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image of Gut Microecosystem and Metabolic Dysfunction-Associated Steatotic Liver Disease: Exploring the Crosstalk and Advancing Therapeutic Strategies

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global health concern. In recent years, the gut microbiota, often referred to as the body's “second genome,” has been recognized as playing a crucial role in the pathogenesis of MASLD.

PubMed was searched for articles published in the last decade using keywords like “MASLD,” “NAFLD,” “gut microbiota,” “FXR,” and “Trace elements.” The progress of the latest NAFLD clinical trial was also reviewed from the Chinese Clinical Trial Registry, organized by clinical phase.

In the development of MASLD, the gut microbiota not only participates in regulating host gene expression but also exerts a core influence on immune function and affects the liver's reparative capabilities. Furthermore, the metabolic products of the gut microbiota are involved in the occurrence and development of liver diseases through the gut-liver axis. A diet high in fat can trigger metabolic inflammation, changes in gut microbiota, and abnormalities in metabolic products, all of which may initiate inflammatory responses. The emerging strategies for treating MASLD are surprising. Clinical trial information for chemical drugs was obtained from the Chinese platform for registration and disclosure of drug clinical trials, and it was found that in the current drug development, some drugs have advanced to Phase III clinical trials.

The diversity of gut bacteria among individuals and the impact of microbial composition beyond bacteria should not be overlooked. Whether drug therapy combined with dietary patterns is more effective than monotherapy remains to be seen.

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2025-10-28
2026-01-31
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References

  1. Bauer K.C. Littlejohn P.T. Ayala V. Creus-Cuadros A. Finlay B.B. Nonalcoholic fatty liver disease and the gut-liver axis: Exploring an undernutrition perspective. Gastroenterology 2022 162 7 1858 1875.e2 10.1053/j.gastro.2022.01.058 35248539
    [Google Scholar]
  2. Guo X. Yin X. Liu Z. Wang J. Non-alcoholic fatty liver disease (NAFLD) pathogenesis and natural products for prevention and treatment. Int. J. Mol. Sci. 2022 23 24 15489 10.3390/ijms232415489 36555127
    [Google Scholar]
  3. Juanola O. Martínez-López S. Francés R. Gómez-Hurtado I. Non-alcoholic fatty liver disease: Metabolic, genetic, epigenetic and environmental risk factors. Int. J. Environ. Res. Public Health 2021 18 10 5227 10.3390/ijerph18105227 34069012
    [Google Scholar]
  4. Shaheen M. Pan D. Schrode K.M. Kermah D. Puri V. Zarrinpar A. Elisha D. Najjar S.M. Friedman T.C. Reassessment of the hispanic disparity: Hepatic steatosis is more prevalent in mexican americans than other hispanics. Hepatol. Commun. 2021 5 12 2068 2079 10.1002/hep4.1775 34558824
    [Google Scholar]
  5. Yuan S. Chen J. Li X. Fan R. Arsenault B. Gill D. Giovannucci E.L. Zheng J. Larsson S.C. Lifestyle and metabolic factors for nonalcoholic fatty liver disease: Mendelian randomization study. Eur. J. Epidemiol. 2022 37 7 723 733 10.1007/s10654‑022‑00868‑3 35488966
    [Google Scholar]
  6. Yuan H. Shyy J.Y.J. Martins-Green M. Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1. J. Hepatol. 2009 51 3 535 547 10.1016/j.jhep.2009.03.026 19556020
    [Google Scholar]
  7. Ferro D. Baratta F. Pastori D. Cocomello N. Colantoni A. Angelico F. Del Ben M. New insights into the pathogenesis of non-alcoholic fatty liver disease: gut-derived lipopolysaccharides and oxidative stress. Nutrients 2020 12 9 2762 10.3390/nu12092762 32927776
    [Google Scholar]
  8. Younossi Z. Tacke F. Arrese M. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2019 69 6 2672 2682 10.1002/hep.30251 30179269
    [Google Scholar]
  9. Marušić M. Paić M. Knobloch M. NAFLD, insulin resistance, and diabetes mellitus type 2. Can. J. Gastroenterol. Hepatol. 2021 2021 6613827 10.1155/2021/6613827 33681089
    [Google Scholar]
  10. Nomura K. Yamanouchi T. The role of fructose-enriched diets in mechanisms of nonalcoholic fatty liver disease. J. Nutr. Biochem. 2012 23 3 203 208 10.1016/j.jnutbio.2011.09.006 22129639
