{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:49:36Z","timestamp":1782452976862,"version":"3.54.5"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Ventilator-associated pneumonia (VAP) is a common hospital-acquired infection in the intensive care unit (ICU). It is associated with high morbidity and mortality, which are often compounded by patient frailty and disease severity. Despite adherence to antibiotic treatment guidelines, mortality rates remain persistently high. Critical illness disrupts intestinal function and alters epithelial cell dynamics, specifically increasing apoptosis and decreasing proliferation, thereby compromising the homeostasis of the epithelial monolayer. This increased intestinal permeability facilitates the translocation of bacteria and microbial products. Furthermore, impaired intestinal immunity exacerbates systemic inflammation and organ dysfunction. Previous studies indicate that the early onset of severe acquired immunosuppression in ICU patients significantly increases the risk of secondary infections. The gut-lung axis, which involves bidirectional crosstalk between the gastrointestinal and respiratory systems, is closely linked to immune regulation and the progression of lung diseases. We hypothesize that Shenling Baizhu San (SLBZS), a polysaccharide-rich multi-herb formula traditionally used for gastrointestinal disorders, could reduce susceptibility to VAP by reshaping the gut microbiota, enhancing the intestinal mucosal barrier, and modulating the transition from systemic inflammation to critical illness-induced immunoparalysis (CIIP) through microbiota-derived metabolites such as short-chain fatty acids (SCFAs). Validating this hypothesis would provide a novel, integrative therapeutic strategy for managing high-risk VAP patients.<\/jats:p>","DOI":"10.3389\/fmed.2026.1829153","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:43:46Z","timestamp":1782452626000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Preventing ventilator-associated pneumonia via the gut-lung axis: the Shenling Baizhu San hypothesis"],"prefix":"10.3389","volume":"13","author":[{"given":"Xinyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Second Clinical Medical College, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Li","sequence":"additional","affiliation":[{"name":"Second Clinical Medical College, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Lai","sequence":"additional","affiliation":[{"name":"Second Clinical Medical College, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanxi","family":"Ren","sequence":"additional","affiliation":[{"name":"Second Clinical Medical College, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saiyin","family":"Chaoketu","sequence":"additional","affiliation":[{"name":"Department of Wu-Liao and Rehabilitation, International Mongolian Hospital of Inner Mongolia","place":["Hohhot, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guofeng","family":"Cai","sequence":"additional","affiliation":[{"name":"Second Clinical Medical College, Heilongjiang University of Chinese Medicine","place":["Harbin, China"]},{"name":"Hanan Branch of the Second Affiliated Hospital of Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"92","DOI":"10.12688\/f1000research.129080.1","article-title":"Hospital-acquired and ventilator-associated pneumonia caused by multidrug-resistant gram-negative pathogens: understanding epidemiology, resistance patterns, and implications with COVID-19","volume":"12","author":"Hammoudi Halat","year":"2023","journal-title":"F1000Res"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e61","DOI":"10.1093\/cid\/ciw353","article-title":"Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the infectious diseases society of America and the American thoracic society","volume":"63","author":"Kalil","year":"2016","journal-title":"Clin Infect Dis"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1007\/s00134-020-05980-0","article-title":"Ventilator-associated pneumonia in adults: a narrative review","volume":"46","author":"Papazian","year":"2020","journal-title":"Intensive Care Med"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1186\/s13054-022-04127-5","article-title":"The central and biodynamic role of gut microbiota in critically ill patients","volume":"26","author":"Wozniak","year":"2022","journal-title":"Crit Care"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1186\/s13054-022-04259-8","article-title":"The central role of the gut in intensive care","volume":"26","author":"Corriero","year":"2022","journal-title":"Crit Care"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s13054-025-05309-7","article-title":"A review of gut failure as a cause and consequence of critical illness","volume":"29","author":"Soranno","year":"2025","journal-title":"Crit Care"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"110243","DOI":"10.1016\/j.mehy.2020.110243","article-title":"Premises