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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\u2013immune axis, supporting its development as a functional food intervention in managing immunodeficiency conditions.<\/jats:p>","DOI":"10.3390\/nu18111793","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T11:25:31Z","timestamp":1780399531000},"page":"1793","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Yam Protects Immunocompromised Mice from Influenza Infection via the Gut\u2013SCFA\u2013GPCR\u2013Immune Axis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5538-7511","authenticated-orcid":false,"given":"Qingjun","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"},{"name":"Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9512-465X","authenticated-orcid":false,"given":"Xinyan","family":"Qu","sequence":"additional","affiliation":[{"name":"Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menglin","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"},{"name":"Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4656-2407","authenticated-orcid":false,"given":"Yingying","family":"Song","sequence":"additional","affiliation":[{"name":"Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Xu","sequence":"additional","affiliation":[{"name":"Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8931-4046","authenticated-orcid":false,"given":"Quanbo","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjing","family":"Dong","sequence":"additional","affiliation":[{"name":"Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4236-2483","authenticated-orcid":false,"given":"Xiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"},{"name":"Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.exger.2018.02.007","article-title":"Impact of stress on aged immune system compartments: Overview from fundamental to clinical data","volume":"105","author":"Fali","year":"2018","journal-title":"Exp. 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