Role of Akkermansia muciniphila in the development of nonalcoholic fatty liver disease: current knowledge and perspectives

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and a common cause of liver cirrhosis and cancer. Akkermansia muciniphila (A. muciniphila) is a next-generation probiotic that has been reported to improve metabolic disorders. Emerging evidence indicates the therapeutic potential of A. muciniphila for NAFLD, especially in the inflammatory stage, nonalcoholic steatohepatitis. Here, the current knowledge on the role of A. muciniphila in the progression of NAFLD was summarized. A. muciniphila abundancy is decreased in animals and humans with NAFLD. The recovery of A. muciniphila presented benefits in preventing hepatic fat accumulation and inflammation in NAFLD. The details of how microbes regulate hepatic immunity and lipid accumulation in NAFLD were further discussed. The modulation mechanisms by which A. muciniphila acts to improve hepatic inflammation are mainly attributed to the alleviation of inflammatory cytokines and LPS signals and the downregulation of microbiota-related innate immune cells (such as macrophages). This review provides insights into the roles of A. muciniphila in NAFLD, thereby providing a blueprint to facilitate clinical therapeutic applications.

Keywords

Akkermansia muciniphila / NAFLD / NASH / steatosis / inflammation

References

[1] Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol 2019; 70(1): 151–171

[2] Lazarus JV, Mark HE, Anstee QM, Arab JP, Batterham RL, Castera L, Cortez-Pinto H, Crespo J, Cusi K, Dirac MA, Francque S, George J, Hagström H, Huang TT, Ismail MH, Kautz A, Sarin SK, Loomba R, Miller V, Newsome PN, Ninburg M, Ocama P, Ratziu V, Rinella M, Romero D, Romero-Gómez M, Schattenberg JM, Tsochatzis EA, Valenti L, Wong VW, Yilmaz Y, Younossi ZM, Zelber-Sagi; SNAFLD Consensus Consortium. Advancing the global public health agenda for NAFLD: a consensus statement. Nat Rev Gastroenterol Hepatol 2022; 19(1): 60–78

[3] Sharpton SR, Schnabl B, Knight R, Loomba R. Current concepts, opportunities, and challenges of gut microbiome-based personalized medicine in nonalcoholic fatty liver disease. Cell Metab 2021; 33(1): 21–32

[4] Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med 2018; 24(7): 908–922

[5] Aron-Wisnewsky J, Warmbrunn MV, Nieuwdorp M, Clément K. Nonalcoholic fatty liver disease: modulating gut microbiota to improve severity?. Gastroenterology 2020; 158(7): 1881–1898

[6] Kolodziejczyk AA, Zheng D, Shibolet O, Elinav E. The role of the microbiome in NAFLD and NASH. EMBO Mol Med 2019; 11(2): e9302

[7] Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab 2013; 24(11): 537–545

[8] Leung C, Rivera L, Furness JB, Angus PW. The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol 2016; 13(7): 412–425

[9] Bajaj JS, Khoruts A. Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis. J Hepatol 2020; 72(5): 1003–1027

[10] Zhang T, Li Q, Cheng L, Buch H, Zhang F. Akkermansia muciniphila is a promising probiotic. Microb Biotechnol 2019; 12(6): 1109–1125

[11] CaniPDDepommier CDerrienMEverardAde VosWM. Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol 2022; [Epub ahead of print] doi: 10.1038/s41575-022-00631-9

[12] Zhai Q, Feng S, Arjan N, Chen W. A next generation probiotic, Akkermansia muciniphila. Crit Rev Food Sci Nutr 2019; 59(19): 3227–3236

[13] Yan J, Sheng L, Li H. Akkermansia muciniphila: is it the Holy Grail for ameliorating metabolic diseases?. Gut Microbes 2021; 13(1): 1984104

[14] 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

[15] Derrien M, Collado MC, Ben-Amor K, Salminen S, de Vos WM. The mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract. Appl Environ Microbiol 2008; 74(5): 1646–1648

[16] ZhaoQYu JHaoYZhouHHuY ZhangCZheng HWangXZengFHuJ GuLWangZ ZhaoFYue CZhouPZhangHHuangN WuWZhouY LiJ. Akkermansia muciniphila plays critical roles in host health. Crit Rev Microbiol 2022; [Epub ahead of print] doi: 10.1080/1040841X.2022.2037506