among SARS-CoV-2, dysbiosis and diarrhea: walking through the ACE2\/mTOR\/autophagy route","volume":"144","author":"de Oliveira","year":"2020","journal-title":"Med Hypotheses"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/nrmicro.2016.142","article-title":"Emerging pathogenic links between microbiota and the gut\u2013lung axis","volume":"15","author":"Budden","year":"2017","journal-title":"Nat Rev Microbiol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1717822","DOI":"10.3389\/fmicb.2025.1717822","article-title":"Lung and gut microbiota profiling in severe community acquired pneumonia patients: a prospective pilot study","volume":"16","author":"Zou","year":"2025","journal-title":"Front Microbiol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"814","DOI":"10.3389\/fphar.2020.00814","article-title":"Shen-Ling-Bai-Zhu-san improves dextran sodium sulfate-induced colitis by inhibiting caspase-1\/caspase-11-mediated pyroptosis","volume":"11","author":"Chao","year":"2020","journal-title":"Front Pharmacol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1016\/j.biopha.2018.03.158","article-title":"Effects of shenling baizhu powder herbal formula on intestinal microbiota in high-fat diet-induced NAFLD rats","volume":"102","author":"Zhang","year":"2018","journal-title":"Biomed Pharmacother"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1186\/s12906-020-02958-9","article-title":"Shen-ling-bai-zhu-san ameliorates inflammation and lung injury by increasing the gut microbiota in the murine model of Streptococcus pneumonia-induced pneumonia","volume":"20","author":"Feng","year":"2020","journal-title":"BMC Complementary Med Ther"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1038\/s41385-019-0160-6","article-title":"Microbes, metabolites, and the gut-lung axis","volume":"12","author":"Dang","year":"2019","journal-title":"Mucosal Immunol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s40560-025-00786-y","article-title":"Gut integrity in intensive care: alterations in host permeability and the microbiome as potential therapeutic targets","volume":"13","author":"Oami","year":"2025","journal-title":"J Intensive Care"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1038\/s41591-023-02243-5","article-title":"Dysbiosis of a microbiota\u2013immune metasystem in critical illness is associated with nosocomial infections","volume":"29","author":"Schlechte","year":"2023","journal-title":"Nat Med"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"L65","DOI":"10.1152\/ajplung.00421.2020","article-title":"Lung immune tone via gut-lung axis: gut-derived LPS and short-chain fatty acids\u2019 immunometabolic regulation of lung IL-1\u03b2, FFAR2, and FFAR3 expression","volume":"321","author":"Liu","year":"2021","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1016\/j.cell.2016.05.041","article-title":"From dietary Fiber to host physiology: short-chain fatty acids as key bacterial metabolites","volume":"165","author":"Koh","year":"2016","journal-title":"Cell"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"2450","DOI":"10.1016\/j.immuni.2021.10.012","article-title":"The immunology of sepsis","volume":"54","author":"van der Poll","year":"2021","journal-title":"Immunity"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s13613-022-01010-y","article-title":"Monitoring of circulating monocyte HLA-DR expression in a large cohort of intensive care patients: relation with secondary infections","volume":"12","author":"de Roquetaillade","year":"2022","journal-title":"Ann Intensive Care"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1130214","DOI":"10.3389\/fimmu.2023.1130214","article-title":"Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis","volume":"14","author":"Joshi","year":"2023","journal-title":"Front Immunol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"108059","DOI":"10.1016\/j.micpath.2025.108059","article-title":"Altered gut microbiota composition and its clinical correlations in patients with severe pneumonia: a single-center observational study in China","volume":"209","author":"Ni","year":"2025","journal-title":"Microb Pathog"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"e27822","DOI":"10.1016\/j.heliyon.2024.e27822","article-title":"People are an organic unity: gut-lung axis and pneumonia","volume":"10","author":"Guo","year":"2024","journal-title":"Heliyon"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"iqae008","DOI":"10.1093\/oxfimm\/iqae008","article-title":"The gut-lung axis: the impact of the gut mycobiome on pulmonary diseases and infections","volume":"5","author":"Sey","year":"2024","journal-title":"Oxf Open Immunol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e24032","DOI":"10.1016\/j.heliyon.2024.e24032","article-title":"Unraveling the gut-lung axis: exploring complex mechanisms in disease interplay","volume":"10","author":"Eladham","year":"2024","journal-title":"Heliyon"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1796938","DOI":"10.3389\/fimmu.2026.1796938","article-title":"Gut