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It has been employed for decades in the treatment of severe pneumonia with significant clinical efficacy. This study aimed to evaluate the protective effects of KBD against influenza virus-induced severe pneumonia in a murine model and to elucidate the underlying molecular mechanisms. Methods: The chemical profile of KBD was characterized using UPLC-Q-TOF-MS. A severe pneumonia model was established in C57BL\/6J mice via intranasal infection with influenza A\/Puerto Rico\/8\/34 (H1N1, PR8). Multiple parameters, including 14-day survival rate, body weight, lung index, histopathological changes, viral load, and pulmonary cytokine\/chemokine levels, were assessed. Furthermore, multi-omics analyses were integrated to characterize the gut microbiota and metabolic profiles. Fecal microbiota transplantation (FMT) was subsequently performed to validate the functional role of the gut microbiota and its metabolites. Results: KBD treatment significantly improved the survival rate by 40%, reduced the lung index by 27.85%, and alleviated lung injury. It also markedly lowered the viral load by 80.88%, suppressed pro-inflammatory cytokine levels, and restored intestinal barrier integrity. Mechanistically, KBD restored gut microbiota diversity by increasing the abundance of Firmicutes and Bacteroidetes, enriching beneficial genera such as Bifidobacterium and Faecalibaculum, and reducing Verrucomicrobiota. Integrated transcriptomic and metabolomic analyses revealed that KBD enhanced short-chain fatty acid (SCFA) metabolism and up-regulated pyruvate metabolism. Finally, FMT confirmed that the therapeutic benefits of KBD were transferable via the microbiota to microbiota-depleted mice. Conclusions: KBD exerts robust protection against severe influenza pneumonia, a process primarily mediated by the gut microbiota\u2013SCFA axis. The enhancement of mitochondrial energy metabolism also appears to play a critical role in its therapeutic mechanism.<\/jats:p>","DOI":"10.3390\/ph19071029","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:50:37Z","timestamp":1782867037000},"page":"1029","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Kai-Bi-Bu-Fei Decoction Protects Mice Against Influenza Virus-Induced Severe Pneumonia via Gut Microbiota\u2013Short Chain Fatty Acid Axis"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3714-6866","authenticated-orcid":false,"given":"Mingzhe","family":"Wang","sequence":"first","affiliation":[{"name":"Respiratory Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Xue","sequence":"additional","affiliation":[{"name":"Respiratory Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herong","family":"Cui","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Cheng","sequence":"additional","affiliation":[{"name":"Respiratory Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintong","family":"Li","sequence":"additional","affiliation":[{"name":"Respiratory Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Ren","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianzhen","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weicheng","family":"Nie","sequence":"additional","affiliation":[{"name":"Respiratory Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqiong","family":"Song","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0202-6575","authenticated-orcid":false,"given":"Chengjun","family":"Ban","sequence":"additional","affiliation":[{"name":"Respiratory Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2026, June 15). 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