[17] Si J, Kang H, You HJ, Ko G. Revisiting the role of Akkermansia muciniphila as a therapeutic bacterium. Gut Microbes 2022; 14(1): 2078619

[18] Depommier C, Everard A, Druart C, Plovier H, Van Hul M, Vieira-Silva S, Falony G, Raes J, Maiter D, Delzenne NM, de Barsy M, Loumaye A, Hermans MP, Thissen JP, de Vos WM, Cani PD. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med 2019; 25(7): 1096–1103

[19] Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA 2013; 110(22): 9066–9071

[20] Bae M, Cassilly CD, Liu X, Park SM, Tusi BK, Chen X, Kwon J, Filipčík P, Bolze AS, Liu Z, Vlamakis H, Graham DB, Buhrlage SJ, Xavier RJ, Clardy J. Akkermansia muciniphila phospholipid induces homeostatic immune responses. Nature 2022; 608(7921): 168–173

[21] Kim S, Lee Y, Kim Y, Seo Y, Lee H, Ha J, Lee J, Choi Y, Oh H, Yoon Y. Akkermansia muciniphila prevents fatty liver disease, decreases serum triglycerides, and maintains gut homeostasis. Appl Environ Microbiol 2020; 86(7): e03004–19

[22] Grander C, Adolph TE, Wieser V, Lowe P, Wrzosek L, Gyongyosi B, Ward DV, Grabherr F, Gerner RR, Pfister A, Enrich B, Ciocan D, Macheiner S, Mayr L, Drach M, Moser P, Moschen AR, Perlemuter G, Szabo G, Cassard AM, Tilg H. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut 2018; 67(5): 891–901

[23] Keshavarz Azizi Raftar S, Ashrafian F, Yadegar A, Lari A, Moradi HR, Shahriary A, Azimirad M, Alavifard H, Mohsenifar Z, Davari M, Vaziri F, Moshiri A, Siadat SD, Zali MR. 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

[24] Derrien M, Belzer C, de Vos WM. Akkermansia muciniphila and its role in regulating host functions. Microb Pathog 2017; 106: 171–181

[25] Wu W, Lv L, Shi D, Ye J, Fang D, Guo F, Li Y, He X, Li L. Protective effect of Akkermansia muciniphila against immune-mediated liver injury in a mouse model. Front Microbiol 2017; 8: 1804

[26] Chelakkot C, Choi Y, Kim DK, Park HT, Ghim J, Kwon Y, Jeon J, Kim MS, Jee YK, Gho YS, Park HS, Kim YK, Ryu SH. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Exp Mol Med 2018; 50(2): e450

[27] 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. Nat Microbiol 2016; 1(2): 15021

[28] Kim S, Shin YC, Kim TY, Kim Y, Lee YS, Lee SH, Kim MN, O E, Kim KS, Kweon MN. Mucin degrader Akkermansia muciniphila accelerates intestinal stem cell-mediated epithelial development. Gut Microbes 2021; 13(1): 1892441

[29] Pérez MM, Martins LMS, Dias MS, Pereira CA, Leite JA, Gonçalves ECS, de Almeida PZ, de Freitas EN, Tostes RC, Ramos SG, de Zoete MR, Ryffel B, Silva JS, Carlos D. Interleukin-17/interleukin-17 receptor axis elicits intestinal neutrophil migration, restrains gut dysbiosis and lipopolysaccharide translocation in high-fat diet-induced metabolic syndrome model. Immunology 2019; 156(4): 339–355

[30] Lee JS, Tato CM, Joyce-Shaikh B, Gulen MF, Cayatte C, Chen Y, Blumenschein WM, Judo M, Ayanoglu G, McClanahan TK, Li X, Cua DJ. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 2015; 43(4): 727–738

[31] Tarantino G, Costantini S, Finelli C, Capone F, Guerriero E, La Sala N, Gioia S, Castello G. Is serum interleukin-17 associated with early atherosclerosis in obese patients?. J Transl Med 2014; 12(1): 214

[32] Qu S, Fan L, Qi Y, Xu C, Hu Y, Chen S, Liu W, Liu W, Si J. Akkermansia muciniphila alleviates dextran sulfate sodium (DSS)-induced acute colitis by NLRP3 activation. Microbiol Spectr 2021; 9(2): e0073021

[33] Wang L, Tang L, Feng Y, Zhao S, Han M, Zhang C, Yuan G, Zhu J, Cao S, Wu Q, Li L, Zhang Z. 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

