Alpha-aminobutyric acid (ABA) is a nonproteinogenic amino acid, a metabolite which could be generated from the metabolism of methionine, threonine, serine and glycine or as a gut-microbiome-derived metabolite. Changes in ABA levels have been embroiled in metabolic dysfunction-associated steatotic liver disease (MASLD) intervention studies, but their relation to MASLD pathogenesis remains unclear. Hence, this present study aimed to investigate the effect of oral ABA supplementation on the progression of a high fat/high cholesterol diet (HFD) induced MASLD mice model. ABA was found to remodel the gut microbiome composition and ameliorate MASLD parameters in HFD-fed mice. ABA mitigated HFD-induced gain in liver weight, hepatic steatosis, insulin resistance, serum and hepatic triglyceride levels, and liver cholesterol levels. Modulation of lipid metabolism was observed in the liver, in which expression of proteins and/or genes involved in de novo lipogenesis were suppressed, while those involved in fatty acid oxidation and autophagy were upregulated together with cellular antioxidant capacity, in addition to the enhancement of the AMPK/SIRT1 pathway. ABA reshaped the gut composition by enriching nine bacterial species, including Helicobacter hepaticus, Desulfovibrio sp. G11, Parabacteroides distasonis, and Bacteroides fragilis, while diminishing the abundance of 16 species, which included four Helicobacter species. KEGG pathway analysis of microbial functions found that ABA impeded secondary bile acid biosynthesis - which was reflected in the faecal BA composition analysis. Notably, ABA also inhibited ileal FXR-Fgf15 signaling, allowing for increased hepatic Cyp7a1 expression to eliminate cholesterol buildup in the liver. Overall, our findings indicate that ABA could be used as a promising therapeutic approach for the intervention of MASLD.
