Shenqi funeng xingnao prescription regulated the TNF/NOD‒like receptor signaling pathway and brain-gut axis...

Central fatigue is a phenomenon in which changes in the function of the central nervous system lead to decreased athletic ability and increased fatigue symptoms. Shenqi Funeng Xingnao Prescription (SQFNXNP) is a traditional Chinese medicine prescription applied to alleviate exercise-induced fatigue; however, the molecular mechanism underlying its effects on central fatigue remain elusive.

This study explored the therapeutic effects and potential molecular mechanisms of SQFNXNP on central fatigue.

A chronic fatigue model was constructed to evaluate the therapeutic effects of SQFNXNP at alleviating central fatigue, including pathological changes in the hippocampus and intestine, as well as abnormal levels of neurotransmitters and inflammation. Transcriptomic analysis revealed core gene targets, which were further validated using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Furthermore, metagenomics was applied to explore changes in gut microbial composition and associated signaling pathways. Further validation of key proteins was conducted using western blotting (WB). Correlation analysis was further applied to identify differentially abundant metabolites related to the core targets. Compounds with prototype structures in the brain tissue after SQFNXNP administration were identified by ultra-high performance liquid chromatography-mass spectrometry analysis. A virtual screening procedure was used to screen for potential ingredients of SQFNXNP that could alleviate central fatigue.

SQFNXNP alleviated exercise-induced histopathological damage and mitochondrial injury in the hippocampi of mice, decreased cell apoptosis and necrosis, increased cell proliferation, and restored abnormal levels of monoamine neurotransmitters. Moreover, SQFNXNP treatment decreased inflammatory levels in the body, alleviated histopathological damage to the intestine, reduced cell apoptosis in the intestine, increased the expression of key intestinal barrier proteins, restored the goblet cell density and mucus layer integrity in the intestine, and regulated the imbalance in the gut microbiota and central fatigue-related signaling pathways. RT-qPCR and WB further revealed that SQFNXNP regulated the TNF and NOD-like receptor (NLR) signaling pathways by targeting MMP9, PTGS2 (COX-2), MAPK14, BCL2, TLR4, TNF-α, IL1B, P-AKT1, NIKBIA, and IL6 proteins. The virtual screening procedure revealed that the potential components of SQFNXNP for alleviating central fatigue were oleanolic acid and ginsenoside re.

SQFNXNP regulated the TNF/NLR signaling pathway and brain-gut axis dysfunction caused by exercise-induced fatigue, thus providing a traditional Chinese medicine strategy for treating central fatigue in the clinic.