, Jiang X, Cao M, Ge J, Bao Q, Tang L, Chen Y, Li L. Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease. Sci Rep. 2016;6(1):32002. doi:10.1038/srep32002.
   PubMedGoogle Scholar
• Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335–336. doi:10.1038/nmeth.f.303.
   PubMed Web of Science ®Google Scholar
• McDonald D, Price MN, Goodrich J, Nawrocki EP, DeSantis TZ, Probst A, Andersen GL, Knight R, Hugenholtz P. An improved Greengenes taxonomy with explicit ranks for ecological and evolutionary analyses of bacteria and archaea. Isme J. 2012;6(3):610–618. doi:10.1038/ismej.2011.139.
   PubMed Web of Science ®Google Scholar
• Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB, Lesniewski RA, Oakley BB, Parks DH, Robinson CJ, et al. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol. 2009;75(23):7537–7541. doi:10.1128/aem.01541-09.
   PubMed Web of Science ®Google Scholar
• Langille MG, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, Clemente JC, Burkepile DE, Vega Thurber RL, Knight R, et al. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol. 2013;31(9):814–821. doi:10.1038/nbt.2676.
   PubMed Web of Science ®Google Scholar
• Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018;36(5):411–420. doi:10.1038/nbt.4096.
   PubMed Web of Science ®Google Scholar