Yam Protects Immunocompromised Mice from Influenza Infection via the Gut–SCFA–GPCR–Immune Axis

Background/Objectives: Immunodeficiency can be induced by a variety of factors, such as aging, stress and poor nutrition, and leads to increased susceptibility to infection and disease. The current research was conducted to determine the immunoenhancing potential of yam and its underlying mechanism in a murine model of cyclophosphamide (CTX)-induced immunosuppression. Methods: The gut microbial community and generation of short-chain fatty acids (SCFAs) in response to yam were analyzed by 16S rRNA sequencing and GC-MS. The immune cells in the spleen were analyzed using flow cytometry. GPR41/GPR43/GPR109A triple-knockout mice were used to demonstrate the critical involvement of SCFAs in mediating the protective effect of yam, and RNA-sequencing technology was applied to investigate the potential mechanism by which yam orchestrated the observed metabolic, immune and reparative responses. Results: Yam alleviated the decline in spleen and thymus indices and modulated the frequency of B cells and CD4+ and CD8+ T cells and promoted the production of IgA, IgG and IgM. Yam increased the secretion of cytokines in the intestine and upregulated the levels of claudin and ZO-1. Yam also increased the content of SCFAs and induced beneficial modifications to the gut microbiota composition. The immune-enhancing activity of yam was confirmed, as evidenced by a notable decrease in viral load in immunosuppressed mice inoculated with influenza virus and its capacity to mitigate inflammatory response in pulmonary tissues. Conclusions: This study suggests that yam enhances immunity by synergistically regulating the gut–immune axis, supporting its development as a functional food intervention in managing immunodeficiency conditions.