[34] Liu Y, Yang M, Tang L, Wang F, Huang S, Liu S, Lei Y, Wang S, Xie Z, Wang W, Zhao X, Tang B, Yang S. TLR4 regulates RORγt⁺ regulatory T-cell responses and susceptibility to colon inflammation through interaction with Akkermansia muciniphila. Microbiome 2022; 10(1): 98

[35] Lukovac S, Belzer C, Pellis L, Keijser BJ, de Vos WM, Montijn RC, Roeselers G. Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids. MBio 2014; 5(4): e01438–14

[36] 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

[37] Stockinger B, Shah K, Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function. Nat Rev Gastroenterol Hepatol 2021; 18(8): 559–570

[38] Rao Y, Kuang Z, Li C, Guo S, Xu Y, Zhao D, Hu Y, Song B, Jiang Z, Ge Z, Liu X, Li C, Chen S, Ye J, Huang Z, Lu Y. Gut Akkermansia muciniphila ameliorates metabolic dysfunction-associated fatty liver disease by regulating the metabolism of L-aspartate via gut-liver axis. Gut Microbes 2021; 13(1): 1927633

[39] Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy. J Hepatol 2020; 72(3): 558–577

[40] Chopyk DM, Grakoui A. Contribution of the intestinal microbiome and gut barrier to hepatic disorders. Gastroenterology 2020; 159(3): 849–863

[41] Plovier H, Everard A, Druart C, Depommier C, Van Hul M, Geurts L, Chilloux J, Ottman N, Duparc T, Lichtenstein L, Myridakis A, Delzenne NM, Klievink J, Bhattacharjee A, van der Ark KC, Aalvink S, Martinez LO, Dumas ME, Maiter D, Loumaye A, Hermans MP, Thissen JP, Belzer C, de Vos WM, Cani PD. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med 2017; 23(1): 107–113

[42] Yoon HS, Cho CH, Yun MS, Jang SJ, You HJ, Kim JH, Han D, Cha KH, Moon SH, Lee K, Kim YJ, Lee SJ, Nam TW, Ko G. Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice. Nat Microbiol 2021; 6(5): 563–573

[43] Holst JJ, Deacon CF, Vilsbøll T, Krarup T, Madsbad S. Glucagon-like peptide-1, glucose homeostasis and diabetes. Trends Mol Med 2008; 14(4): 161–168

[44] Shi Z, Lei H, Chen G, Yuan P, Cao Z, Ser HL, Zhu X, Wu F, Liu C, Dong M, Song Y, Guo Y, Chen C, Hu K, Zhu Y, Zeng XA, Zhou J, Lu Y, Patterson AD, Zhang L. Impaired intestinal Akkermansia muciniphila and aryl hydrocarbon receptor ligands contribute to nonalcoholic fatty liver disease in mice. mSystems 2021; 6(1): e00985–20

[45] Wang H, Wang L, Li Y, Luo S, Ye J, Lu Z, Li X, Lu H. The HIF-2α/PPARα pathway is essential for liraglutide-alleviated, lipid-induced hepatic steatosis. Biomed Pharmacother 2021; 140: 111778

[46] Everard A, Lazarevic V, Gaïa N, Johansson M, Ståhlman M, Backhed F, Delzenne NM, Schrenzel J, François P, Cani PD. Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. ISME J 2014; 8(10): 2116–2130

[47] Mehrpouya-Bahrami P, Chitrala KN, Ganewatta MS, Tang C, Murphy EA, Enos RT, Velazquez KT, McCellan J, Nagarkatti M, Nagarkatti P. Blockade of CB1 cannabinoid receptor alters gut microbiota and attenuates inflammation and diet-induced obesity. Sci Rep 2017; 7(1): 15645

[48] Natividad JM, Lamas B, Pham HP, Michel ML, Rainteau D, Bridonneau C, da Costa G, van Hylckama Vlieg J, Sovran B, Chamignon C, Planchais J, Richard ML, Langella P, Veiga P, Sokol H. Bilophila wadsworthia aggravates high fat diet induced metabolic dysfunctions in mice. Nat Commun 2018; 9(1): 2802

[49] Hussain A, Yadav MK, Bose S, Wang JH, Lim D, Song YK, Ko SG, Kim H. Daesiho-Tang is an effective herbal formulation in attenuation of obesity in mice through alteration of gene expression and modulation of intestinal microbiota. PLoS One 2016; 11(11): e0165483

