Short‐Chain Fatty Acids Linking the Gut–Liver Axis to Steatotic Liver Disease and Fibrogenesis

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Abstract
The human gut microbiota (GM) functions as a vital immunometabolic organ that influences liver physiology through the gut–liver axis. Disruption of this carefully regulated network is increasingly acknowledged as a fundamental driver of steatotic liver disease (SLD) and liver fibrosis, conditions characterized by convergent inflammatory, metabolic, and immune‐mediated mechanisms. Microbial dysbiosis, combined with compromised intestinal barrier integrity, facilitates endotoxin translocation and elevates the portal delivery of microbial products and metabolites to the liver, thereby perpetuating chronic hepatic inflammation, hepatocellular injury, and progressive fibrogenic signaling. Among microbial‐derived metabolites, short‐chain fatty acids (SCFAs), produced via dietary fiber fermentation, serve as essential molecular links between diet, microbiota, and host responses. SCFAs possess pleiotropic effects that transcend intestinal homeostasis, extending to the regulation of hepatic metabolism and immune function. They influence these processes through mechanisms such as G‐protein–coupled receptor (GPR) activation, epigenetic modulation via histone deacetylase (HDAC) inhibition, and intracellular signaling cascades. In doing so, SCFAs modulate inflammatory pathways, including nuclear factor kappa B (NF‐κB) and inflammasome activation, while shaping innate and adaptive immune responses. Within the hepatic environment, these metabolites impact Kupffer cell (KC) activation, cytokine production, and hepatic stellate cell (HSC) activation, directly affecting the progression of steatosis and fibrogenesis. It is noteworthy that SCFA signaling is metabolite‐specific and context‐dependent. For example, butyrate consistently demonstrates barrier‐protective, anti‐inflammatory, and anti‐fibrotic properties, whereas acetate and propionate exhibit dual roles that depend on concentration, cellular targets, and disease stage. Emerging evidence further underscores extensive crosstalk between SCFAs and key regulatory pathways, including transforming growth factor‐beta (TGF‐β) and AMP‐activated protein kinase (AMPK) signaling, which coordinate responses to metabolic stress, inflammatory resolution, and extracellular matrix (ECM) remodeling. This review consolidates current advances in understanding the microbiota–SCFA–immune axis in SLD and hepatic fibrosis, highlighting how microbial metabolites coordinate immunometabolic signaling at the gut–liver interface. Elucidating this integrated network offers a robust conceptual framework for developing targeted, postbiotic‐ and pathway‐based therapeutic strategies aimed at restoring hepatic homeostasis and mitigating disease progression.

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