Available online 9 May 2024, 101924

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Gut microbiota plays key functions in the human body, and its alteration is associated with several human disorders. Moreover, its manipulation is being investigated as a potential therapeutic strategy. In this narrative review we will dissect the involvement of the gut microbiota and of the gut–liver axis on metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, we will review the effects of lifestyle interventions commonly used for MASLD (i.e. Mediterranean diet and physical exercise) on gut microbiome, to understand if their beneficial effect can be microbially mediated. Finally, we will discuss the role and the available evidence of therapeutic microbiome modulators, including prebiotics, probiotics, symbiotics, and fecal microbiota transplantation (FMT), in the management of MASLD.

Section snippetsINTRODUCTION

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a burdensome condition that has become a relevant cause of chronic liver disease globally. It is characterized by at least 5% of intrahepatic fat and one or more cardiometabolic conditions in individuals who do not consume excessive amounts of alcohol (1).

The incidence of MASLD has grown along with the prevalence of overweight and obesity in both pediatric and adult populations, mainly in developed countries. The prevalence of

METHODS

We conducted a narrative review of literature to assess the role of gut microbiome (GM) in the pathogenesis of MASLD, including the involvement of the gut-liver axis, and the potential of GM modulation as a therapeutic tool. The most relevant published papers were identified including observational, prospective and retrospective studies, case-control studies, cohort studies, systematic review and meta-analysis, and clinical trials investigating GM modulation in patients with MASLD. The review

The pathogenic pathways of MASLD

The progression of simple steatosis involves a variety of factors that act synergistically in genetically predisposed individuals. As a result, a multiple-hit hypothesis has emerged, with metabolic dysfunction, GM, and dysregulated immunity serving as the three essential cornerstones of its understanding (9).

Obesity, typically associated with a western diet (WD), leads to the liver exporting excess energy as very-low-density lipoproteins (VLDL), resulting in increased intrahepatic free fatty

Lifestyle interventions: diet and physical exercise

Lifestyle interventions, including diet and physical exercise, are among the most important treatment options for MASLD. Indeed, in the absence of authorized pharmacological treatments for MASLD, the clinical recommendations from the European Association for the Study of Obesity (EASO), the European Association for the Study of the Liver (EASL), and the European Association for the Study of Diabetes (EASD), suggest lifestyle treatments, such as dietary modifications and regular exercise, as the

CONCLUSION

MASLD is a pathology that is often underdiagnosed but is becoming increasingly important globally. Lifestyle and genetic factors play a crucial role in the development of this disease. Therefore, GM modulation through the establishment of healthy lifestyle habits, such as the MD and regular physical exercise, can play a key role in the management of this condition. Additionally, treatments with prebiotics, probiotics, symbiotics, or even FMT deserve further research to assess their

Declaration of Competing Interest

AG reports personal fees for consultancy for Eisai S.r.l., 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, Sinergie S.r.l. Board MRGE and Sanofi S.p.A; personal fees for acting as a speaker for Takeda S.p.A, AbbVie and Sandoz S.p.A; and personal fees for acting on advisory boards for VSL3 and Eisai. GI has received personal fees for acting as speaker for Alfa Sigma, Biocodex, Illumina, Malesci, Sofar and Tillotts Pharma, and for acting as consultant/advisor for Biocodex, Malesci,

FUNDINGS

This work was supported by the Ricerca Finalizzata Giovani Ricercatori 2018 of the Italian Ministry of Health (project GR-2018-12365734) and by the Fondo Italiano per la Scienza 2021 of the Italian Ministry of University and Research (project FIS_00001711) to GI; by the BIOMIS grant of the Italian Ministry of Research to AG, GC, and GI; by the Ricerca Finalizzata 2016 of the Italian Ministry of Health (project RF-2016-02362055) to GC. The funders had no role in any decision to publish or

PRACTICE POINTS•

The increasing prevalence of poor lifestyle habits, overweight and obesity are closely related to Metabolic dysfunction-associated liver disease (MASLD)

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There is a lack of effective treatments to prevent progression of MASLD.

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Gut microbiota modulation may be a potential therapeutic tool for these patients.

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Unhealthy lifestyle may lead to gut barrier dysfunction and dysbiosis contributing overweight, obesity and to MASLD development.

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Mediterranean diet and physical exercise as part of a healthy

RESEARCH AGENDA•

Metabolic dysfunction-associated liver disease (MASLD) is a condition in which liver steatosis is associated with at least one of five cardiometabolic risk factors. MASLD is a growing health problem in recent years due to the increasing prevalence of poor lifestyle habits and therefore of overweight and obesity.