[50] Lee J, Jang JY, Kwon MS, Lim SK, Kim N, Lee J, Park HK, Yun M, Shin MY, Jo HE, Oh YJ, Ryu BH, Ko MY, Joo W, Choi HJ. Mixture of two Lactobacillus plantarum strains modulates the gut microbiota structure and regulatory T cell response in diet-induced obese mice. Mol Nutr Food Res 2018; 62(24): e1800329

[51] Wang L, Wu Y, Zhuang L, Chen X, Min H, Song S, Liang Q, Li AD, Gao Q. Puerarin prevents high-fat diet-induced obesity by enriching Akkermansia muciniphila in the gut microbiota of mice. PLoS One 2019; 14(6): e0218490

[52] Schneeberger M, Everard A, Gómez-Valadés AG, Matamoros S, Ramírez S, Delzenne NM, Gomis R, Claret M, Cani PD. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep 2015; 5(1): 16643

[53] Ye JZ, Li YT, Wu WR, Shi D, Fang DQ, Yang LY, Bian XY, Wu JJ, Wang Q, Jiang XW, Peng CG, Ye WC, Xia PC, Li LJ. Dynamic alterations in the gut microbiota and metabolome during the development of methionine-choline-deficient diet-induced nonalcoholic steatohepatitis. World J Gastroenterol 2018; 24(23): 2468–2481

[54] Brahe LK, Le Chatelier E, Prifti E, Pons N, Kennedy S, Hansen T, Pedersen O, Astrup A, Ehrlich SD, Larsen LH. Specific gut microbiota features and metabolic markers in postmenopausal women with obesity. Nutr Diabetes 2015; 5(6): e159

[55] Zhang X, Shen D, Fang Z, Jie Z, Qiu X, Zhang C, Chen Y, Ji L. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One 2013; 8(8): e71108

[56] Yassour M, Lim MY, Yun HS, Tickle TL, Sung J, Song YM, Lee K, Franzosa EA, Morgan XC, Gevers D, Lander ES, Xavier RJ, Birren BW, Ko G, Huttenhower C. Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes. Genome Med 2016; 8(1): 17

[57] Li J, Zhao F, Wang Y, Chen J, Tao J, Tian G, Wu S, Liu W, Cui Q, Geng B, Zhang W, Weldon R, Auguste K, Yang L, Liu X, Chen L, Yang X, Zhu B, Cai J. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome 2017; 5(1): 14

[58] Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, Kayser BD, Levenez F, Chilloux J, Hoyles L, MICRO-Obes Consortium; Dumas ME, Rizkalla SW, Doré J, Cani PD, Clément K. 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

[59] Hoyles L, Fernández-Real JM, Federici M, Serino M, Abbott J, Charpentier J, Heymes C, Luque JL, Anthony E, Barton RH, Chilloux J, Myridakis A, Martinez-Gili L, Moreno-Navarrete JM, Benhamed F, Azalbert V, Blasco-Baque V, Puig J, Xifra G, Ricart W, Tomlinson C, Woodbridge M, Cardellini M, Davato F, Cardolini I, Porzio O, Gentileschi P, Lopez F, Foufelle F, Butcher SA, Holmes E, Nicholson JK, Postic C, Burcelin R, Dumas ME. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med 2018; 24(7): 1070–1080

[60] Nistal E, Sáenz de Miera LE, Ballesteros Pomar M, Sánchez-Campos S, García-Mediavilla MV, Álvarez-Cuenllas B, Linares P, Olcoz JL, Arias-Loste MT, García-Lobo JM, Crespo J, González-Gallego J, Jorquera Plaza F. An altered fecal microbiota profile in patients with non-alcoholic fatty liver disease (NAFLD) associated with obesity. Rev Esp Enferm Dig 2019; 111(4): 275–282

[61] Tsai HJ, Tsai YC, Hung WW, Hung WC, Chang CC, Dai CY. Gut microbiota and non-alcoholic fatty liver disease severity in type 2 diabetes patients. J Pers Med 2021; 11(3): 238

[62] Lee NY, Shin MJ, Youn GS, Yoon SJ, Choi YR, Kim HS, Gupta H, Han SH, Kim BK, Lee DY, Park TS, Sung H, Kim BY, Suk KT. Lactobacillus attenuates progression of nonalcoholic fatty liver disease by lowering cholesterol and steatosis. Clin Mol Hepatol 2021; 27(1): 110–124

