Abstract
Introduction Acute lung injury (ALI) is a major cause of morbidity and mortality after intestinal ischemia/reperfusion (I/R). Gut microbiota and their metabolic byproducts act as important modulators of the gut–lung axis. This study aimed to define the role of succinate, a key microbiota metabolite, in intestinal I/R-induced ALI progression.
Methods Gut and lung microbiota of mice subjected to intestinal I/R were analysed using 16S rRNA gene sequencing. Succinate level alterations were measured in Germ-free (GF) mice or conventional mice treated with antibiotics. Succinate-induced alveolar macrophage polarisation and its effects on alveolar epithelial apoptosis were evaluated in succinate receptor1 (Sucnr1)-deficient mice and in murine alveolar macrophages transfected with Sucnr1-siRNA. Succinate levels were measured in patients undergoing cardiopulmonary bypass, including intestinal I/R.
Results Succinate accumulated in lungs after intestinal I/R, and this was associated with an imbalance of succinate-producing and succinate-consuming bacteria in the gut, but not the lungs. Succinate accumulation was absent in GF mice and was reversed by gut microbiota depletion with antibiotics, indicating that gut microbiota are a source of lung succinate. Moreover, succinate promoted alveolar macrophage polarisation, alveolar epithelial apoptosis, and lung injury during intestinal I/R. Conversely, knockdown of Sucnr1 or blockage of SUCNR1 in vitro and in vivo reversed the effects of succinate by modulating PI3K-AKT/HIF-1α pathway. Plasma succinate levels significantly correlated with intestinal I/R-related lung injury after cardiopulmonary bypass.
Conclusion Gut microbiota-derived succinate exacerbates intestinal I/R–induced ALI through SUCNR1-dependent alveolar macrophage polarisation, identifying succinate as a novel target for gut-derived ALI in critically ill patients.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflicts of interest: The authors declare that they have no no competing interests.
- Received January 14, 2021.
- Accepted October 2, 2022.
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