Yupingfeng alleviates allergic rhinitis by modulating gut microbiota and succinate to inhibit mTOR/S6K signaling

Yupingfeng granules (YPF), derived from the classic traditional Chinese medicine prescription Yupingfeng powder, have been recommended in clinical practice guidelines for the management of allergic rhinitis (AR), and their clinical efficacy is widely recognized. However, the underlying pharmacological mechanisms have not been thoroughly investigated.

This study aimed to investigate whether YPF protects the nasal epithelial barrier and alleviates AR by modulating the gut microbiota and pathways related to its metabolites.

An OVA-induced AR mouse model was established and phenotypically evaluated. The dependence of YPF efficacy on gut microbiota was assessed by 16S rRNA sequencing, antibiotic depletion, and fecal microbiota transplantation. ¹H-NMR metabolomics was used to identify key metabolites, followed by exogenous supplementation for validation. Nasal mucosal transcriptome sequencing was performed to explore downstream pathways, and functional validation was conducted in OVA-induced HNEpCs through metabolite intervention, YPF co-treatment, mTOR knockdown, and MHY1485 treatment.

YPF dose-dependently reduced nasal rubbing and sneezing, attenuated IgE-mediated type 2 inflammation, and ameliorated nasal epithelial barrier injury in OVA-induced AR mice. YPF remodeled the gut microbiota and increased microbial diversity. Gut microbiota depletion attenuated the protective effects of YPF, whereas FMT from YPF donors reproduced them. Metabolomic analysis identified succinate as a key YPF-responsive metabolite, and exogenous succinate aggravated nasal epithelial barrier injury. Transcriptomic analysis suggested that succinate-induced nasal mucosal injury may involve mTOR signaling activation. In vitro, succinate aggravated OVA-induced barrier injury in HNEpCs, with disrupted Occludin distribution and enhanced mTOR/S6K phosphorylation, whereas YPF co-treatment reversed these changes. mTOR knockdown mimicked the protective effects of YPF, whereas MHY1485 attenuated them.

YPF alleviates OVA-induced AR by remodeling the gut microbiota, reducing succinate accumulation, and suppressing mTOR/S6K signaling to preserve nasal epithelial barrier integrity.