Exploring the lung-gut direction of the gut-lung axis in patients with ARDS

Abstract

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.

Fig. 1

In patients with LI/ARDS, damage to the endothelium of pulmonary capillaries occurs, leading to the migration of activated immune cells into the lungs, thereby exacerbating the pulmonary inflammatory response. Within the air space, alveolar macrophages locally secrete cytokines to induce chemotaxis and activate neutrophils, which, in turn, release various pro-inflammatory molecules. The use of MV may further worsen lung injury, potentially resulting in excessive alveolar distension (volutrauma), the repetitive cyclic opening and closure of alveoli (atelectrauma), and the initiation of a complex inflammatory cascade, leading to both local and systemic inflammation (biotrauma). This inflammation can extend to distant organs and systems, exacerbating multiple organ dysfunction. ARDS acute respiratory distress syndrome, IL interleukin, LI lung injury, MODS multiple organ dysfunction syndrome, MV mechanical ventilation, TBI traumatic brain injury, TNF tumor necrosis factor

Fig. 2

The role of the gut in both health and critical illness. In critical illness, alterations in TJ integrity, which is vital for maintaining homeostasis, lead to loss of gut integrity and increased permeability. JAM junctional adhesion molecules, MLCK myosin light chain kinase, ZO zonula occludens

Fig. 3

In patients with LI/ARDS, severe acute inflammation leads to functional alterations of tight junction proteins and activation of MLCK, which are associated with intestinal barrier dysfunction, disruption of the mucus layer integrity, exacerbation of intestinal inflammatory reactions, and gut dysbiosis. MV may cause VILI, further exacerbating systemic inflammation and intestinal damage. Haemodynamic alterations during low-tidal volume MV and hypercapnia induced by protective MV are associated with increased myocardial contractility, decreased systemic vascular resistance, and alterations of vascular tone, leading to changes in splanchnic vascular tone and splanchnic microcirculatory oxygenation. Intestinal dysfunction and loss of gut integrity enhance systemic inflammation and promote the translocation of gut bacteria into the lungs, worsening pre-existing LI-mediated lung dysbiosis. ARDS acute respiratory distress syndrome, LI lung injury, MLCK myosin light chain kinase, MV mechanical ventilation, TJP tight junction proteins, VILI ventilator-induced lung injury