Age‐Associated Gut Microbiota Dysbiosis Impairs Antiviral Defense During Influenza Virus Infection and Identifies Acetate as a Protective Mediator in Senescent Human Lung Cells

Aging is associated with profound alterations in gut microbiota composition and function, including reduced production of short-chain fatty acids (SCFAs), yet it remains unclear whether these age-related microbial changes directly contribute to impaired antiviral defense during influenza A virus (IAV) infection. To address this question, we first characterized age-associated alterations of the gut microbiome and SCFA-related metabolic potential in a murine model of IAV infection. We then used a complementary human senescent lung fibroblast model to determine whether acetate, a major microbiota-derived SCFA, directly modulates antiviral responses in aging-associated lung cells. In old mice, IAV infection was associated with marked microbiota dysbiosis, including reduced abundance of SCFA-producing commensals such as Akkermansia muciniphila and Faecalibaculum rodentium, accompanied by decreased expression of microbial pathways involved in carbohydrate fermentation and acetate production. These findings suggested impaired microbiota-derived metabolic support of antiviral immunity during aging. Based on these observations, mechanistic studies in senescent human lung fibroblasts demonstrated that acetate supplementation significantly reduced viral replication and inflammatory responses. These protective effects were associated with FFAR2/FFAR3 signaling and enhanced histone H3 acetylation, indicating metabolic and epigenetic modulation of the antiviral response. Together, our findings establish a translational link between aging-associated gut microbiota dysfunction and impaired antiviral defense by combining a murine model of aging and influenza infection with mechanistic validation in human senescent lung cells. They identify acetate as a potential mediator of the gut-lung axis and support microbiota-targeted interventions to reduce influenza severity in older individuals.