[63] Özkul C, Yalınay M, Karakan T, Yılmaz G. Determination of certain bacterial groups in gut microbiota and endotoxin levels in patients with nonalcoholic steatohepatitis. Turk J Gastroenterol 2017; 28(5): 361–369

[64] Del Chierico F, Nobili V, Vernocchi P, Russo A, De Stefanis C, Gnani D, Furlanello C, Zandonà A, Paci P, Capuani G, Dallapiccola B, Miccheli A, Alisi A, Putignani L. Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach. Hepatology 2017; 65(2): 451–464

[65] Pan X, Kaminga AC, Liu A, Wen SW, Luo M, Luo J. Gut microbiota, glucose, lipid, and water-electrolyte metabolism in children with nonalcoholic fatty liver disease. Front Cell Infect Microbiol 2021; 11: 683743

[66] Schwimmer JB, Johnson JS, Angeles JE, Behling C, Belt PH, Borecki I, Bross C, Durelle J, Goyal NP, Hamilton G, Holtz ML, Lavine JE, Mitreva M, Newton KP, Pan A, Simpson PM, Sirlin CB, Sodergren E, Tyagi R, Yates KP, Weinstock GM, Salzman NH. Microbiome signatures associated with steatohepatitis and moderate to severe fibrosis in children with nonalcoholic fatty liver disease. Gastroenterology 2019; 157(4): 1109–1122

[67] Ponziani FR, Bhoori S, Castelli C, Putignani L, Rivoltini L, Del Chierico F, Sanguinetti M, Morelli D, Paroni Sterbini F, Petito V, Reddel S, Calvani R, Camisaschi C, Picca A, Tuccitto A, Gasbarrini A, Pompili M, Mazzaferro V. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology 2019; 69(1): 107–120

[68] Liu R, Hong J, Xu X, Feng Q, Zhang D, Gu Y, Shi J, Zhao S, Liu W, Wang X, Xia H, Liu Z, Cui B, Liang P, Xi L, Jin J, Ying X, Wang X, Zhao X, Li W, Jia H, Lan Z, Li F, Wang R, Sun Y, Yang M, Shen Y, Jie Z, Li J, Chen X, Zhong H, Xie H, Zhang Y, Gu W, Deng X, Shen B, Xu X, Yang H, Xu G, Bi Y, Lai S, Wang J, Qi L, Madsen L, Wang J, Ning G, Kristiansen K, Wang W. Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. Nat Med 2017; 23(7): 859–868

[69] Lihn AS, Pedersen SB, Richelsen B. Adiponectin: action, regulation and association to insulin sensitivity. Obes Rev 2005; 6(1): 13–21

[70] Kordy K, Li F, Lee DJ, Kinchen JM, Jew MH, La Rocque ME, Zabih S, Saavedra M, Woodward C, Cunningham NJ, Tobin NH, Aldrovandi GM. Metabolomic predictors of non-alcoholic steatohepatitis and advanced fibrosis in children. Front Microbiol 2021; 12: 713234

[71] Negi CK, Babica P, Bajard L, Bienertova-Vasku J, Tarantino G. Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease. Metabolism 2022; 126: 154925

[72] Moreira GV, Azevedo FF, Ribeiro LM, Santos A, Guadagnini D, Gama P, Liberti EA, Saad M, Carvalho C. Liraglutide modulates gut microbiota and reduces NAFLD in obese mice. J Nutr Biochem 2018; 62: 143–154

[73] Du J, Zhang P, Luo J, Shen L, Zhang S, Gu H, He J, Wang L, Zhao X, Gan M, Yang L, Niu L, Zhao Y, Tang Q, Tang G, Jiang D, Jiang Y, Li M, Jiang A, Jin L, Ma J, Shuai S, Bai L, Wang J, Zeng B, Wu D, Li X, Zhu L. Dietary betaine prevents obesity through gut microbiota-drived microRNA-378a family. Gut Microbes 2021; 13(1): 1862612

[74] Zhang L, Wang Y, Wu F, Wang X, Feng Y, Wang Y. MDG, an Ophiopogon japonicus polysaccharide, inhibits non-alcoholic fatty liver disease by regulating the abundance of Akkermansia muciniphila. Int J Biol Macromol 2022; 196: 23–34

