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Focusing on the interactions among gut-originating short-chain fatty acids (SCFAs), neutrophil function, and histone deacetylases (HDACs), this research examined the exacerbating effects of a high-calorie diet on pneumonia in rats. Methods: Male Sprague-Dawley rats (3 weeks old, 110 \u00b1 10 g) were allocated among four groups: normal diet (N), high-calorie diet (G), LPS-induced pneumonia (P), and high-calorie diet combined with lipopolysaccharide (LPS)-induced pneumonia (GP). LPS was administered via aerosolization for three days. Fecal, serum, and lung SCFA levels were quantified via GC-MS. Neutrophil extracellular traps (NETs) formation, neutrophil apoptosis, and HDAC activity were assessed using immunofluorescence, TUNEL assays, and qRT-PCR. Propionate supplementation and HDAC inhibitor (trichostatin A) interventions were applied to validate mechanistic pathways. Results: The group GP exhibited exacerbated lung inflammation, increased NETs release, and reduced neutrophil apoptosis compared to the group P. Propionate levels in feces, serum, and lung tissues decreased sharply in GP rats, correlating with elevated HDAC1\/2\/3\/6 activity and reduced histone acetylation. Propionate supplementation or HDAC inhibition significantly attenuated lung injury, suppressed NETs, and restored neutrophil apoptosis. Conclusions: High-calorie diets exacerbate pneumonia by depleting gut-derived propionate, which drives HDAC-mediated NETs overproduction and impairs neutrophil apoptosis. Restoring propionate levels or targeting HDACs may offer therapeutic strategies for diet-aggravated respiratory diseases. Mechanistically, propionate-mediated HDAC inhibition demonstrates proof-of-concept efficacy in modulating H4 acetylation, warranting further investigation in disease-specific pneumonia models.<\/jats:p>","DOI":"10.3390\/nu17132242","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T04:43:37Z","timestamp":1751863417000},"page":"2242","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["High-Calorie Diets Exacerbate Lipopolysaccharide-Induced Pneumonia by Promoting Propionate-Mediated Neutrophil Extracellular Traps"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6210-6396","authenticated-orcid":false,"given":"Yingqiu","family":"Sun","sequence":"first","affiliation":[{"name":"Qi-Huang Chinese Medicine School, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Chinese Medicine Epidemic Disease, Beijing University of Chinese Medicine, Beijing 102488, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyu","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyan","family":"Hu","sequence":"additional","affiliation":[{"name":"Qi-Huang Chinese Medicine School, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingpu","family":"Ma","sequence":"additional","affiliation":[{"name":"Qi-Huang Chinese Medicine School, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxuan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiegang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Gu","sequence":"additional","affiliation":[{"name":"Institute of Chinese Medicine Epidemic Disease, Beijing University of Chinese Medicine, Beijing 102488, China"},{"name":"School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/s41579-024-01116-z","article-title":"Streptococcus Pneumoniae Epidemiology, Pathogenesis and Control","volume":"23","author":"Narciso","year":"2024","journal-title":"Nat. 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