An intermittent energy restriction diet ameliorates comorbid MASLD and T2DM through the Klebsiella pneumoniae/LPS/Hepatic HADHA-K353 acetylation axis

The intermittent energy restriction (iER) represents an effective dietary strategy for improving metabolic diseases including metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM), yet the underlying mechanisms remain elusive. In this study, we integrated human clinical data, mouse models, and in vitro experiments to investigate the role of iER in modulating the gut-liver axis in comorbid MASLD and T2DM. We demonstrate that an iER diet improves hyperglycemia, hepatic steatosis and decreases the abundance of gut pathogen Klebsiella pneumoniae, which is strongly associated with reductions in blood endotoxin, lipopolysaccharide (LPS) levels, suggesting a potential role of K. pneumoniae-derived LPS in mediating effects of the iER on hepatometabolic improvements. We confirm that K. pneumoniae-derived LPS exacerbates lipid accumulation and inflammation using an in vitro model. Mechanistically, we reveal a core target of protein lysine acetylation (Kac), hydroxyacyl-CoA dehydrogenase -subunit (HADHA) Lys353 in the liver of db/db mice through a multi-omics analysis. The iER decreases HADHA-K353 acetylation and enhances its enzyme activity. A Kac-mimicking mutation (K353R) increases its enzyme activity and stability, blocks its binding to the inflammasome adaptor ASC, and alleviates lipid accumulation and inflammation in K. pneumoniae-derived LPS induced in vitro model. This study provides novel insights into the potential benefits of the iER in comorbid MASLD and T2DM.