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.

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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