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Review

Breaking the barriers: the role of gut homeostasis in Metabolic-Associated Steatotic Liver Disease (MASLD)

ORCID Icon, & ORCID Icon
Article: 2331460 | Received 10 Nov 2023, Accepted 13 Mar 2024, Published online: 21 Mar 2024
 

ABSTRACT

Obesity, insulin resistance (IR), and the gut microbiome intricately interplay in Metabolic-associated Steatotic Liver Disease (MASLD), previously known as Non-Alcoholic Fatty Liver Disease (NAFLD), a growing health concern. The complex progression of MASLD extends beyond the liver, driven by “gut-liver axis,” where diet, genetics, and gut-liver interactions influence disease development. The pathophysiology of MASLD involves excessive liver fat accumulation, hepatocyte dysfunction, inflammation, and fibrosis, with subsequent risk of hepatocellular carcinoma (HCC). The gut, a tripartite barrier, with mechanical, immune, and microbial components, engages in a constant communication with the liver. Recent evidence links dysbiosis and disrupted barriers to systemic inflammation and disease progression. Toll-like receptors (TLRs) mediate immunological crosstalk between the gut and liver, recognizing microbial structures and triggering immune responses. The “multiple hit model” of MASLD development involves factors like fat accumulation, insulin resistance, gut dysbiosis, and genetics/environmental elements disrupting the gut-liver axis, leading to impaired intestinal barrier function and increased gut permeability. Clinical management strategies encompass dietary interventions, physical exercise, pharmacotherapy targeting bile acid (BA) metabolism, and microbiome modulation approaches through prebiotics, probiotics, symbiotics, and fecal microbiota transplantation (FMT). This review underscores the complex interactions between diet, metabolism, microbiome, and their impact on MASLD pathophysiology and therapeutic prospects.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2331460

List of Abbreviations

ALD=

Alcohol-associated liver disease

AMPK=

AMP-activated protein kinase

BA=

Bile acid

BSEP=

Bile salt export pump

CA=

Cholic acid

CDCA=

Chenodeoxycholic acid

CLD=

Chronic liver disease

DAMP=

Damage-associated molecular pattern

ECM=

Extracellular matrix

FGF=

Fibroblast growth factor

FGFR=

Fibroblast growth factor receptor

FL=

Fatty liver

FMT=

Fecal microbiota transplant

FXR=

Farnesoid X receptor

GALT=

Gut associated lymphoid tissue

GF=

Germ free

GI=

Gastrointestinal

GVB=

Gut vascular barrier

HCC=

Hepatocellular carcinoma

H&E=

Hematoxylin and eosin staining

HFD=

High fat diet

HSC=

Hepatic stellate cell

ICAM −1=

Intercellular adhesion molecule-1

IEC=

Intestinal epithelial cell

IgA=

Immunoglobulin A\

ILF=

Isolated lymphoid follicles

IR=

Insulin resistance

KC=

Kupfer cell

LPL=

Lipoprotein lipase

LPS=

Lipopolysaccharide

MAMP=

Microorganism-associated molecular patterns

MASH=

Metabolic dysfunction associated steatohepatitis

MASLD=

Metabolic dysfunction associated steatotic liver disease

MetALD=

Metabolic associated liver disease and increased alcohol intake

MLN=

Mesenteric lymph nodes

MNL=

Mesenteric lymph nodes lymphocytes

MS=

Metabolic syndrome

MUC2=

Mucin-2

NAFLD=

Non-alcoholic fatty liver disease

NASH=

Non-alcoholic steatohepatitis

NF-κB=

Nuclear factor- κB

NLR=

NOD-like receptors

NTCP=

Na+/taurocholate cotransporting polypeptide

OST=

Organic solute transporter

PAMP=

Pathogen-associated molecular patterns

PGN=

Peptidoglycan

PPs=

Peyer Patches

PRR=

Pattern recognition receptors

PV-1=

Plasmalemma vesicle-associated protein-1

ROS=

Reactive oxygen species

SCFA=

Short chain fatty acid

sIgA=

Secretory Immunoglobulin A

TG=

Triglyceride

TJ=

Tight junction

TLR=

Toll-like receptor

VCAM=

Vascular cell adhesion molecule

VLDL=

Very low density lipoprotein

WAT=

White adipose tissue

WD=

Western diet

ZO=

Zona occludens.

Additional information

Funding

This work was supported by MICINN PID2020-117827RB-IOO/AEI/10.13039/501100011033, PID2020-117941RB-IOO//AEI/10.13039/501100011033 and EXOHEP2 (S2022/BMD-7409) from Comunidad de Madrid. This project has received funding from the European Horizon´s research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement No 101095679. The research group belongs to the validated Research Groups Ref. 970935 ¨Liver Pathophysiology¨. R.B.-U is supported by programa de Financiación de Universidad Complutense de Madrid - Banco Santander, CT63/19.