Exploring the Potential of Oral Butyrate Supplementation in Metabolic Dysfunction-Associated Steatotic Liver Disease: Subgroup Insights from an Interventional Study

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common cause of chronic liver disease and is closely associated with metabolic ab-normalities and cardiovascular risks. Butyrate, a short-chain fatty acid produced by gut microbiota, has the potential to enhance liver health by modulating inflammation and supporting gut barrier integrity. This study aimed to investigate and compare the effects of sodium butyrate and calcium butyrate in patients with MASLD. Methods: In this single-center, randomized clinical trial, 181 patients with MASLD were enrolled and assigned to receive either sodium butyrate (n=121) or calcium butyrate (n=60) supplementation at a daily dose of 1000 mg. The primary endpoint was the change in liver steatosis, measured using the Controlled Attenuation Parameter (CAP) via Fi-broScan®. Secondary endpoints included liver stiffness, biochemical parameters, se-rum and fecal calprotectin levels, stool short-chain fatty acid levels, and microbiome composition. A subgroup analysis compared responders (a ≥5% reduction in CAP) to non-responders. Results: There were no significant changes in CAP values for either group (ΔCAP: sodium butyrate, 0.84; calcium butyrate, –0.23; p=0.70). Sodium butyrate significantly reduced serum trimethylamine N-oxide, while calcium butyrate led to a decrease in fecal calprotectin levels. Responders demonstrated a lower body mass in-dex, higher levels of high-sensitivity C-reactive protein and HbA1c, and distinct mi-crobiome profiles, characterized by lower abundance of Subdoligranulum and higher abundance of Catenibacterium. Conclusions: Although butyrate supplementation did not significantly improve liver steatosis as measured by CAP, the differing effects on metabolic and inflammatory markers suggest that there may be potential benefits for specific subgroups of patients with MASLD. K