Metabolic dysfunction-associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver disease worldwide, and our understanding of its pathogenesis continues to evolve. MASLD progresses from steatosis to steatohepatitis, fibrosis, and cirrhosis, and this Review explores how the gut microbiome and their metabolites contribute to MASLD pathogenesis. We explore the complexity and importance of the intestinal barrier function and how disruptions of the intestinal barrier and dysbiosis work in concert to promote the onset and progression of MASLD. The Review focuses on specific bacterial, viral, and fungal communities that impact the trajectory of MASLD and how specific metabolites (including ethanol, bile acids, short chain fatty acids, and other metabolites) contribute to disease pathogenesis. Finally, we underscore how knowledge of the interaction between gut microbes and the intestinal barrier may be leveraged for MASLD microbial-based therapeutics. Here, we include a discussion of the therapeutic potential of prebiotics, probiotics, postbiotics, and microbial-derived metabolites.

Figure 1. Gut barrier dysfunction in MASLD.

The intestinal epithelial barrier provides the main line of defense against translocation of gut microbiota. The barrier includes epithelial cell microvilli, an outer and inner mucous layer, and tight junction proteins located between adjacent epithelial cells. The figure compares (A) a normal intestinal epithelial barrier with diverse gut microbiome to (B) an impaired intestinal epithelial barrier as observed in MASLD with subsequent translocation of bacterial products, metabolites, and viable bacteria.

Figure 2. Microbial products and metabolites influence fibrogenic responses in the liver.

PAMPs (such as LPS) and microbial metabolites (e.g., SCFAs, ethanol, bile acids) that translocate to circulation from the gut enter the liver via the portal vein. LPS stimulates a proinflammatory and ultimately fibrogenic cascade via Kupffer cells, which are liver-resident macrophages. Gut dysbiosis alters production of microbial metabolites, and these irregularities are associated with a variety of adverse effects in hepatocytes, including inflammatory processes that exacerbate fibrogenesis.

Figure 3. Changes in the gut microbiota associated with MASLD.

Patients with steatosis exhibit alterations in their gut bacterial, fungal, and viral microbiomes. As the disease progresses towards fibrosis and cirrhosis, further microbiota changes are observed.

Figure 4. Influence of gut microbial metabolites on MASLD.

A dysbiotic gut microbiota produces less beneficial metabolites such as the SCFA acetate, or tryptophan metabolites indole-3-propionic acid (IPA) and indole-3-acetic (IAA), which stabilize the gut barrier during health. On the other hand, ethanol as a fermentation byproduct of bacteria and fungi causes triglyceride accumulation and death of hepatocytes, resulting in inflammation and fibrosis. Patients with MASLD have an increased bacterial metabolism of primary to unconjugated secondary bile acids in the gut, which are hepatotoxic and cause disease progression and HCC. It might also result in increased bile acid synthesis by hepatocytes.