    [Google Scholar]
  11. Badmus O.O. Hillhouse S.A. Anderson C.D. Hinds T.D. Stec D.E. Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways. Clin. Sci. (Lond.) 2022 136 18 1347 1366 10.1042/CS20220572 36148775
    [Google Scholar]
  12. Ameer F. Scandiuzzi L. Hasnain S. Kalbacher H. Zaidi N. De novo lipogenesis in health and disease. Metabolism 2014 63 7 895 902 10.1016/j.metabol.2014.04.003 24814684
    [Google Scholar]
  13. Lian C.Y. Zhai Z.Z. Li Z.F. Wang L. High fat diet-triggered non-alcoholic fatty liver disease: A review of proposed mechanisms. Chem. Biol. Interact. 2020 330 109199 10.1016/j.cbi.2020.109199 32805210
    [Google Scholar]
  14. Nakamura A. Terauchi Y. Lessons from mouse models of high-fat diet-induced NAFLD. Int. J. Mol. Sci. 2013 14 11 21240 21257 10.3390/ijms141121240 24284392
    [Google Scholar]
  15. Nakamura A. Tajima K. Zolzaya K. Sato K. Inoue R. Yoneda M. Fujita K. Nozaki Y. Kubota K.C. Haga H. Kubota N. Nagashima Y. Nakajima A. Maeda S. Kadowaki T. Terauchi Y. Protection from non-alcoholic steatohepatitis and liver tumourigenesis in high fat-fed insulin receptor substrate-1-knockout mice despite insulin resistance. Diabetologia 2012 55 12 3382 3391 10.1007/s00125‑012‑2703‑1 22955994
    [Google Scholar]
  16. Degli Esposti D. Hamelin J. Bosselut N. Saffroy R. Sebagh M. Pommier A. Martel C. Lemoine A. Mitochondrial roles and cytoprotection in chronic liver injury. Biochem. Res. Int. 2012 2012 1 16 10.1155/2012/387626 22745910
    [Google Scholar]
  17. Williams S.L. Mash D.C. Züchner S. Moraes C.T. Somatic mtDNA mutation spectra in the aging human putamen. PLoS Genet. 2013 9 12 e1003990 10.1371/journal.pgen.1003990 24339796
    [Google Scholar]
  18. Kamfar S. Danaei B. Rahimi S. Zeinali V. Novel blood and tissue-based mitochondrial D-loop mutations detected in an Iranian NAFLD patient cohort. Mitochondrion 2024 77 101888 10.1016/j.mito.2024.101888 38697590
    [Google Scholar]
  19. Garrett W.S. Gordon J.I. Glimcher L.H. Homeostasis and inflammation in the intestine. Cell 2010 140 6 859 870 10.1016/j.cell.2010.01.023 20303876
    [Google Scholar]
  20. Linares D.M. Ross P. Stanton C. Beneficial Microbes: The pharmacy in the gut. Bioengineered 2016 7 1 11 20 10.1080/21655979.2015.1126015 26709457
    [Google Scholar]
  21. Liu J. Wu A. Cai J. She Z.G. Li H. The contribution of the gut-liver axis to the immune signaling pathway of NAFLD. Front. Immunol. 2022 13 968799 10.3389/fimmu.2022.968799 36119048
    [Google Scholar]
  22. Illiano P. Brambilla R. Parolini C. The mutual interplay of gut microbiota, diet and human disease. FEBS J. 2020 287 5 833 855 10.1111/febs.15217 31955527
    [Google Scholar]
  23. Larsson E. Tremaroli V. Lee Y.S. Koren O. Nookaew I. Fricker A. Nielsen J. Ley R.E. Bäckhed F. Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88. Gut 2012 61 8 1124 1131 10.1136/gutjnl‑2011‑301104 22115825
    [Google Scholar]
  24. Boccuto L. Tack J. Ianiro G. Abenavoli L. Scarpellini E. Human genes involved in the interaction between host and gut microbiome: regulation and pathogenic mechanisms. Genes (Basel) 2023 14 4 857 10.3390/genes14040857 37107615
    [Google Scholar]
  25. Wang X. Cai Z. Wang Q. Wu C. Sun Y. Wang Z. Xu X. Xue W. Cao Z. Zhang M. Zhu Y. Lin H. Zhang Y. Yuan M. Zhao Y. Gao A. Yu Y. Bi Y. Ning G. Wang W. Wang J. Liu R. Bacteroides methylmalonyl-CoA mutase produces propionate that promotes intestinal goblet cell differentiation and homeostasis. Cell Host Microbe 2024 32 1 63 78.e7 10.1016/j.chom.2023.11.005 38056459
    [Google Scholar]
  26. Chen L. Li S. Peng C. Gui Q. Li J. Xu Z. Yang Y. Lactobacillus rhamnosus GG promotes recovery of the colon barrier in septic mice through accelerating ISCs regeneration. Nutrients 2023 15 3 672 10.3390/nu15030672 36771378
    [Google Scholar]
  27. Wang J. Xu W. Wang R. Cheng R. Tang Z. Zhang M. The outer membrane protein Amuc_1100 of Akkermansia muciniphila promotes intestinal 5-HT biosynthesis and extracellular availability through TLR2 signalling. Food Funct. 2021 12 8 3597 3610 10.1039/D1FO00115A 33900345
    [Google Scholar]
  28. Takiishi T. Fenero C.I.M. Câmara N.O.S. Intestinal barrier and gut microbiota: Shaping our immune responses throughout life. Tissue Barriers 2017 5 4 e1373208 10.1080/21688370.2017.1373208 28956703