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The presence of MASLD is not only associated with risk of death from cardiovascular events, but also with risk of liver fibrosis and hepatocarcinoma. For this reason, the lack of

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Declaration of Competing Interest

AG reports personal fees for consultancy for Eisai S.r.l., 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, Sinergie S.r.l. Board MRGE and Sanofi S.p.A; personal fees for acting as a speaker for Takeda S.p.A, AbbVie and Sandoz S.p.A; and personal fees for acting on advisory boards for VSL3 and Eisai. GI has received personal fees for acting as speaker for Alfa Sigma, Biocodex, Illumina, Malesci, Sofar and Tillotts Pharma, and for acting as consultant/advisor for Biocodex, Malesci,

ACKNOWLEDGEMENTS

Sandra García-Mateo has received ODISEA grant by GETECCU “Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa”.

The staff of the Fondazione Policlinico Gemelli IRCCS thanks the Fondazione Roma for the invaluable support to their scientific research.

BIBLIOGRAPHY (89)CaesarR. et al.Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling

Cell Metab.

(2015 Oct 6)

SinghN. et al.Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis

Immunity

(2014 Jan 16)

Serra-MajemL. et al.Benefits of the Mediterranean diet: Epidemiological and molecular aspects

Molecular Aspects of Medicine

(2019)

Delgado-ListaJ. et al.Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial

The Lancet

(2022 May 14)

OrciL.A. et al.Exercise-based Interventions for Nonalcoholic Fatty Liver Disease: A Meta-analysis and Meta-regression

Clinical Gastroenterology and Hepatology

(2016)

SeethalerB. et al.Short-chain fatty acids are key mediators of the favorable effects of the Mediterranean diet on intestinal barrier integrity: data from the randomized controlled LIBRE trial

American Journal of Clinical Nutrition

(2022 Oct 1)

ReddyA. et al.Adherence to a Mediterranean diet may improve serum adiponectin in adults with nonalcoholic fatty liver disease: The MEDINA randomized controlled trial

Nutrition Research

(2023 Nov 1)

SharptonS.R. et al.Gut microbiome-targeted therapies in nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression

American Journal of Clinical Nutrition

(2019)

Rinella ME, Lazarus J V, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multi-society Delphi consensus statement...Martínez-DomínguezS.J. et al.Inflammatory Bowel Disease Is an Independent Risk Factor for Metabolic Dysfunction–Associated Steatotic Liver Disease in Lean Individuals

Inflamm Bowel Dis

(2023 Aug 22)

VernonG. et al.Systematic review: The epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults

Alimentary Pharmacology and Therapeutics

(2011)

AnsteeQ.M. et al.Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis

Nat Rev Gastroenterol Hepatol [Internet]

(2013)

NdumeleC.E. et al.Hepatic steatosis, obesity, and the metabolic syndrome are independently and additively associated with increased systemic inflammation

Arterioscler Thromb Vasc Biol

(2011 Aug)

SmithG.I. et al.Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease

Journal of Clinical Investigation

(2020 Mar 2)

NielsenS. et al.Splanchnic lipolysis in human obesity

Journal of Clinical Investigation

(2004 Jun 1)

Yazıcı D, Sezer H. Insulin resistance, obesity and lipotoxicity. In: Advances in Experimental Medicine and Biology....TanaseD.M. et al.The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD)

Journal of Diabetes Research

(2020)

ZmoraN. et al.You are what you eat: diet, health and the gut microbiota

Nature Reviews Gastroenterology and Hepatology

(2019)

ProctorL.M. et al.The Integrative Human Microbiome Project

Nature

(2019 May 30)

García-MonteroC. et al.Nutritional components in western diet versus mediterranean diet at the gut microbiota-immune system interplay. implications for health and disease

Nutrients

(2021 Feb 1)

LevyM. et al.Dysbiosis and the immune system

Nat Rev Immunol [Internet]

(2017)

Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. Vol....ZhangX. et al.Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites

Gut

(2021 Apr 1)

SprussA. et al.Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice

Hepatology

(2009)

CaniP.D. et al.Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice

Diabetes

(2008 Jun)

DevkotaS. et al.Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice

Nature

(2012)

ChambersE.S. et al.Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults

Gut

(2015 Nov 1)

FuscoW. et al.Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota

Nutrients

(2023)

HryckowianA.J. et al.Microbiota-Accessible carbohydrates suppress Clostridium difficile infection in a murine model

Nat Microbiol

(2018 Jun 1)

ZhuL. et al.Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH

Hepatology

(2013 Feb)

EverardA. et al.Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity

Proc Natl Acad Sci U S A.

(2013 May 28)

LoombaR. et al.Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease

Cell Metab

(2017)

AlferinkL.J.M. et al.Microbiomics, Metabolomics, Predicted Metagenomics, and Hepatic Steatosis in a Population-Based Study of 1,355 Adults

Hepatology

(2021 Mar 1)

SbernaA.L. et al.European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO) clinical practice recommendations for the management of non-alcoholic fatty liver disease: evaluation of their application in people with Type 2 diabetes

Diabetic Medicine

(2018 Mar 1)

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