PT  - JOURNAL ARTICLE
AU  - Yi-Heng Wang
AU  - Zheng-Zheng Yan
AU  - Si-Dan Luo
AU  - Jing-Juan Hu
AU  - Mei Wu
AU  - Jin Zhao
AU  - Wei-Feng Liu
AU  - Cai Li
AU  - Ke-Xuan Liu
TI  - Gut microbiota-derived succinate aggravates acute lung injury after intestinal ischaemia/reperfusion in mice
AID  - 10.1183/13993003.00840-2022
DP  - 2023 Feb 01
TA  - European Respiratory Journal
PG  - 2200840
VI  - 61
IP  - 2
4099  - http://erj.ersjournals.com/content/61/2/2200840.short
4100  - http://erj.ersjournals.com/content/61/2/2200840.full
SO  - Eur Respir J2023 Feb 01; 61
AB  - Introduction Acute lung injury (ALI) is a major cause of morbidity and mortality after intestinal ischaemia/reperfusion (I/R). The gut microbiota and its 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 mice or conventional mice treated with antibiotics. Succinate-induced alveolar macrophage polarisation and its effects on alveolar epithelial apoptosis were evaluated in succinate receptor 1 (Sucnr1)-deficient mice and in murine alveolar macrophages transfected with Sucnr1-short interfering RNA. 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 germ-free mice and was reversed by gut microbiota depletion with antibiotics, indicating that the gut microbiota is 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 the phosphoinositide 3-kinase-AKT/hypoxia-inducible factor-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.Succinate accumulation in the lungs is associated with the imbalance of succinate-producing and -consuming bacteria in the gut during intestinal ischaemia/reperfusion. Lung injury was exacerbated by succinate via alveolar macrophage polarisation. https://bit.ly/3fTR9AM