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Of all potential target organs and systems, the lung appears to be the most vulnerable to damage after ABI. The pathophysiology of the bidirectional brain\u2013lung interactions is multifactorial and involves inflammatory cascades, immune suppression, and dysfunction of the autonomic system. Indeed, the systemic effects of inflammatory mediators in patients with ABI create a systemic inflammatory environment (\u201cfirst hit\u201d) that makes extracranial organs vulnerable to secondary procedures that enhance inflammation, such as mechanical ventilation (MV), surgery, and infections (\u201csecond hit\u201d). Moreover, accumulating evidence supports the knowledge that gut microbiota constitutes a critical superorganism and an organ on its own, potentially modifying various physiological functions of the host. Furthermore, experimental and clinical data suggest the existence of a communication network among the brain, gastrointestinal tract, and its microbiome, which appears to regulate immune responses, gastrointestinal function, brain function, behavior, and stress responses, also named the \u201cgut-microbiome\u2013brain axis.\u201d Additionally, recent research evidence has highlighted a crucial interplay between the intestinal microbiota and the lungs, referred to as the \u201cgut-lung axis,\u201d in which alterations during critical illness could result in bacterial translocation, sustained inflammation, lung injury, and pulmonary fibrosis. In the present work, we aimed to further elucidate the pathophysiology of acute lung injury (ALI) in patients with ABI by attempting to develop the \u201cdouble-hit\u201d theory, proposing the \u201ctriple-hit\u201d hypothesis, focused on the influence of the gut\u2013lung axis on the lung. Particularly, we propose, in addition to sympathetic hyperactivity, blast theory, and double-hit theory, that dysbiosis and intestinal dysfunction in the context of ABI alter the gut\u2013lung axis, resulting in the development or further aggravation of existing ALI, which constitutes the \u201cthird hit.\u201d<\/jats:p>","DOI":"10.1186\/s13054-024-04855-w","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T07:15:33Z","timestamp":1709795733000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Pathophysiology of acute lung injury in patients with acute brain injury: the triple-hit hypothesis"],"prefix":"10.1186","volume":"28","author":[{"given":"Mairi","family":"Ziaka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aristomenis","family":"Exadaktylos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,7]]},"reference":[{"issue":"2","key":"4855_CR1","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1097\/MCC.0000000000000707","volume":"26","author":"C Robba","year":"2020","unstructured":"Robba C, et al. 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