    [Google Scholar]
  29. Wang R. Tang R. Li B. Ma X. Schnabl B. Tilg H. Gut microbiome, liver immunology, and liver diseases. Cell. Mol. Immunol. 2021 18 1 4 17 10.1038/s41423‑020‑00592‑6 33318628
    [Google Scholar]
  30. Long C. Zhou X. Xia F. Zhou B. Intestinal barrier dysfunction and gut microbiota in non-alcoholic fatty liver disease: Assessment, mechanisms, and therapeutic considerations. Biology 2024 13 4 243 10.3390/biology13040243 38666855
    [Google Scholar]
  31. Cianci R. Franza L. Schinzari G. Rossi E. Ianiro G. Tortora G. Gasbarrini A. Gambassi G. Cammarota G. The interplay between immunity and microbiota at intestinal immunological niche: The case of cancer. Int. J. Mol. Sci. 2019 20 3 501 10.3390/ijms20030501 30682772
    [Google Scholar]
  32. Deng C.J. Lo T.H. Chan K.Y. Li X. Wu M.Y. Xiang Z. Wong C.M. Role of B lymphocytes in the pathogenesis of NAFLD: A 2022 update. Int. J. Mol. Sci. 2022 23 20 12376 10.3390/ijms232012376 36293233
    [Google Scholar]
  33. Round J.L. Lee S.M. Li J. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 2011 332 6032 974 977 10.1126/science.1206095 21512004
    [Google Scholar]
  34. Ludwig I.S. Broere F. Manurung S. Lambers T.T. van der Zee R. van Eden W. Lactobacillus rhamnosus GG-derived soluble mediators modulate adaptive immune cells. Front. Immunol. 2018 9 1546 10.3389/fimmu.2018.01546 30042761
    [Google Scholar]
  35. Yan F. Liu L. Dempsey P.J. Tsai Y.H. Raines E.W. Wilson C.L. Cao H. Cao Z. Liu L. Polk D.B. A Lactobacillus rhamnosus GG-derived soluble protein, p40, stimulates ligand release from intestinal epithelial cells to transactivate epidermal growth factor receptor. J. Biol. Chem. 2013 288 42 30742 30751 10.1074/jbc.M113.492397 24043629
    [Google Scholar]
  36. Sun Y.Y. Li X.F. Meng X.M. Huang C. Zhang L. Li J. Macrophage phenotype in liver injury and repair. Scand. J. Immunol. 2017 85 3 166 174 10.1111/sji.12468 27491503
    [Google Scholar]
  37. Carpi R.Z. Barbalho S.M. Sloan K.P. Laurindo L.F. Gonzaga H.F. Grippa P.C. Zutin T.L.M. Girio R.J.S. Repetti C.S.F. Detregiachi C.R.P. Bueno P.C.S. Mazuqueli Pereira E.S.B. Goulart R.A. Haber J.F.S. The effects of probiotics, prebiotics and synbiotics in non-alcoholic fat liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH): a systematic review. Int. J. Mol. Sci. 2022 23 15 8805 10.3390/ijms23158805 35955942
    [Google Scholar]
  38. Ahn S.B. Jun D.W. Kang B.K. Lim J.H. Lim S. Chung M.J. Randomized, double-blind, placebo-controlled study of a multispecies probiotic mixture in nonalcoholic fatty liver disease. Sci. Rep. 2019 9 1 5688 10.1038/s41598‑019‑42059‑3 30952918
    [Google Scholar]
  39. Reshef N. Gophna U. Reshef L. Konikoff F. Gabay G. Zornitzki T. Knobler H. Maor Y. Prebiotic treatment in patients with nonalcoholic fatty liver disease (NAFLD)-a randomized pilot trial. Nutrients 2024 16 11 1571 10.3390/nu16111571 38892505
    [Google Scholar]
  40. Zhang C. Fang T. Shi L. Wang Y. Deng X. Wang J. Zhou Y. The synbiotic combination of probiotics and inulin improves NAFLD though modulating gut microbiota. J. Nutr. Biochem. 2024 125 109546 10.1016/j.jnutbio.2023.109546 38072206
    [Google Scholar]
  41. Chen J. Vitetta L. Gut microbiota metabolites in NAFLD pathogenesis and therapeutic implications. Int. J. Mol. Sci. 2020 21 15 5214 10.3390/ijms21155214 32717871
    [Google Scholar]
  42. Chávez-Talavera O. Tailleux A. Lefebvre P. Staels B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 2017 152 7 1679 1694.e3 10.1053/j.gastro.2017.01.055 28214524
    [Google Scholar]
  43. Ridlon J.M. Harris S.C. Bhowmik S. Kang D.J. Hylemon P.B. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes 2016 7 1 22 39 10.1080/19490976.2015.1127483 26939849
    [Google Scholar]
  44. Watanabe M. Houten S.M. Mataki C. Christoffolete M.A. Kim B.W. Sato H. Messaddeq N. Harney J.W. Ezaki O. Kodama T. Schoonjans K. Bianco A.C. Auwerx J. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006 439 7075 484 489 10.1038/nature04330 16400329
    [Google Scholar]
  45. Cai J. Sun L. Gonzalez F.J. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe 2022 30 3 289 300 10.1016/j.chom.2022.02.004 35271802
    [Google Scholar]