microbiota dysbiosis in infants and young children with severe pneumonia and sepsis: a matched case-control study identifying potential biomarkers for early risk stratification","volume":"17","author":"Yang","year":"2026","journal-title":"Front Immunol"},{"key":"ref26","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbag173","article-title":"Integrative multi-omics analysis reveals microbiota alterations and clinical indicators predictive of pulmonary fibrosis progression following SARS-CoV-2 infection","volume":"27","author":"Liu","year":"2026","journal-title":"Brief Bioinform"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1007\/s00134-011-2459-y","article-title":"Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of the ESICM working group on abdominal problems","volume":"38","author":"Reintam Blaser","year":"2012","journal-title":"Intensive Care Med"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"9985147","DOI":"10.1155\/2022\/9985147","article-title":"Effect of Shenling Baizhu San on intestinal flora in a rat model of ulcerative colitis with spleen deficiency and dampness","author":"Luo","year":"2022","journal-title":"Evid Based Complement Alternat Med"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"112105","DOI":"10.1016\/j.jep.2019.112105","article-title":"A review of pharmacological and clinical studies on the application of Shenling Baizhu San in treatment of ulcerative colitis","volume":"244","author":"Ma","year":"2019","journal-title":"J Ethnopharmacol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"3722","DOI":"10.3390\/nu17233722","article-title":"Polysaccharides from Atractylodes macrocephala: a review of mechanistic and therapeutic insights into intestinal disorders","volume":"17","author":"Li","year":"2025","journal-title":"Nutrients"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41538-025-00416-9","article-title":"Regulatory effects of Poria cocos polysaccharides on gut microbiota and metabolites: evaluation of prebiotic potential","volume":"9","author":"Zhou","year":"2025","journal-title":"NPJ Sci Food"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"123103","DOI":"10.1016\/j.carbpol.2024.123103","article-title":"De-starched Panax ginseng polysaccharide: preparation, in vitro digestion, fermentation properties and the activating effect of the resultant products on RAW264.7 cells","volume":"351","author":"Xu","year":"2025","journal-title":"Carbohydr Polym"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.19540\/j.cnki.cjcmm.20221111.702","article-title":"Effects of total ginsenosides from Panax ginseng stems and leaves on gut microbiota and short-chain fatty acids metabolism in acute lung injury mice","volume":"48","author":"Ding","year":"2023","journal-title":"China J Chin Mater Med"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.intimp.2016.02.011","article-title":"Ginsenoside Rg3 ameliorates lipopolysaccharide-induced acute lung injury in mice through inactivating the nuclear factor-\u03baB (NF-\u03baB) signaling pathway","volume":"34","author":"Cheng","year":"2016","journal-title":"Int Immunopharmacol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"2934","DOI":"10.1016\/j.celrep.2020.02.013","article-title":"Gut Dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production","volume":"30","author":"Sencio","year":"2020","journal-title":"Cell Rep"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"773261","DOI":"10.3389\/fimmu.2022.773261.","article-title":"Acetate improves the killing of Streptococcus pneumoniae by alveolar macrophages via NLRP3 inflammasome and glycolysis-HIF-1\u03b1 axis","volume":"13","author":"Machado","year":"2022","journal-title":"Front Immunol"},{"key":"ref37","doi-asserted-by":"publisher","DOI":"10.1128\/msystems.00587-00520","article-title":"Microbiota-derived short-chain fatty acids promote LAMTOR2-mediated immune responses in macrophages","volume":"5","author":"Wu","year":"2020","journal-title":"mSystems"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"134003","DOI":"10.1016\/j.foodchem.2022.134003","article-title":"Gut microbial fermentation promotes the intestinal anti-inflammatory activity of Chinese yam polysaccharides","volume":"402","author":"Bai","year":"2023","journal-title":"Food Chem"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"129994","DOI":"10.1016\/j.ijbiomac.2024.129994","article-title":"In vitro fermentation characteristics of polysaccharides from coix seed and its effects on the gut microbiota","volume":"262","author":"Ge","year":"2024","journal-title":"Int J Biol Macromol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"148064","DOI":"10.1016\/j.gene.2023.148064","article-title":"Network pharmacology combined with an animal model to reveal the material basis and mechanism of Amomum villosum in alleviating constipation in