Can low butyrate and depletion of Akkermansia and Faecalibacterium promote metabolic-associated fatty liver disease?

The association between gut dysbiosis, intestinal permeability, and the development of metabolic-associated fatty liver disease (MASLD, formerly NAFLD) is well-established through the "gut-liver axis." In older adults, maintaining this axis is critical as age-related changes in microbiota composition can exacerbate metabolic and inflammatory risks.

Microbiota and barrier integrity

The depletion of specific commensal bacteria, notably Faecalibacterium prausnitzii and Akkermansia muciniphila, is a hallmark of reduced gut barrier function.

• Butyrate production: F. prausnitzii is a primary producer of butyrate, a short-chain fatty acid (SCFA) that serves as the essential energy source for colonocytes. A. muciniphila supports this by degrading mucin into oligosaccharides, which act as substrates for butyrate producers through cross-feeding.
• Tight junction regulation: Butyrate maintains barrier integrity by upregulating the expression of tight junction proteins, including claudin-1, occludin, and ZO-1. This occurs primarily via the activation of the AMPK signaling pathway and SP1 transcription factors.
• Permeability markers: Low levels of these bacteria correlate with higher levels of zonulin, a protein that modulates paracellular permeability, leading to "leaky gut."

Pathogenesis of MASLD via portal circulation

When the intestinal barrier is compromised, the portal vein—the direct circulatory link between the gut and the liver—becomes a conduit for pro-inflammatory triggers.

• Endotoxemia: A primary signal is lipopolysaccharide (LPS), a component of gram-negative bacterial cell walls. In patients with MASLD, serum LPS levels are significantly elevated and correlate directly with the severity of hepatic steatosis.
• Hepatic inflammation: Upon reaching the liver, LPS binds to Toll-like receptor 4 (TLR4) on Kupffer cells (resident macrophages). This activates the NF-κB signaling pathway, triggering the release of pro-inflammatory cytokines that drive the transition from simple steatosis to steatohepatitis (MASH) and subsequent fibrosis.

Bottom line

The depletion of A. muciniphila and F. prausnitzii reduces butyrate availability, compromising tight junctions and allowing the translocation of LPS into the portal circulation. This process triggers TLR4-mediated hepatic inflammation, serving as a primary driver for the development and progression of metabolic-associated fatty liver disease.