  46. Xi Y. Li H. Role of farnesoid X receptor in hepatic steatosis in nonalcoholic fatty liver disease. Biomed. Pharmacother. 2020 121 109609 10.1016/j.biopha.2019.109609 31731192
    [Google Scholar]
  47. Ramos Pittol J.M. Milona A. Morris I. Willemsen E.C.L. van der Veen S.W. Kalkhoven E. van Mil S.W.C. FXR isoforms control different metabolic functions in liver cells via binding to specific DNA motifs. Gastroenterology 2020 159 5 1853 1865.e10 10.1053/j.gastro.2020.07.036 32712104
    [Google Scholar]
  48. Gapp B. Jourdain M. Bringer P. Kueng B. Weber D. Osmont A. Zurbruegg S. Knehr J. Falchetto R. Roma G. Dietrich W. Valdez R. Beckmann N. Nigsch F. Sanyal A.J. Ksiazek I. Farnesoid X receptor agonism, acetyl-coenzyme a carboxylase inhibition, and back translation of clinically observed endpoints of de novo lipogenesis in a murine NASH model. Hepatol. Commun. 2020 4 1 109 125 10.1002/hep4.1443 31909359
    [Google Scholar]
  49. Panzitt K. Zollner G. Marschall H.U. Wagner M. Recent advances on FXR-targeting therapeutics. Mol. Cell. Endocrinol. 2022 552 111678 10.1016/j.mce.2022.111678 35605722
    [Google Scholar]
  50. Nian F. Wu L. Xia Q. Tian P. Ding C. Lu X. Akkermansia muciniphila and Bifidobacterium bifidum prevent NAFLD by regulating FXR expression and gut microbiota. J. Clin. Transl. Hepatol. 2023 10.14218/JCTH.2022.00415 37408808
    [Google Scholar]
  51. Radun R. Trauner M. Role of FXR in bile acid and metabolic homeostasis in NASH: Pathogenetic concepts and therapeutic opportunities. Semin. Liver Dis. 2021 41 4 461 475 10.1055/s‑0041‑1731707 34289507
    [Google Scholar]
  52. Gillard J. Clerbaux L.A. Nachit M. Sempoux C. Staels B. Bindels L.B. Tailleux A. Leclercq I.A. Bile acids contribute to the development of non-alcoholic steatohepatitis in mice. JHEP Rep Innov. Hepatol. 2022 4 1 100387 10.1016/j.jhepr.2021.100387 34825156
    [Google Scholar]
  53. Luo M. Yan J. Wu L. Wu J. Chen Z. Jiang J. Chen Z. He B. Probiotics alleviated nonalcoholic fatty liver disease in high-fat diet-fed rats via gut microbiota/FXR/FGF15 signaling pathway. J. Immunol. Res. 2021 2021 1 10 10.1155/2021/2264737 34458376
    [Google Scholar]
  54. Schumacher J.D. Kong B. Pan Y. Zhan L. Sun R. Aa J. Rizzolo D. Richardson J.R. Chen A. Goedken M. Aleksunes L.M. Laskin D.L. Guo G.L. The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis. Toxicol. Appl. Pharmacol. 2017 330 1 8 10.1016/j.taap.2017.06.023 28673684
    [Google Scholar]
  55. Ji Y. Yin Y. Li Z. Zhang W. Gut microbiota-derived components and metabolites in the progression of non-alcoholic fatty liver disease (NAFLD). Nutrients 2019 11 8 1712 10.3390/nu11081712 31349604
    [Google Scholar]
  56. Coppola S. Avagliano C. Calignano A. Berni Canani R. The protective role of butyrate against obesity and obesity-related diseases. Molecules 2021 26 3 682 10.3390/molecules26030682 33525625
    [Google Scholar]
  57. Chen J. Vitetta L. Inflammation-modulating effect of butyrate in the prevention of colon cancer by dietary fiber. Clin. Colorectal Cancer 2018 17 3 e541 e544 10.1016/j.clcc.2018.05.001 29866614
    [Google Scholar]
  58. Vallianou N. Christodoulatos G.S. Karampela I. Tsilingiris D. Magkos F. Stratigou T. Kounatidis D. Dalamaga M. Understanding the role of the gut microbiome and microbial metabolites in non-alcoholic fatty liver disease: Current evidence and perspectives. Biomolecules 2021 12 1 56 10.3390/biom12010056 35053205
    [Google Scholar]
  59. Zhou D. Chen Y.W. Zhao Z.H. Yang R.X. Xin F.Z. Liu X.L. Pan Q. Zhou H. Fan J.G. Sodium butyrate reduces high-fat diet-induced non-alcoholic steatohepatitis through upregulation of hepatic GLP-1R expression. Exp. Mol. Med. 2018 50 12 1 12 10.1038/s12276‑018‑0183‑1 30510243
    [Google Scholar]
  60. Iannucci L.F. Sun J. Singh B.K. Zhou J. Kaddai V.A. Lanni A. Yen P.M. Sinha R.A. Short chain fatty acids induce UCP2-mediated autophagy in hepatic cells. Biochem. Biophys. Res. Commun. 2016 480 3 461 467 10.1016/j.bbrc.2016.10.072 27773823
    [Google Scholar]
  61. Amiri P. Arefhosseini S. Bakhshimoghaddam F. Jamshidi Gurvan H. Hosseini S.A. Mechanistic insights into the pleiotropic effects of butyrate as a potential therapeutic agent on NAFLD management: A systematic review. Front. Nutr. 2022 9 1037696 10.3389/fnut.2022.1037696 36532559
    [Google Scholar]
