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Probiotics Mixture, Prohep: a Potential Adjuvant for Low-Dose Sorafenib in Metabolic Dysfunction-Associated Steatotic
Fangfei Zhang1, Emily Kwun Kwan Lo1, Congjia Chen1
1School of Biological Sciences, University of Hong Kong, Pok Fu Lam, Hong Kong S. A. R., China.
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.
Insights
Prohep, a probiotic, prevents metabolic dysfunction-associated steatotic liver disease-associated hepatocellular carcinoma (MASLD-HCC) by modulating gut microbiota and producing beneficial SCFAs. It also enhances low-dose sorafenib efficacy for MASLD-HCC treatment.
Area of Science:
- Hepatology
- Gastroenterology
- Oncology
Background:
- Metabolic dysfunction-associated steatotic liver disease-associated hepatocellular carcinoma (MASLD-HCC) is a growing health concern.
- Targeting gut microbiota presents a novel therapeutic strategy for MASLD-HCC.
- Probiotic interventions show promise in modulating the gut microbiome and influencing liver health.
Purpose of the Study:
- To investigate the prophylactic and adjuvant therapeutic effects of Prohep, a probiotic mixture, in a murine model of MASLD-HCC.
- To explore the impact of Prohep on gut microbiota composition, short-chain fatty acid (SCFA) production, and key molecular pathways involved in liver cancer.
- To evaluate Prohep's potential to enhance the efficacy of low-dose sorafenib in treating MASLD-HCC.
Main Methods:
- Establishment of a MASLD-HCC mice model using diethylnitrosamine (DEN) and a high-fat high-cholesterol (HFHC) diet.
- Gut microbiome profiling via shotgun sequencing.
- Assessment of Prohep's effects on liver steatosis, tumor development, SCFA levels, AMPK activation, lipogenesis, antioxidant enzyme expression, and the PI3K/mTOR pathway.
Main Results:
- Prohep supplementation significantly suppressed MASLD-HCC development by modulating gut microbiota and increasing propionate and valerate production.
- Prohep activated AMPK, reduced lipogenesis, decreased lipid uptake, enhanced antioxidant enzymes, and inhibited the PI3K/mTOR pathway.
- As an adjuvant therapy, Prohep improved low-dose sorafenib efficacy, reducing tumor burden, inflammation, and increasing superoxide dismutase (SOD) expression, alongside enhanced butyrate production.
Conclusions:
- Prohep exhibits anti-tumorigenic properties against MASLD-HCC through gut microbiota modulation and SCFA production.
- Prohep enhances the therapeutic effects of low-dose sorafenib, offering a potential combination therapy for MASLD-HCC.
- Gut microbiota modulation is crucial for developing effective neoadjuvant therapies and long-term management strategies for MASLD-HCC.
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