Gut derived (S)-Equol mitigates influenza viral pneumonia by modulating macrophage polarization via Nrf2 mediated AKT/ERK/NF-κb signaling pathways.

Respiratory virus including influenza A virus (IAV) infection induces alterations in gut microbiota structure and function, which in turn plays an essential role in the pathogenic process. Alterations in gut microbiota are usually accompanied with changes in metabolites. The specific relationship between dynamic changes in gut microbiota and serum metabolites in influenza remains unclear. In this study, we depicted dynamic changes in composition of gut microbiota by using metagenomic sequencing in an influenza mouse model. Through mass spectrometry based metabolomic, we identified (S)-Equol as a notable protective metabolite derived from intestinal flora. Serum (S)-Equol level decreased from the initial infection phase and increased gradually during the convalescence phase, which was positively associated with the changes in some Eggerthella and Bifidobacterium species. Antibiotic treatment reduced serum (S)-Equol level and exacerbated lung pathological damage. Oral administration of (S)-Equol relieved disease severity and controlled inflammatory infiltration. Mechanistically, (S)-Equol activated Nrf2 in macrophages, thereby inhibited AKT, ERK and NF-κB phosphorylation. The inhibition of these signaling pathways ultimately restrained pro-inflammatory cytokines release and repressed pro-inflammatory macrophage polarization. Moreover, serum (S)-Equol level was lower in influenza patients at progressed phase and was negatively correlated with serum levels of IL-6, IL-1β, and TNF-α. Collectively, our data highlighted gut derived (S)-Equol a promising postbiotic for alleviating influenza pneumonia.