  62. Leung C. Rivera L. Furness J.B. Angus P.W. The role of the gut microbiota in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 2016 13 7 412 425 10.1038/nrgastro.2016.85 27273168
    [Google Scholar]
  63. Agus A. Planchais J. Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 2018 23 6 716 724 10.1016/j.chom.2018.05.003 29902437
    [Google Scholar]
  64. Ritze Y. Bárdos G. Hubert A. Böhle M. Bischoff S.C. Effect of tryptophan supplementation on diet-induced non-alcoholic fatty liver disease in mice. Br. J. Nutr. 2014 112 1 1 7 10.1017/S0007114514000440 24708895
    [Google Scholar]
  65. Yanko R. Levashov M. Chaka O.G. Nosar V. Khasabov S. Khasabova I. Tryptophan prevents the development of non-alcoholic fatty liver disease. Diabetes Metab. Syndr. Obes. 2023 16 4195 4204 10.2147/DMSO.S444278 38152280
    [Google Scholar]
  66. Shimada Y. Kinoshita M. Harada K. Mizutani M. Masahata K. Kayama H. Takeda K. Commensal bacteria-dependent indole production enhances epithelial barrier function in the colon. PLoS One 2013 8 11 e80604 10.1371/journal.pone.0080604 24278294
    [Google Scholar]
  67. Hu W. Yan G. Ding Q. Cai J. Zhang Z. Zhao Z. Lei H. Zhu Y.Z. Update of Indoles: Promising molecules for ameliorating metabolic diseases. Biomed. Pharmacother. 2022 150 112957 10.1016/j.biopha.2022.112957 35462330
    [Google Scholar]
  68. Kumar A. Sperandio V. Indole signaling at the host-microbiota-pathogen interface. MBio 2019 10 3 e01031 e19 10.1128/mBio.01031‑19 31164470
    [Google Scholar]
  69. Ma L. Li H. Hu J. Indole alleviates diet-induced hepatic steatosis and inflammation in a manner involving myeloid cell 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3. Hepatology 2020 72 4 1191 1203 10.1002/hep.31115 31953865
    [Google Scholar]
  70. Chai C. Chen L. Deng M.G. Liang Y. Liu F. Nie J.Q. Dietary choline intake and non-alcoholic fatty liver disease (NAFLD) in U.S. adults: National Health and Nutrition Examination Survey (NHANES) 2017–2018. Eur. J. Clin. Nutr. 2023 77 12 1160 1166 10.1038/s41430‑023‑01336‑1 37634048
    [Google Scholar]
  71. DiStefano J.K. The role of choline, soy isoflavones, and probiotics as adjuvant treatments in the prevention and management of NAFLD in postmenopausal women. Nutrients 2023 15 12 2670 10.3390/nu15122670 37375574
    [Google Scholar]
  72. Wiedeman A. Barr S. Green T. Xu Z. Innis S. Kitts D. Dietary choline intake: Current state of knowledge across the life cycle. Nutrients 2018 10 10 1513 10.3390/nu10101513 30332744
    [Google Scholar]
  73. Chen Y. Liu Y. Zhou R. Chen X. Wang C. Tan X. Wang L. Zheng R. Zhang H. Ling W. Zhu H. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci. Rep. 2016 6 1 19076 10.1038/srep19076 26743949
    [Google Scholar]
  74. Tan X. Liu Y. Long J. Chen S. Liao G. Wu S. Li C. Wang L. Ling W. Zhu H. Trimethylamine N-oxide aggravates liver steatosis through modulation of bile acid metabolism and inhibition of farnesoid X receptor signaling in nonalcoholic fatty liver disease. Mol. Nutr. Food Res. 2019 63 17 1900257 10.1002/mnfr.201900257 31095863
    [Google Scholar]
  75. Arias N. Arboleya S. Allison J. Kaliszewska A. Higarza S.G. Gueimonde M. Arias J.L. The relationship between choline bioavailability from diet, intestinal microbiota composition, and its modulation of human diseases. Nutrients 2020 12 8 2340 10.3390/nu12082340 32764281
    [Google Scholar]
  76. Zhu W. Gregory J.C. Org E. Buffa J.A. Gupta N. Wang Z. Li L. Fu X. Wu Y. Mehrabian M. Sartor R.B. McIntyre T.M. Silverstein R.L. Tang W.H.W. DiDonato J.A. Brown J.M. Lusis A.J. Hazen S.L. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 2016 165 1 111 124 10.1016/j.cell.2016.02.011 26972052
    [Google Scholar]
  77. Koeth R.A. Wang Z. Levison B.S. Buffa J.A. Org E. Sheehy B.T. Britt E.B. Fu X. Wu Y. Li L. Smith J.D. DiDonato J.A. Chen J. Li H. Wu G.D. Lewis J.D. Warrier M. Brown J.M. Krauss R.M. Tang W.H.W. Bushman F.D. Lusis A.J. Hazen S.L. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 2013 19 5 576 585 10.1038/nm.3145 23563705
    [Google Scholar]
  78. Zhang R. Xu Z. Xue G. Combined methylation and transcriptome analysis of liver injury of nonalcoholic fatty liver disease induced by high alcohol-producing Klebsiella pneumoniae. Microbiol. Spectr. 2023 11 3 e0532322 10.1128/spectrum.05323‑22 37022192
