Synbiotics and antioxidants synergistically attenuate disease progression in metabolic dysfunction-associated steatotic liver disease

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is linked to gut dysbiosis, highlighting gut microbiome modulation as a promising therapeutic strategy. This study investigated the synergistic effects of synbiotics and antioxidants in MASLD. METHODS: We evaluated the effects of synbiotics, antioxidants, and their combination (SLD07) on metabolic and histopathological parameters and energy balance (Promethion system) in high-fat diet-fed mice. Plasma metabolome and faecal microbiome were analysed. In a 3-month pilot study of patients with MASLD (n = 27), we examined the safety and efficacy of SLD07 (20 billion CFU/day), with microbiome alterations assessed by metagenomic sequencing. RESULTS: In mice, SLD07 significantly attenuated metabolic and hepatic parameters, including body weight gain, white adipose tissue, serum triglycerides, low-density lipoprotein, liver histology (p < 0.05), and increased the respiratory exchange ratio (p < 0.001). Synbiotics enhanced glucose tolerance and insulin sensitivity (p < 0.05), while antioxidants primarily reduced adipose tissue (p < 0.05). Liver tissue MDA levels were reduced only in the combination group, whereas GSSG levels were reduced in the combination and antioxidants alone groups (p < 0.05). Liver transcriptomics revealed that all treatments reversed HFD-upregulated inflammation and oxidative pathways, with the combination showing the broadest effect. Gut microbiota was mainly modulated by synbiotics, while systemic metabolome changes were driven by antioxidants. In the clinical pilot study, treatment reduced liver fat and stiffness (p < 0.01), increased Bifidobacterium, and upregulated the L-glutamine pathway, with no serious adverse events. CONCLUSION: This integrated translational investigation demonstrates that the synbiotic-antioxidant combination alleviates MASLD through dual modulation of gut microbiota and systemic oxidative stress.