mice","volume":"897","author":"Liu","year":"2024","journal-title":"Gene"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"831","DOI":"10.3390\/molecules30040831","article-title":"Antiviral and immune enhancement effect of Platycodon grandiflorus in viral diseases: a potential broad-Spectrum antiviral drug","volume":"30","author":"Gao","year":"2025","journal-title":"Molecules"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"883355","DOI":"10.3389\/fphar.2022.883355","article-title":"Shen-Ling-Bai-Zhu-san (SL) and SL derived-polysaccharide (PL) ameliorate the severity of diarrhea-induced by high lactose via modification of colonic fermentation","volume":"13","author":"Xue","year":"2022","journal-title":"Front Pharmacol"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"5161","DOI":"10.1038\/s41467-023-40553-x","article-title":"Fiber supplementation protects from antibiotic-induced gut microbiome dysbiosis by modulating gut redox potential","volume":"14","author":"Penumutchu","year":"2023","journal-title":"Nat Commun"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"wrae101","DOI":"10.1093\/ismejo\/wrae101","article-title":"Pectin supplementation accelerates post-antibiotic gut microbiome reconstitution orchestrated with reduced gut redox potential","volume":"18","author":"Xu","year":"2024","journal-title":"ISME J"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.chom.2020.12.012","article-title":"Role of dietary fiber in the recovery of the human gut microbiome and its metabolome","volume":"29","author":"Tanes","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/s41564-018-0150-6","article-title":"Microbiota-accessible carbohydrates suppress Clostridium difficile infection in a murine model","volume":"3","author":"Hryckowian","year":"2018","journal-title":"Nat Microbiol"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1577105","DOI":"10.3389\/fimmu.2025.1577105","article-title":"Sepsis-induced immunosuppression: mechanisms, biomarkers and immunotherapy","volume":"16","author":"Gao","year":"2025","journal-title":"Front Immunol"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"515","DOI":"10.3390\/diagnostics15050515","article-title":"The role of I-FABP, REG3\u03b1, sCD14-ST, and LBP as indicators of GI tract injury in MODS patients","volume":"15","author":"Turgunov","year":"2025","journal-title":"Diagnostics"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.3390\/diagnostics13111976","article-title":"Fecal and circulating biomarkers for the non-invasive assessment of intestinal permeability","volume":"13","author":"Perez-Diaz-del-Campo","year":"2023","journal-title":"Diagnostics"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/s13054-020-2830-x","article-title":"Monocytic HLA-DR expression kinetics in septic shock patients with different pathogens, sites of infection and adverse outcomes","volume":"24","author":"Leijte","year":"2020","journal-title":"Crit Care"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1002\/cyto.a.24249","article-title":"Monocyte HLA-DR measurement by flow cytometry in COVID-19 patients: an interim review","volume":"97","author":"Benlyamani","year":"2020","journal-title":"Cytometry A"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J Basic Clin Pharm"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1186\/cc13775","article-title":"Ventilator-associated pneumonia in the ICU","volume":"18","author":"Kalanuria","year":"2014","journal-title":"Crit Care"},{"key":"ref54","doi-asserted-by":"publisher","DOI":"10.3390\/life10070106","article-title":"Pharmacokinetic interactions between herbal medicines and drugs: their mechanisms and clinical relevance","volume":"10","author":"Rombol\u00e0","year":"2020","journal-title":"Life (Basel)"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1177\/08971900221100205","article-title":"Bioavailability of orally administered drugs in critically ill patients","volume":"36","author":"Forsberg","year":"2023","journal-title":"J Pharm Pract"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1007\/s00134-020-06050-1","article-title":"Antimicrobial therapeutic drug monitoring in critically ill adult patients: a position paper","volume":"46","author":"Abdul-Aziz","year":"2020","journal-title":"Intensive Care Med"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1002\/jpen.2490","article-title":"Developing guidance for feeding tube administration of oral medications","volume":"47","author":"Klang","year":"2023","journal-title":"JPEN J Parenter Enteral Nutr"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1829153\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:43:48Z","timestamp":1782452628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1829153\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":57,"alternative-id":["10.3389\/fmed.2026.1829153"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1829153","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]},"article-number":"1829153"}}