The gut serves as a vital immunological organ orchestrating immune responses and influencing distant mucosal sites, notably the respiratory mucosa. It is increasingly recognized as a central driver of critical illnesses, with intestinal hyperpermeability facilitating bacterial translocation, systemic inflammation, and organ damage. The “gut-lung” axis emerges as a pivotal pathway, where gut-derived injurious factors trigger acute lung injury (ALI) through the systemic circulation. Direct and indirect effects of gut microbiota significantly impact immune responses. Dysbiosis, particularly intestinal dysbiosis, termed as an imbalance of microbial species and a reduction in microbial diversity within certain bodily microbiomes, influences adaptive immune responses, including differentiating T regulatory cells (Tregs) and T helper 17 (Th17) cells, which are critical in various lung inflammatory conditions. Additionally, gut and bone marrow immune cells impact pulmonary immune activity, underscoring the complex gut-lung interplay. Moreover, lung microbiota alterations are implicated in diverse gut pathologies, affecting local and systemic immune landscapes. Notably, lung dysbiosis can reciprocally influence gut microbiota composition, indicating bidirectional gut-lung communication. In this review, we investigate the pathophysiology of ALI/acute respiratory distress syndrome (ARDS), elucidating the role of immune cells in the gut-lung axis based on recent experimental and clinical research. This exploration aims to enhance understanding of ALI/ARDS pathogenesis and to underscore the significance of gut-lung interactions in respiratory diseases.

During the last decade, experimental and clinical studies have demonstrated that isolated acute brain injury (ABI) may cause severe dysfunction of peripheral extracranial organs and systems. Of all potential target organs and systems, the lung appears to be the most vulnerable to damage after brain injury (BI). The pathophysiology of these brain–lung interactions are complex and involve neurogenic pulmonary oedema, inflammation, neurodegeneration, neurotransmitters, immune suppression and dysfunction of the autonomic system. The systemic effects of inflammatory mediators in patients with BI create a systemic inflammatory environment that makes extracranial organs vulnerable to secondary procedures that enhance inflammation, such as mechanical ventilation (MV), surgery and infections. Indeed, previous studies have shown that in the presence of a systemic inflammatory environment, specific neurointensive care interventions—such as MV—may significantly contribute to the development of lung injury, regardless of the underlying mechanisms. Although current knowledge supports protective ventilation in patients with BI, it must be born in mind that ABI-related lung injury has distinct mechanisms that involve complex interactions between the brain and lungs. In this context, the role of extracerebral pathophysiology, especially in the lungs, has often been overlooked, as most physicians focus on intracranial injury and cerebral dysfunction. The present review aims to fill this gap by describing the pathophysiology of complications due to lung injuries in patients with a single ABI, and discusses the possible impact of MV in neurocritical care patients with normal lungs.

Acute respiratory distress syndrome (ARDS) represents a life-threatening inflammatory reaction marked by refractory hypoxaemia and pulmonary oedema. Despite advancements in treatment perspectives, ARDS still carries a high mortality rate, often due to systemic inflammatory responses leading to multiple organ dysfunction syndrome (MODS). Indeed, the deterioration and associated mortality in patients with acute lung injury (LI)/ARDS is believed to originate alongside respiratory failure mainly from the involvement of extrapulmonary organs, a consequence of the complex interaction between initial inflammatory cascades related to the primary event and ongoing mechanical ventilation-induced injury resulting in multiple organ failure (MOF) and potentially death. Even though recent research has increasingly highlighted the role of the gastrointestinal tract in this process, the pathophysiology of gut dysfunction in patients with ARDS remains mainly underexplored. This review aims to elucidate the complex interplay between lung and gut in patients with LI/ARDS. We will examine various factors, including systemic inflammation, epithelial barrier dysfunction, the effects of mechanical ventilation (MV), hypercapnia, and gut dysbiosis. Understanding these factors and their interaction may provide valuable insights into the pathophysiology of ARDS and potential therapeutic strategies to improve patient outcomes.

It has been convincingly demonstrated in recent years that isolated acute brain injury (ABI) may cause severe dysfunction of peripheral extracranial organs and systems. 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–lung 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 (“first hit”) that makes extracranial organs vulnerable to secondary procedures that enhance inflammation, such as mechanical ventilation (MV), surgery, and infections (“second hit”). 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 “gut-microbiome–brain axis.” Additionally, recent research evidence has highlighted a crucial interplay between the intestinal microbiota and the lungs, referred to as the “gut-lung axis,” 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 “double-hit” theory, proposing the “triple-hit” hypothesis, focused on the influence of the gut–lung 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–lung axis, resulting in the development or further aggravation of existing ALI, which constitutes the “third hit.”

A complex interrelation between lung and brain in patients with acute lung injury (ALI) has been established by experimental and clinical studies during the last decades. Although, acute brain injury represents one of the most common insufficiencies in patients with ALI and acute respiratory distress syndrome (ARDS), the underlying pathophysiology of the observed crosstalk remains poorly understood due to its complexity. Specifically, it involves numerous pathophysiological parameters such as hypoxemia, neurological adverse events of lung protective ventilation, hypotension, disruption of the BBB, and neuroinflammation in such a manner that the brain of ARDS patients—especially hippocampus—becomes very vulnerable to develop secondary lung-mediated acute brain injury. A protective ventilator strategy could reduce or even minimize further systemic release of inflammatory mediators and thus maintain brain homeostasis. On the other hand, mechanical ventilation with low tidal volumes may lead to self-inflicted lung injury, hypercapnia and subsequent cerebral vasodilatation, increased cerebral blood flow, and intracranial hypertension. Therefore, by describing the pathophysiology of ARDS-associated acute brain injury we aim to highlight and discuss the possible influence of mechanical ventilation on ALI-associated acute brain injury.

In recent years, it has been convincingly demonstrated that acute brain injury may cause severe cardiac complications—such as neurogenic stress cardiomyopathy (NSC), a specific form of takotsubo cardiomyopathy. The pathophysiology of these brain-heart interactions is complex and involves sympathetic hyperactivity, activation of the hypothalamic-pituitary-adrenal axis, as well as immune and inflammatory pathways. There have been great strides in our understanding of the axis from the brain to the heart in patients with isolated acute brain injury and more specifically in patients with stroke. On the other hand, in patients with NSC, research has mainly focused on hemodynamic dysfunction due to arrhythmias, regional wall motion abnormality, or left ventricular hypokinesia that leads to impaired cerebral perfusion pressure. Comparatively little is known about the underlying secondary and delayed cerebral complications. The aim of the present review is to describe the stroke-heart-brain axis and highlight the main pathophysiological mechanisms leading to secondary and delayed cerebral injury in patients with concurrent hemorrhagic or ischemic stroke and NSC as well as to identify further areas of research that could potentially improve outcomes in this specific patient population.