    [Google Scholar]
  79. Yuan J. Chen C. Cui J. Lu J. Yan C. Wei X. Zhao X. Li N. Li S. Xue G. Cheng W. Li B. Li H. Lin W. Tian C. Zhao J. Han J. An D. Zhang Q. Wei H. Zheng M. Ma X. Li W. Chen X. Zhang Z. Zeng H. Ying S. Wu J. Yang R. Liu D. Fatty liver disease caused by high-alcohol-producing klebsiella pneumoniae. Cell Metab. 2019 30 4 675 688.e7 10.1016/j.cmet.2019.08.018 31543403
    [Google Scholar]
  80. Dai X. Hou H. Zhang W. Liu T. Li Y. Wang S. Wang B. Cao H. Microbial metabolites: Critical regulators in NAFLD. Front. Microbiol. 2020 11 567654 10.3389/fmicb.2020.567654 33117316
    [Google Scholar]
  81. Chen X. Zhang Z. Li H. Zhao J. Wei X. Lin W. Zhao X. Jiang A. Yuan J. Endogenous ethanol produced by intestinal bacteria induces mitochondrial dysfunction in non‐alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 2020 35 11 2009 2019 10.1111/jgh.15027 32150306
    [Google Scholar]
  82. Mbaye B. Wasfy R.M. Alou M.T. Borentain P. Gerolami R. Dufour J.C. Million M. A catalog of ethanol-producing microbes in humans. Future Microbiol. 2024 19 8 697 714 10.2217/fmb‑2023‑0250 38700288
    [Google Scholar]
  83. Mbaye B. Borentain P. Magdy Wasfy R. Alou M.T. Armstrong N. Mottola G. Meddeb L. Ranque S. Gérolami R. Million M. Raoult D. Endogenous ethanol and triglyceride production by gut pichia kudriavzevii, candida albicans and candida glabrata yeasts in non-alcoholic steatohepatitis. Cells 2022 11 21 3390 10.3390/cells11213390 36359786
    [Google Scholar]
  84. Duan Y. Pan X. Luo J. Xiao X. Li J. Bestman P.L. Luo M. Association of inflammatory cytokines with non-alcoholic fatty liver disease. Front. Immunol. 2022 13 880298 10.3389/fimmu.2022.880298 35603224
    [Google Scholar]
  85. Santamarina A.B. Calder P.C. Estadella D. Pisani L.P. Anthocyanins ameliorate obesity-associated metainflammation: Preclinical and clinical evidence. Nutr. Res. 2023 114 50 70 10.1016/j.nutres.2023.04.004 37201432
    [Google Scholar]
  86. Hotamisligil G.S. Inflammation, metaflammation and immunometabolic disorders. Nature 2017 542 7640 177 185 10.1038/nature21363 28179656
    [Google Scholar]
  87. Donath M.Y. Shoelson S.E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 2011 11 2 98 107 10.1038/nri2925 21233852
    [Google Scholar]
  88. Liang H. Lum H. Alvarez A. A low dose lipid infusion is sufficient to induce insulin resistance and a pro-inflammatory response in human subjects. PLoS One 2018 13 4 e0195810 10.1371/journal.pone.0195810 29649324
    [Google Scholar]
  89. Kubes P. Mehal W.Z. Sterile inflammation in the liver. Gastroenterology 2012 143 5 1158 1172 10.1053/j.gastro.2012.09.008 22982943
    [Google Scholar]
  90. Ertunc M.E. Hotamisligil G.S. Lipid signaling and lipotoxicity in metaflammation: Indications for metabolic disease pathogenesis and treatment. J. Lipid Res. 2016 57 12 2099 2114 10.1194/jlr.R066514 27330055
    [Google Scholar]
  91. Ahima R.S. Lazar M.A. Adipokines and the peripheral and neural control of energy balance. Mol. Endocrinol. 2008 22 5 1023 1031 10.1210/me.2007‑0529 18202144
    [Google Scholar]
  92. Hotamisligil G.S. Foundations of immunometabolism and implications for metabolic health and disease. Immunity 2017 47 3 406 420 10.1016/j.immuni.2017.08.009 28930657
    [Google Scholar]
  93. du Plessis J. van Pelt J. Korf H. Mathieu C. van der Schueren B. Lannoo M. Oyen T. Topal B. Fetter G. Nayler S. van der Merwe T. Windmolders P. Van Gaal L. Verrijken A. Hubens G. Gericke M. Cassiman D. Francque S. Nevens F. van der Merwe S. Association of adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease. Gastroenterology 2015 149 3 635 648.e14 10.1053/j.gastro.2015.05.044 26028579
    [Google Scholar]
  94. Schoeler M. Caesar R. Dietary lipids, gut microbiota and lipid metabolism. Rev. Endocr. Metab. Disord. 2019 20 4 461 472 10.1007/s11154‑019‑09512‑0 31707624
    [Google Scholar]
  95. Pandey S. Kawai T. Akira S. Microbial sensing by Toll-like receptors and intracellular nucleic acid sensors. Cold Spring Harb. Perspect. Biol. 2015 7 1 a016246 10.1101/cshperspect.a016246 25301932
    [Google Scholar]
  96. Wang J. Zhu N. Su X. Gao Y. Yang R. Gut-microbiota-derived metabolites maintain gut and systemic immune homeostasis. Cells 2023 12 5 793 10.3390/cells12050793 36899929
