Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex, heterogeneous condition influenced by genetic predisposition and environmental factors, including diet and alcohol consumption. The gut-liver axis, a crucial communication pathway between the gut microbiome and the liver, is increasingly recognized as a pivotal therapeutic target.
Gut microbiota dysbiosis contributes significantly to MASLD pathogenesis through the transfer of microbial metabolites and inflammatory signals to the liver. This process is modulated by diet, particularly diets high in processed foods and energy-dense components.
Increased portal vein permeability in MASLD facilitates the passage of microbial products and immune cells into the hepatic parenchyma, triggering hepatic inflammation. This inflammation, in turn, can alter gut microbiome composition and diversity, creating a vicious cycle where gut dysbiosis exacerbates liver inflammation and metabolic dysfunction, thereby accelerating MASLD progression.
The critical role of gut dysbiosis in MASLD pathogenesis suggests therapeutic strategies targeting the gut-liver axis to augment existing clinical interventions. Lifestyle modifications, including adherence to healthy dietary patterns and regular physical activity, have demonstrated efficacy in reducing MASLD risk [
1]. Recent research [
2] indicates that intermittent fasting (IF) can restructure the gut microbiome, alter microbial metabolites, and increase energy expenditure. IF, particularly the 5:2 regimen, shows promise in preventing MASLD development, improving established disease and fibrosis, and delaying progression to hepatocellular carcinoma [
3]. A randomized clinical trial demonstrated a 20.5% reduction in liver fat within 12 weeks using the 5:2 IF regimen, exhibiting superior patient compliance compared to continuous calorie restriction [
4].
Furthermore, restoring intestinal barrier function to prevent microbial translocation and reduce liver inflammation is a key therapeutic objective [
5]. Recent research highlights the IL-22 signaling pathway as a novel therapeutic target. IL-22, a cytokine produced by innate lymphoid cells and Th17/22 cells, maintains gut barrier integrity and is suppressed by high-fructose, high-fat diets. Preclinical studies demonstrate that IL-22 administration improves MASLD and related metabolic conditions by restoring intestinal homeostasis via STAT3 signaling in intestinal epithelial cells and modulating the gut-liver axis [
6].
Compared to healthy controls, patients with MASLD exhibit increased abundances of Pseudomonadota and Bacillota, alongside decreased abundances of Bacteroidota and Prevotellaceae. A previous study demonstrated that β -glucan attenuated liver inflammation and fibrosis in a murine model of MASLD by increasing the relative abundance of protective gut microbiota taxa and reducing the translocation of TLR4 ligands [
7].
Modulation of the gut microbiota with prebiotics, probiotics, and postbiotics represents a promising therapeutic strategy for MASLD. Prebiotics, non-digestible food ingredients, selectively promote the growth of beneficial gut bacteria, producing metabolites like short-chain fatty acids that improve gut health and modulate immune responses. Studies have demonstrated the anti-MASLD effects of B. bifidum (probiotic) and tryptophan (prebiotic) through amelioration of liver inflammation and steatosis,5 while combined probiotic therapies have shown promise in inhibiting MASLD progression.
Studies [
8,
9] demonstrate that fecal microbiota transplantation (FMT) can improve glucose metabolism and insulin sensitivity in individuals with type 2 diabetes mellitus (T2DM) by restoring gut microbiome balance and enhancing intestinal barrier function and metabolic capacity. Furthermore, FMT combined with dietary intervention has improved glycemic control and other markers of intestinal metabolism in T2DM [
10], suggesting potential applicability to MASLD. These findings underscore the importance of considering the gut microbiome in the prevention and treatment of MASLD.
In summary, the article examines the complex interplay between the gut microbiota, diet, and immune responses in the pathogenesis of MASLD, emphasizing the potential of a comprehensive therapeutic approach centered on the gut-liver axis. Modulation of cytokine signaling to restore intestinal homeostasis and influence the gut-liver axis offers a novel strategy for MASLD management, with the potential to address underlying disease mechanisms.
FOOTNOTES
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Authors’ contribution
Pingping Jin and Xinyi Lu wrote the manuscript and revised. Yu Chen and Daozhen Chen revised the manuscript.
-
Acknowledgements
This work was supported by Qinghai Province Key Research and Development and Transformation Plan Specific fund of Science and Technology Assistance to Qinghai (No. 2022-QY-216).
Figure was created with BioRender.com.
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Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
fecal microbiota transplantation
metabolic dysfunction-associated steatotic liver disease
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