[75] Wang X, Liu D, Wang Z, Cai C, Jiang H, Yu G. Porphyran-derived oligosaccharides alleviate NAFLD and related cecal microbiota dysbiosis in mice. FASEB J 2021; 35(6): e21458

[76] Han R, Qiu H, Zhong J, Zheng N, Li B, Hong Y, Ma J, Wu G, Chen L, Sheng L, Li H. Si Miao Formula attenuates non-alcoholic fatty liver disease by modulating hepatic lipid metabolism and gut microbiota. Phytomedicine 2021; 85: 153544

[77] Ghosh S, Yang X, Wang L, Zhang C, Zhao L. Active phase prebiotic feeding alters gut microbiota, induces weight-independent alleviation of hepatic steatosis and serum cholesterol in high-fat diet-fed mice. Comput Struct Biotechnol J 2021; 19: 448–458

[78] Hua X, Sun DY, Zhang WJ, Fu JT, Tong J, Sun SJ, Zeng FY, Ouyang SX, Zhang GY, Wang SN, Li DJ, Miao CY, Wang P. P7C3-A20 alleviates fatty liver by shaping gut microbiota and inducing FGF21/FGF1, via the AMP-activated protein kinase/CREB regulated transcription coactivator 2 pathway. Br J Pharmacol 2021; 178(10): 2111–2130

[79] Bao T, He F, Zhang X, Zhu L, Wang Z, Lu H, Wang T, Li Y, Yang S, Wang H. Inulin exerts beneficial effects on non-alcoholic fatty liver disease via modulating gut microbiome and suppressing the lipopolysaccharide-Toll-like receptor 4-Mψ-nuclear factor-κB-Nod-like receptor protein 3 pathway via gut-liver axis in mice. Front Pharmacol 2020; 11: 558525

[80] Cui H, Li Y, Wang Y, Jin L, Yang L, Wang L, Liao J, Wang H, Peng Y, Zhang Z, Wang H, Liu X. Da-Chai-Hu Decoction ameliorates high fat diet-induced nonalcoholic fatty liver disease through remodeling the gut microbiota and modulating the serum metabolism. Front Pharmacol 2020; 11: 584090

[81] Nakano H, Wu S, Sakao K, Hara T, He J, Garcia S, Shetty K, Hou DX. Bilberry anthocyanins ameliorate NAFLD by improving dyslipidemia and gut microbiome dysbiosis. Nutrients 2020; 12(11): 3252

[82] Mu J, Tan F, Zhou X, Zhao X. Lactobacillus fermentum CQPC06 in naturally fermented pickles prevents non-alcoholic fatty liver disease by stabilizing the gut-liver axis in mice. Food Funct 2020; 11(10): 8707–8723

[83] Xie K, He X, Chen K, Sakao K, Hou DX. Ameliorative effects and molecular mechanisms of vine tea on western diet-induced NAFLD. Food Funct 2020; 11(7): 5976–5991

[84] Nishiyama M, Ohtake N, Kaneko A, Tsuchiya N, Imamura S, Iizuka S, Ishizawa S, Nishi A, Yamamoto M, Taketomi A, Kono T. Increase of Akkermansia muciniphila by a diet containing Japanese traditional medicine bofutsushosan in a mouse model of non-alcoholic fatty liver disease. Nutrients 2020; 12(3): 839

[85] Li X, Wang Y, Xing Y, Xing R, Liu Y, Xu Y. Changes of gut microbiota during silybin-mediated treatment of high-fat diet-induced non-alcoholic fatty liver disease in mice. Hepatol Res 2020; 50(1): 5–14

[86] Porras D, Nistal E, Martínez-Flórez S, Olcoz JL, Jover R, Jorquera F, González-Gallego J, García-Mediavilla MV, Sánchez-Campos S. Functional interactions between gut microbiota transplantation, quercetin, and high-fat diet determine non-alcoholic fatty liver disease development in germ-free mice. Mol Nutr Food Res 2019; 63(8): e1800930

[87] Régnier M, Rastelli M, Morissette A, Suriano F, Le Roy T, Pilon G, Delzenne NM, Marette A, Van Hul M, Cani PD. Rhubarb supplementation prevents diet-induced obesity and diabetes in association with increased Akkermansia muciniphila in mice. Nutrients 2020; 12(10): 2932