    [Google Scholar]
  97. Yan Y. Yao D. Li X. Immunological mechanism and clinical application of PAMP adjuvants. Recent Patents Anticancer Drug Discov. 2021 16 1 30 43 10.2174/1574892816666210201114712 33563182
    [Google Scholar]
  98. García-Weber D. Arrieumerlou C. ADP-heptose: A bacterial PAMP detected by the host sensor ALPK1. Cell. Mol. Life Sci. 2021 78 1 17 29 10.1007/s00018‑020‑03577‑w 32591860
    [Google Scholar]
  99. Zhou P. She Y. Dong N. Li P. He H. Borio A. Wu Q. Lu S. Ding X. Cao Y. Xu Y. Gao W. Dong M. Ding J. Wang D.C. Zamyatina A. Shao F. Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose. Nature 2018 561 7721 122 126 10.1038/s41586‑018‑0433‑3 30111836
    [Google Scholar]
  100. Mohr A.E. Crawford M. Jasbi P. Fessler S. Sweazea K.L. Lipopolysaccharide and the gut microbiota: Considering structural variation. FEBS Lett. 2022 596 7 849 875 10.1002/1873‑3468.14328 35262962
    [Google Scholar]
  101. Di Vincenzo F. Del Gaudio A. Petito V. Lopetuso L.R. Scaldaferri F. Gut microbiota, intestinal permeability, and systemic inflammation: A narrative review. Intern. Emerg. Med. 2024 19 2 275 293 10.1007/s11739‑023‑03374‑w 37505311
    [Google Scholar]
  102. Correia J.C. Massart J. de Boer J.F. Porsmyr-Palmertz M. Martínez-Redondo V. Agudelo L.Z. Sinha I. Meierhofer D. Ribeiro V. Björnholm M. Sauer S. Dahlman-Wright K. Zierath J.R. Groen A.K. Ruas J.L. Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism. Mol. Metab. 2015 4 12 891 902 10.1016/j.molmet.2015.09.005 26909306
    [Google Scholar]
  103. Kremoser C. FXR agonists for NASH: How are they different and what difference do they make? J. Hepatol. 2021 75 1 12 15 10.1016/j.jhep.2021.03.020 33985820
    [Google Scholar]
  104. Wang K. Zhang Y. Wang G. Hao H. Wang H. FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid. Med. Res. Rev. 2024 44 2 568 586 10.1002/med.21991 37899676
    [Google Scholar]
  105. Yamashita Y. Gohda K. Iguchi Y. Fujimori K. Oda K. Masuda A. Une M. Teno N. Discovery of FXR/PPARγ dual partial agonist. Bioorg. Med. Chem. 2023 85 117238 10.1016/j.bmc.2023.117238 37028120
    [Google Scholar]
  106. EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol. 2016 64 6 1388 1402 10.1016/j.jhep.2015.11.004 27062661
    [Google Scholar]
  107. Asrih M. Jornayvaz F.R. Diets and nonalcoholic fatty liver disease: The good and the bad. Clin. Nutr. 2014 33 2 186 190 10.1016/j.clnu.2013.11.003 24262589
    [Google Scholar]
  108. Anania C. Perla F.M. Olivero F. Pacifico L. Chiesa C. Mediterranean diet and nonalcoholic fatty liver disease. World J. Gastroenterol. 2018 24 19 2083 2094 10.3748/wjg.v24.i19.2083 29785077
    [Google Scholar]
  109. Dayi T. Oniz A. Effects of the Mediterranean diet polyphenols on cancer development. J. Prev Med. Hyg 2022 63 2 E74 E80.(Suppl. 3) 36479482
    [Google Scholar]
  110. Laganà P. Anastasi G. Marano F. Piccione S. Singla R.K. Dubey A.K. Delia S. Coniglio M.A. Facciolà A. Di Pietro A. Haddad M.A. Al-Hiary M. Caruso G. Phenolic substances in foods: Health effects as anti-inflammatory and antimicrobial agents. J. AOAC Int. 2019 102 5 1378 1387 10.5740/jaoacint.19‑0131 31200787
    [Google Scholar]
  111. Rees K. Takeda A. Martin N. Mediterranean-style diet for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst. Rev. 2019 3 3 CD009825 10.1002/14651858.CD009825.pub3 30864165
    [Google Scholar]
  112. Laffond A. Rivera-Picón C. Rodríguez-Muñoz P.M. Juárez-Vela R. Ruiz de Viñaspre-Hernández R. Navas-Echazarreta N. Sánchez-González J.L. Mediterranean diet for primary and secondary prevention of cardiovascular disease and mortality: An updated systematic review. Nutrients 2023 15 15 3356 10.3390/nu15153356 37571293
    [Google Scholar]
  113. Pavlidou E. Papadopoulou S.K. Fasoulas A. Papaliagkas V. Alexatou O. Chatzidimitriou M. Mentzelou M. Giaginis C. Diabesity and dietary interventions: Evaluating the impact of Mediterranean diet and other types of diets on obesity and type 2 diabetes management. Nutrients 2023 16 1 34 10.3390/nu16010034 38201865
    [Google Scholar]
  114. Mentella M.C. Scaldaferri F. Ricci C. Gasbarrini A. Miggiano G.A.D. Cancer and mediterranean diet: A review. Nutrients 2019 11 9 2059 10.3390/nu11092059 31480794
    [Google Scholar]
