Probiotics Mixture, Prohep: a Potential Adjuvant for Low-Dose Sorafenib in Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatocellular Carcinoma Suppression Through Modulating Gut Microbiota.

Abstract

Targeting gut microbiota is an innovative approach to mitigate the development of metabolic dysfunction-associated steatotic liver disease-associated hepatocellular carcinoma (MASLD-HCC). This study aims to investigate the effects of Prohep, a probiotic mixture, both as a prophylactic measure and as an adjuvant therapy for low-dose sorafenib. A MASLD-HCC mice model was established by diethylnitrosamine (DEN) injection with feeding of a high-fat high-cholesterol (HFHC) diet. Gut microbiome profiles were later identified through shotgun sequencing. Our findings demonstrated that Prohep supplementation effectively suppressed MASLD-HCC development in mice. This protective effect was attributed to the modulation of gut microbiota and the increased production of short-chain fatty acids (SCFAs), propionate, and valerate. Prohep also activated AMPK, which decreased lipogenesis, reduced lipid uptake, and enhanced antioxidant enzyme expressions. Additionally, the cancer proliferation pathway PI3K/mTOR was inhibited in response to Prohep treatment. As an adjuvant therapy, Prohep improved the efficacy of low-dose sorafenib, as indicated by reduced tumor counts, alleviated inflammation, and increased hepatic superoxide dismutase (SOD) expression. The combination led to enhanced butyrate production, contributing to the overall therapeutic effects, thanks to the gut microbiota modulatory effects of Prohep. These results underscore Prohep's anti-tumorigenic properties and its potential to enhance the therapeutic outcomes of low-dose sorafenib in MASLD-HCC treatment. The study highlights the importance of gut microbiota modulation for developing effective neoadjuvant therapies and long-term management strategies for MASLD-HCC.