Oral probiotic extracellular vesicle therapy mitigates Influenza A Virus infection via blunting IL-17 signaling
Hongxia Zhou, Wuying Huang, Jie‐Ting Li, Peier Chen, Lihan Shen, Wenjing Huang, Kailin Mai, Heyan Zou, Xueqin Shi, Yunceng Weng, Yuhua Liu, Zifeng Yang, Caiwen Ou
Abstract
The influenza A virus (IAV) damages intestinal mucosal tissues beyond the respiratory tract. Probiotics play a crucial role in maintaining the balance and stability of the intestinal microecosystem. Extracellular vesicles (EVs) derived from probiotics have emerged as potential mediators of host immune response and anti-inflammatory effect. However, the specific anti-inflammatory effects and underlying mechanisms of probiotics-derived EVs on IAV remain unclear. In the present study, we investigated the therapeutic efficacy of Lactobacillus reuteri EHA2-derived EVs (LrEVs) in a mouse model of IAV infection. Oral LrEVs were distributed in the liver, lungs, and gastrointestinal tract. In mice infected with IAV, oral LrEVs administration alleviated IAV-induced damages in the lungs and intestines, modified the microbiota compositions, and increased the levels of short-chain fatty acids in those organs. Mechanistically, LrEVs exerted their protective effects against IAV infection by blunting the pro-inflammatory IL-17 signaling. Furthermore, FISH analysis detected miR-4239, one of the most abundant miRNAs in LrEVs, in both lung and intestinal tissues. We confirmed that miR-4239 directly targets IL-17a . Our findings paved the ground for future application of LrEVs in influenza treatment and offered new mechanistic insights regarding the anti-inflammatory role of miR-4239. Schematic illustration of potential mechanisms via which LrEVs protect the host from H1N1 influenza virus infection by synergistically regulating intestinal and pulmonary immunity . LrEVs were distributed in small intestine and lung tissue after oral administration and exerted therapeutic effects on IAV infection by synergistically regulating IL-17-producing cells in the intestinal and lung, with miR-4239 playing a crucial regulatory role in IL-17A expression. • Orally administered LrEVs are distributed in the liver, lungs, and gastrointestinal tract. • LrEVs regulated microbiota dysregulation and increased short-chain fatty acid levels. • The protective effects of LrEVs were linked to the blunting the pro-inflammatory IL-17 signaling including suppressing Th17 cell differentiation and migration, regulating IL-17 - producing ILCs. • miR-4239, one of the most abundant miRNAs in LrEVs, was detected in lung and intestinal tissues which confirmed that directly targets IL-17a.