Sodium Acetate and Butyrate Synergistically Ameliorate Ethanol-Induced Hepatic Inflammation via NF-κB Modulation

Alcohol-associated liver diseases (ALDs) represent a significant global health burden, yet effective FDA-approved treatments remain elusive. Chronic ethanol exposure triggers severe hepatic inflammation and oxidative stress, leading to hepatocellular damage. Current therapeutic strategies often fall short in addressing the complex interplay of inflammatory pathways. Short-chain fatty acids (SCFAs) like acetate and butyrate have emerged as potential therapeutic agents due to their known anti-inflammatory and metabolic regulatory properties, offering a novel approach to mitigate ALD progression by targeting key signaling cascades.

Researchers investigated the hepatoprotective effects of sodium acetate (NaA) and sodium butyrate (NaB), alone and in combination, against ethanol-induced injury. In vitro, Buffalo Rat Liver-3A (BRL3A) cells were treated with 1.5 mM NaA, 5 mM NaB, or a combination of 0.1 mM NaA + 1 mM NaB. Cell viability, reactive oxygen species (ROS) levels, and nuclear morphology were assessed. In vivo, male Wistar rats were used in an ethanol-induced liver injury model, with NaA, NaB, and their combination administered. Hepatic injury was evaluated via serum biochemical markers, hematoxylin and eosin (H&E) staining, and immunohistochemistry (IHC). Gene expression of pro- and anti-inflammatory cytokines, CYP2E1, and antioxidative stress markers was profiled by RT-qPCR, while protein levels of TNF-α, MCP-1, IL-1β, IL-6, HO-1, and Nrf2 were quantified using ELISA.

The study demonstrated significant protective effects of SCFAs against ethanol-induced liver damage. In BRL3A cells, optimal viability was observed at 1.5 mM NaA, 5 mM NaB, and the 0.1 mM NaA + 1 mM NaB combination. Both in vitro and in vivo, treatment with NaA, NaB, and their combination consistently resulted in reduced ROS levels and preserved nuclear integrity. Notably, the combined treatment led to a marked reduction in the expression of pro-inflammatory cytokines such as TNF-α, MCP-1, IL-1β, and IL-6, alongside decreased neutrophil infiltration in hepatic tissue. Conversely, beneficial antioxidative stress markers like HO-1 and Nrf2 were upregulated. These findings were further supported by in silico analysis, which revealed conserved amino acid interactions and favorable affinities of NaA and NaB for TNF-α and MCP-1 compared to established inhibitors. The most significant finding highlights the synergistic action:

This study is the first demonstration to report the synergistic effects of NaA and NaB on the feedback loop of the nuclear factor kappa B (NF-κB) signaling pathway, suggesting a potent combined mechanism for ameliorating ethanol-induced inflammation.