[88] Juárez-Fernández M, Porras D, Petrov P, Román-Sagüillo S, García-Mediavilla MV, Soluyanova P, Martínez-Flórez S, González-Gallego J, Nistal E, Jover R, Sánchez-Campos S. The synbiotic combination of Akkermansia muciniphila and quercetin ameliorates early obesity and NAFLD through gut microbiota reshaping and bile acid metabolism modulation. Antioxidants (Basel) 2021; 10(12): 2001

[89] Guevara-Cruz M, Flores-López AG, Aguilar-López M, Sánchez-Tapia M, Medina-Vera I, Díaz D, Tovar AR, Torres N. Improvement of lipoprotein profile and metabolic endotoxemia by a lifestyle intervention that modifies the gut microbiota in subjects with metabolic syndrome. J Am Heart Assoc 2019; 8(17): e012401

[90] Palleja A, Kashani A, Allin KH, Nielsen T, Zhang C, Li Y, Brach T, Liang S, Feng Q, Jørgensen NB, Bojsen-Møller KN, Dirksen C, Burgdorf KS, Holst JJ, Madsbad S, Wang J, Pedersen O, Hansen T, Arumugam M. Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota. Genome Med 2016; 8(1): 67

[91] Depommier C, Van Hul M, Everard A, Delzenne NM, De Vos WM, Cani PD. Pasteurized Akkermansia muciniphila increases whole-body energy expenditure and fecal energy excretion in diet-induced obese mice. Gut Microbes 2020; 11(5): 1231–1245

[92] Higarza SG, Arboleya S, Arias JL, Gueimonde M, Arias N. Akkermansia muciniphila and environmental enrichment reverse cognitive impairment associated with high-fat high-cholesterol consumption in rats. Gut Microbes 2021; 13(1): 1880240

[93] Yang Y, Zhong Z, Wang B, Xia X, Yao W, Huang L, Wang Y, Ding W. Early-life high-fat diet-induced obesity programs hippocampal development and cognitive functions via regulation of gut commensal Akkermansia muciniphila. Neuropsychopharmacology 2019; 44(12): 2054–2064

[94] Eslam M, Sanyal AJ, George; Jnternational Consensus Panel. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020; 158(7): 1999–2014.e1

[95] Lomonaco R, Ortiz-Lopez C, Orsak B, Webb A, Hardies J, Darland C, Finch J, Gastaldelli A, Harrison S, Tio F, Cusi K. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology 2012; 55(5): 1389–1397

[96] Khan RS, Newsome PN. NAFLD in 2017: novel insights into mechanisms of disease progression. Nat Rev Gastroenterol Hepatol 2018; 15(2): 71–72

[97] Ashrafian F, Shahriary A, Behrouzi A, Moradi HR, Keshavarz Azizi Raftar S, Lari A, Hadifar S, Yaghoubfar R, Ahmadi Badi S, Khatami S, Vaziri F, Siadat SD. Akkermansia muciniphila-derived extracellular vesicles as a mucosal delivery vector for amelioration of obesity in mice. Front Microbiol 2019; 10: 2155

[98] Shen J, Tong X, Sud N, Khound R, Song Y, Maldonado-Gomez MX, Walter J, Su Q. Low-density lipoprotein receptor signaling mediates the triglyceride-lowering action of Akkermansia muciniphila in genetic-induced hyperlipidemia. Arterioscler Thromb Vasc Biol 2016; 36(7): 1448–1456

[99] Zhao S, Liu W, Wang J, Shi J, Sun Y, Wang W, Ning G, Liu R, Hong J. Akkermansia muciniphila improves metabolic profiles by reducing inflammation in chow diet-fed mice. J Mol Endocrinol 2017; 58(1): 1–14

[100] Gao X, Xie Q, Kong P, Liu L, Sun S, Xiong B, Huang B, Yan L, Sheng J, Xiang H. Polyphenol- and caffeine-rich postfermented Pu-erh Tea improves diet-induced metabolic syndrome by remodeling intestinal homeostasis in mice. Infect Immun 2018; 86(1): e00601–17

[101] Sheng L, Jena PK, Liu HX, Hu Y, Nagar N, Bronner DN, Settles ML, Bäumler AJ, Wan YY. Obesity treatment by epigallocatechin-3-gallate-regulated bile acid signaling and its enriched Akkermansia muciniphila. FASEB J 2018; 32(12): fj201800370R

