Butyrate limits inflammatory macrophage niche in NASH

Area of Science:

• Immunology
• Gastroenterology
• Metabolic Diseases

Background:

• Non-alcoholic steatohepatitis (NASH) is characterized by immune cell infiltration and gut-liver axis dysregulation.
• Gut microbiota metabolites, including short-chain fatty acids (SCFA), influence NASH pathogenesis.
• The precise mechanisms of sodium butyrate's (NaBu) beneficial effects in NASH are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms behind sodium butyrate's (NaBu) anti-inflammatory effects in non-alcoholic steatohepatitis (NASH).
• To investigate NaBu's impact on immune cell function and recruitment in NASH models.

Main Methods:

• Utilized lipopolysaccharide (LPS)-stimulated macrophages and a diet-induced murine NASH model.
• Assessed macrophage polarization, recruitment, apoptosis, and gene expression.
• Investigated histone deacetylase (HDAC) inhibition and NF-κB pathway modulation by NaBu.

Main Results:

• NaBu demonstrated significant anti-inflammatory effects in M1-polarized macrophages and a NASH mouse model.
• NaBu reduced inflammatory macrophage recruitment and induced apoptosis of proinflammatory liver macrophages.
• Mechanistically, NaBu inhibited HDAC, enhanced p65 acetylation, and shifted macrophage transcriptomic signatures towards a prohealing M2-like phenotype.

Conclusions:

• Sodium butyrate (NaBu) effectively mitigates metaflammation in NASH by reprogramming macrophages.
• NaBu's actions include suppressing pro-inflammatory responses, promoting a prohealing phenotype, and inducing apoptosis of harmful immune cells.
• NaBu shows promise as a potential therapeutic and preventive agent for non-alcoholic steatohepatitis (NASH).