  115. Śliwińska S. Jeziorek M. The role of nutrition in Alzheimer’s disease. Rocz. Panstw. Zakl. Hig. 2021 72 1 29 39 [PMID: 33882663
    [Google Scholar]
  116. Plaz Torres M.C. Aghemo A. Lleo A. Bodini G. Furnari M. Marabotto E. Miele L. Giannini E.G. Mediterranean diet and NAFLD: what we know and questions that still need to Be answered. Nutrients 2019 11 12 2971 10.3390/nu11122971 31817398
    [Google Scholar]
  117. Montemayor S. Mascaró C.M. Ugarriza L. Casares M. Llompart I. Abete I. Zulet M.Á. Martínez J.A. Tur J.A. Bouzas C. Adherence to mediterranean diet and NAFLD in patients with metabolic syndrome: The FLIPAN study. Nutrients 2022 14 15 3186 10.3390/nu14153186 35956364
    [Google Scholar]
  118. Haigh L. Kirk C. El Gendy K. Gallacher J. Errington L. Mathers J.C. Anstee Q.M. The effectiveness and acceptability of Mediterranean diet and calorie restriction in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis. Clin. Nutr. 2022 41 9 1913 1931 10.1016/j.clnu.2022.06.037 35947894
    [Google Scholar]
  119. Bailey R.L. West K.P. Black R.E. The epidemiology of global micronutrient deficiencies. Ann. Nutr. Metab. 2015 66 22 33 10.1159/000371618 26045325
    [Google Scholar]
  120. Das P. Babaei P. Nielsen J. Metagenomic analysis of microbe-mediated vitamin metabolism in the human gut microbiome. BMC Genomics 2019 20 1 208 10.1186/s12864‑019‑5591‑7 30866812
    [Google Scholar]
  121. Pickett-Blakely O. Young K. Carr R.M. Micronutrients in nonalcoholic fatty liver disease pathogenesis. Cell. Mol. Gastroenterol. Hepatol. 2018 6 4 451 462 10.1016/j.jcmgh.2018.07.004 30294653
    [Google Scholar]
  122. Skjærven K.H. Jakt L.M. Fernandes J.M.O. Dahl J.A. Adam A.C. Klughammer J. Bock C. Espe M. Parental micronutrient deficiency distorts liver DNA methylation and expression of lipid genes associated with a fatty-liver-like phenotype in offspring. Sci. Rep. 2018 8 1 3055 10.1038/s41598‑018‑21211‑5 29445184
    [Google Scholar]
  123. Du T. Xiang L. Zhang J. Yang C. Zhao W. Li J. Zhou Y. Ma L. Vitamin D improves hepatic steatosis in NAFLD via regulation of fatty acid uptake and β-oxidation. Front. Endocrinol. (Lausanne) 2023 14 1138078 10.3389/fendo.2023.1138078 37033263
    [Google Scholar]
  124. Sindhughosa D.A. Wibawa I.D.N. Mariadi I.K. Somayana G. Additional treatment of vitamin D for improvement of insulin resistance in non-alcoholic fatty liver disease patients: A systematic review and meta-analysis. Sci. Rep. 2022 12 1 7716 10.1038/s41598‑022‑11950‑x 35546181
    [Google Scholar]
  125. Pervez M.A. Khan D.A. Ijaz A. Khan S. Effects of delta-tocotrienol supplementation on liver enzymes, inflammation, oxidative stress and hepatic steatosis in patients with nonalcoholic fatty liver disease. Turk. J. Gastroenterol. 2018 29 2 170 176 10.5152/tjg.2018.17297 29749323
    [Google Scholar]
  126. Vadarlis A. Antza C. Bakaloudi D.R. Doundoulakis I. Kalopitas G. Samara M. Dardavessis T. Maris T. Chourdakis M. Systematic review with meta‐analysis: The effect of vitamin E supplementation in adult patients with non‐alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 2021 36 2 311 319 10.1111/jgh.15221 32810309
    [Google Scholar]
  127. Liu X-H. Chen H-K. Luo J. Potassium affects the association between dietary intake of vitamin C and NAFLD among adults in the United States. PLoS One 2024 19 4 e0295986 10.1371/journal.pone.0295986 38635545
    [Google Scholar]
  128. He Z. Li X. Yang H. Wu P. Wang S. Cao D. Guo X. Xu Z. Gao J. Zhang W. Luo X. Effects of oral vitamin C supplementation on liver health and associated parameters in patients with non-alcoholic fatty liver disease: A randomized clinical trial. Front. Nutr. 2021 8 745609 10.3389/fnut.2021.745609 34595203
    [Google Scholar]
  129. García-Montero C. Fraile-Martínez O. Gómez-Lahoz A.M. Pekarek L. Castellanos A.J. Noguerales-Fraguas F. Coca S. Guijarro L.G. García-Honduvilla N. Asúnsolo A. Sanchez-Trujillo L. Lahera G. Bujan J. Monserrat J. Álvarez-Mon M. Álvarez-Mon M.A. Ortega M.A. Nutritional components in western diet versus mediterranean diet at the gut microbiota–immune system interplay. Implications for health and disease. Nutrients 2021 13 2 699 10.3390/nu13020699 33671569
    [Google Scholar]
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