[102] Katiraei S, de Vries MR, Costain AH, Thiem K, Hoving LR, van Diepen JA, Smits HH, Bouter KE, Rensen PCN, Quax PHA, Nieuwdorp M, Netea MG, de Vos WM, Cani PD, Belzer C, van Dijk KW, Berbée JFP, van Harmelen V. Akkermansia muciniphila exerts lipid-lowering and immunomodulatory effects without affecting neointima formation in hyperlipidemic APOE*3-Leiden. CETP mice. Mol Nutr Food Res 2020; 64(15): e1900732

[103] Lee H, Lee Y, Kim J, An J, Lee S, Kong H, Song Y, Lee CK, Kim K. Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice. Gut Microbes 2018; 9(2): 155–165

[104] Tilg H. The role of cytokines in non-alcoholic fatty liver disease. Dig Dis 2010; 28(1): 179–185

[105] Carpino G, Del Ben M, Pastori D, Carnevale R, Baratta F, Overi D, Francis H, Cardinale V, Onori P, Safarikia S, Cammisotto V, Alvaro D, Svegliati-Baroni G, Angelico F, Gaudio E, Violi F. Increased liver localization of lipopolysaccharides in human and experimental NAFLD. Hepatology 2020; 72(2): 470–485

[106] Sharifnia T, Antoun J, Verriere TG, Suarez G, Wattacheril J, Wilson KT, Peek RM Jr, Abumrad NN, Flynn CR. Hepatic TLR4 signaling in obese NAFLD. Am J Physiol Gastrointest Liver Physiol 2015; 309(4): G270–G278

[107] Michaudel C, Sokol H. The gut microbiota at the service of immunometabolism. Cell Metab 2020; 32(4): 514–523

[108] 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

[109] 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. Hepatology 2013; 57(2): 577–589

[110] 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 Gastroenterol Hepatol 2019; 16(3): 145–159

[111] Yang X, Liu H, Ye T, Duan C, Lv P, Wu X, Liu J, Jiang K, Lu H, Yang H, Xia D, Peng E, Chen Z, Tang K, Ye Z. AhR activation attenuates calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and promoting M2 macrophage polarization. Theranostics 2020; 10(26): 12011–12025

[112] Huang Y, He J, Liang H, Hu K, Jiang S, Yang L, Mei S, Zhu X, Yu J, Kijlstra A, Yang P, Hou S. Aryl Hydrocarbon receptor regulates apoptosis and inflammation in a murine model of experimental autoimmune uveitis. Front Immunol 2018; 9: 1713

[113] Cui Z, Feng Y, Li D, Li T, Gao P, Xu T. Activation of aryl hydrocarbon receptor (AhR) in mesenchymal stem cells modulates macrophage polarization in asthma. J Immunotoxicol 2020; 17(1): 21–30

[114] Bock KW. Aryl hydrocarbon receptor (AHR)-mediated inflammation and resolution: non-genomic and genomic signaling. Biochem Pharmacol 2020; 182: 114220

[115] Lin YH, Luck H, Khan S, Schneeberger PHH, Tsai S, Clemente-Casares X, Lei H, Leu YL, Chan YT, Chen HY, Yang SH, Coburn B, Winer S, Winer DA. Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity. Int J Obes 2019; 43(12): 2407–2421

[116] Wada T, Sunaga H, Miyata K, Shirasaki H, Uchiyama Y, Shimba S. Aryl hydrocarbon receptor plays protective roles against high fat diet (HFD)-induced hepatic steatosis and the subsequent lipotoxicity via direct transcriptional regulation of Socs3 gene expression. J Biol Chem 2016; 291(13): 7004–7016

[117] Yang F, DeLuca JAA, Menon R, Garcia-Vilarato E, Callaway E, Landrock KK, Lee K, Safe SH, Chapkin RS, Allred CD, Jayaraman A. Effect of diet and intestinal AhR expression on fecal microbiome and metabolomic profiles. Microb Cell Fact 2020; 19(1): 219

[118] Raftar SKA, Ashrafian F, Abdollahiyan S, Yadegar A, Moradi HR, Masoumi M, Vaziri F, Moshiri A, Siadat SD, Zali MR. The anti-inflammatory effects of Akkermansia muciniphila and its derivates in HFD/CCl₄-induced murine model of liver injury. Sci Rep 2022; 12(1): 2453

RIGHTS & PERMISSIONS

Higher Education Press