{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T02:45:56Z","timestamp":1790045156425,"version":"4.0.1"},"reference-count":121,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82100752"],"award-info":[{"award-number":["82100752"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:p>Lung injury can lead to specific neurocognitive dysfunction, and the \u201ctriple-hit\u201d phenomenon may be the key theoretical mechanism for the progressive impairment of lung injury-related cognitive impairment. The lung and brain can communicate biologically through immune regulation pathway, hypoxic pathway, neural circuit, mitochondrial dysfunction, and microbial influence, which is called the \u201clung-brain axis.\u201d The gut microbiota is a highly complex community of microorganisms that reside in the gut and communicate with the lung via the \u201cgut-lung axis.\u201d The dysregulation of gut microbiota may lead to the migration of pathogenic bacteria to the lung, and directly or indirectly regulate the lung immune response through their metabolites, which may cause or aggravate lung injury. The gut microbiota and the brain interact through the \u201cgut-brain axis.\u201d The gut microbiota can influence and regulate cognitive function and behavior of the brain through neural pathway mechanisms, immune regulation pathway and hypothalamic\u2013pituitary\u2013adrenal (HPA) axis regulation. Based on the gut microbiota regulation mechanism of the \u201cgut-lung axis\u201d and \u201cgut-brain axis,\u201d combined with the mechanisms of cognitive impairment caused by lung injury, we proposed the \u201ctriple-hit\u201d hypothesis. It states that the pathophysiological changes of lung injury trigger a series of events such as immune disorder, inflammatory responses, and microbiota changes, which activate the \u201clung-gut axis,\u201d thus forming a \u201ctriple-hit\u201d that leads to the development or deterioration of cognitive impairment. This hypothesis provides a more comprehensive framework for studying and understanding brain dysfunction in the context of lung injury. This review proposes the existence of an interactive tandem network for information exchange among the gut, lung, and brain, referred to as the \u201cgut-lung-brain axis.\u201d It further explores the potential mechanism of lung injury-related cognitive impairment caused by multiple interactions of gut microbiota in the \u201cgut-lung-brain axis.\u201d We found that there are many numerous pathophysiological factors that influence the interaction within the \u201cgut-lung-brain axis.\u201d The impact of gut microbiota on cognitive functions related to lung injury may be mediated through mechanisms such as the \u201ctriple-hit\u201d hypothesis, direct translocation of microbes and their metabolites, hypoxic pathway, immune modulation, vagal nerve activity, and the HPA axis regulation, among others. As the research deepens, based on the \u201ctriple-hit\u201d hypothesis of lung injury, it is further discovered that gut microbial therapy can significantly change the pathogenesis of the inflammatory process on the \u201cgut-lung-brain axis.\u201d It can also relieve lung injury and therapeutically modulate brain function and behavior. This perspective provides a new idea for the follow-up treatment of lung injury-related cognitive impairment caused by dysregulation of gut microbiota.<\/jats:p>","DOI":"10.3389\/fnut.2024.1521214","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T11:32:23Z","timestamp":1739446343000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Therapeutic role of gut microbiota in lung injury-related cognitive impairment"],"prefix":"10.3389","volume":"11","author":[{"given":"Yanxia","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangtao","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalan","family":"Zan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"557","DOI":"10.2147\/cia.S245147","article-title":"Influencing factors and exercise intervention of cognitive impairment in elderly patients with chronic obstructive pulmonary disease","volume":"15","author":"Wang","year":"2020","journal-title":"Clin Interv Aging"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3390\/nu13093166","article-title":"The effects of intermittent fasting on brain and cognitive function","volume":"13","author":"Gudden","year":"2021","journal-title":"Nutrients"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/s1474-4422(19)30356-4","article-title":"The gut microbiome in neurological disorders","volume":"19","author":"Cryan","year":"2020","journal-title":"Lancet Neurol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s13054-024-04855-w","article-title":"Pathophysiology of acute lung injury in patients with acute brain injury: the triple-hit hypothesis","volume":"28","author":"Ziaka","year":"2024","journal-title":"Crit Care"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1089\/jamp.2009.0775","article-title":"Acute lung injury: epidemiology, pathogenesis, and treatment","volume":"23","author":"Johnson","year":"2010","journal-title":"J Aerosol Med Pulm Drug Deliv"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1017\/s135561770410711x","article-title":"Quality of life, emotional, and cognitive function following acute respiratory distress syndrome","volume":"10","author":"Hopkins","year":"2004","journal-title":"J Int Neuropsychol Soc"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1186\/cc10259","article-title":"The lung and the brain: a dangerous cross-talk","volume":"15","author":"Pelosi","year":"2011","journal-title":"Crit Care"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.bbi.2018.07.013","article-title":"Two hit induced acute lung injury impairs cognitive function in mice: a potential model to study cross talk between lung and brain","volume":"73","author":"Sahu","year":"2018","journal-title":"Brain Behav Immun"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"100823","DOI":"10.1016\/j.bbih.2024.100823","article-title":"Lung-brain crosstalk: behavioral disorders and neuroinflammation in septic survivor mice. 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