A novel triterpenoid from Alisma orientale alleviates allergic asthma through the gut microbiota-acetate-FFAR2...

Allergic asthma is characterized by immune dysregulation and airway inflammation, and increasing evidence implicates gut microbiota-derived metabolites in its pathogenesis. However, the microbial and metabolic mediators underlying the anti-asthmatic effects of natural products remain insufficiently defined. This study investigated the protective effects of a novel triterpenoid (Tri) isolated from Alisma orientale against ovalbumin-induced allergic asthma and explored the underlying mechanisms.

The therapeutic effects of Tri were evaluated in ovalbumin-induced allergic asthma mice by assessing airway hyperresponsiveness, histopathological changes, and inflammatory mediators. Gut microbiota depletion, fecal microbiota transplantation, 16S rDNA sequencing, targeted short-chain fatty acid analysis, and lung transcriptomic profiling were performed to characterize microbiota-associated changes related to Tri treatment. In addition, Lactobacillus murinus and acetate intervention experiments were conducted in vivo. A co-culture system of 16HBE cells and bone marrow-derived dendritic cells (BMDCs), together with free fatty acid receptor 2 (FFAR2) silencing or overexpression, was used to further assess the involvement of FFAR2 in the immunoregulatory actions associated with Tri.

Tri markedly attenuated airway hyperresponsiveness, inflammatory cell infiltration, collagen deposition, and the production of asthma-related inflammatory mediators in asthmatic mice. These protective effects were attenuated after gut microbiota depletion and were partially transferred by fecal microbiota transplantation. Tri restored gut microbial homeostasis, increased the abundance of Lactobacillus murinus, and elevated short-chain fatty acids, particularly acetate. Supplementation with Lactobacillus murinus or acetate reproduced the anti-asthmatic effects of Tri and was associated with upregulation of FFAR2 and restoration of the Th17/Treg balance. In the co-culture system, FFAR2 silencing or overexpression further supported the involvement of FFAR2 in the immunoregulatory effects of Tri and acetate.

Tri alleviates OVA-induced allergic asthma and is associated with microbiota-derived acetate, enhanced FFAR2-related signaling, and restoration of Th17/Treg balance. These findings suggest that microbiota-derived acetate and FFAR2-related immune regulation may contribute to the anti-asthmatic effects of Tri, although further loss-of-function studies are required to establish direct causality.