Glutamate metabolism reprogramming is involved in the inhibitory effect of ellagic acid on rotavirus replication

Rotavirus (RV) is an important zoonotic pathogen that causes acute diarrhea in infants and young animals. There are several limitations in the prevention and control strategies currently, which result in an urgent need to develop innovative natural active substances against RV. This study aims to explore the RV infection preventive mechanism of ellagic acid (EA) and determine whether it exerts its effect by regulating the glutamine-glutamate metabolic axis.

RV-infected Balb/c mice and IEC-6 cell models were established to conduct mechanistic research by employing untargeted metabolomics, protein immunoblotting (WB), real-time fluorescence quantitative PCR, etc.

The non-targeted metabolomics results revealed that RV infection could disrupt the host's L-glutamate metabolism, and the serum L-glutamate level further decreased after ellagic acid (EA) intervention (P < 0.05). The WB results showed that EA could significantly inhibit the protein expression of glutaminease 1 (GLS1) in the jejunum tissue of mice (P < 0.001). The pathway rescue test using DON, a broad‑spectrum glutamine antagonist, showed that DON could reverse the inhibitory effect of ellagic acid on RV replication, suggesting that glutamine‑glutamate metabolism contributes to the antiviral action of ellagic acid (P < 0.05).

RV promotes glutamine catabolism by up-regulating GLS1 expression, thereby increasing the production of L-glutamate, which serves as a critical metabolic substrate supporting virus replication. Ellagic acid downregulates GLS1 expression and effectively disrupts metabolic processes, depriving the virus of essential nutrient inputs required for efficient propagation. Simultaneously, exerting anti-inflammatory and antioxidant activities to alleviate RV-induced intestinal injury. This study has elucidated new metabolic regulatory mechanistic insights of ellagic acid against RV, thereby providing experimental foundation and theoretical support for the application of natural bioactive compounds in RV prevention and control, as well as in the development of targeted antiviral therapeutics.