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Review
. 2025 Jan 6;14(1):56.
doi: 10.3390/antiox14010056.

Gut Microbiota at the Crossroad of Hepatic Oxidative Stress and MASLD

Fabrizio Termite  1 , Sebastiano Archilei  1 , Francesca D'Ambrosio  1 , Lucrezia Petrucci  1 , Nicholas Viceconti  1 , Roberta Iaccarino  1 , Antonio Liguori  1 , Antonio Gasbarrini  1 , Luca Miele  1
Affiliations
Review

Gut Microbiota at the Crossroad of Hepatic Oxidative Stress and MASLD

Fabrizio Termite et al. Antioxidants (Basel). .

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition marked by excessive lipid accumulation in hepatic tissue. This disorder can lead to a range of pathological outcomes, including metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Despite extensive research, the molecular mechanisms driving MASLD initiation and progression remain incompletely understood. Oxidative stress and lipid peroxidation are pivotal in the "multiple parallel hit model", contributing to hepatic cell death and tissue damage. Gut microbiota plays a substantial role in modulating hepatic oxidative stress through multiple pathways: impairing the intestinal barrier, which results in bacterial translocation and chronic hepatic inflammation; modifying bile acid structure, which impacts signaling cascades involved in lipidic metabolism; influencing hepatocytes' ferroptosis, a form of programmed cell death; regulating trimethylamine N-oxide (TMAO) metabolism; and activating platelet function, both recently identified as pathogenetic factors in MASH progression. Moreover, various exogenous factors impact gut microbiota and its involvement in MASLD-related oxidative stress, such as air pollution, physical activity, cigarette smoke, alcohol, and dietary patterns. This manuscript aims to provide a state-of-the-art overview focused on the intricate interplay between gut microbiota, lipid peroxidation, and MASLD pathogenesis, offering insights into potential strategies to prevent disease progression and its associated complications.

Keywords: farnesoid X receptor; ferroptosis; gut microbiota; intestinal permeability; lipid peroxidation; metabolic dysfunction-associated steatotic liver disease; oxidative stress; platelet activation; trimethylamine N-oxide.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Gut dysbiosis at the crossroad of hepatic oxidative stress and MASLD. BA: bile acids; CYP: cytocrome; FGF-19: fibroblast growth factor 19; FXR: farnesoid X receptor; G.I.: gastro-intestinal; GLP1: glucagon-like peptide-1; HSC: hepatic stellate cell; KC: kuppfer cell; LPS: lipopolysaccharide; MASLD: metabolic dysfunction-associated steatotic liver disease; MMP-2: matrix metalloproteinase 2; NO: nitric oxide; PDGF: platelet-derived growth factor; SCFAs: short-chain fatty acids; SREBP-1c: sterol regulatory element-binding protein 1c; TGF-β: transforming growth factor beta; TGR5: G-protein-coupled bile acid receptor; TIMP1: tissue inhibitor of metalloproteinase 1; TLR4: toll-like receptor 4; TMA: trimethylamine; TMAO: trimethylamine N-oxide.
Figure 2
Figure 2
Biochemical sources of hepatic fat accumulation.
Figure 3
Figure 3
The role of oxidative stress in MASLD. ADP: adenosine diphosphate; ATP: adenosine triphosphate; Cyt C: cytochrome C; DNA: deoxyribonucleic acid; ER: endoplasmic reticulum; FE: ferrum; HNE: 4-hydroxynonenal; MDA: malondialdehyde; MPT: mitochondrial permeability transition; PUFAs: polyunsaturated fatty acids; ROS: reactive oxygen species; TCA: tricarboxylic acid; UPR: unfolded protein response; VLDL: very-low-density lipoproteins.
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References

    1. Rinella M.E., Lazarus J.V., Ratziu V., Francque S.M., Sanyal A.J., Kanwal F., Romero D., Abdelmalek M.F., Anstee Q.M., Arab J.P., et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J. Hepatol. 2023;79:1542–1556. doi: 10.1016/j.jhep.2023.06.003. - DOI - PubMed
    1. Younossi Z.M., Anstee Q.M., 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. Gastroenterol. Hepatol. 2018;15:11–20. doi: 10.1038/nrgastro.2017.109. - DOI - PubMed
    1. Younossi Z.M., Paik J.M., Henry L., Yang J., Fernandes G., Stepanova M., Nader F. The Growing Economic and Clinical Burden of Nonalcoholic Steatohepatitis (NASH) in the United States. J. Clin. Exp. Hepatol. 2023;13:454–467. doi: 10.1016/j.jceh.2022.12.005. - DOI - PMC - PubMed
    1. Cotter T.G., Charlton M. Nonalcoholic Steatohepatitis After Liver Transplantation. Liver Transpl. 2020;26:141–159. doi: 10.1002/lt.25657. - DOI - PubMed
    1. Le P., Payne J.Y., Zhang L., Deshpande A., Rothberg M.B., Alkhouri N., Herman W., Hernandez A.V., Schleicher M., Ye W., et al. Disease State Transition Probabilities Across the Spectrum of NAFLD: A Systematic Review and Meta-Analysis of Paired Biopsy or Imaging Studies. Clin. Gastroenterol. Hepatol. 2023;21:1154–1168. doi: 10.1016/j.cgh.2022.07.033. - DOI - PMC - PubMed

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