Abstract
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.
Abstract
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
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.02233-2022
Availability of data and materials: The raw sequencing data generated in this study have been deposited in NCBI Sequence Read Archive (www.ncbi.nlm.nih.gov/sra) under accession numbers PRJNA828524, PRJNA828538, PRJNA876034 and PRJNA876036.
Author contributions: Ke-Xuan Liu and Cai Li conceived the project, designed the study, and reviewed and edited the manuscript; Yi-Heng Wang and Zheng-Zheng Yan carried out most of the experiments and prepared the original draft; Si-Dan Luo, Jing-Juan Hu and Jin Zhao conducted the experiments; Mei Wu and Cai Li participated in clinical follow-up and blood collections; Wei-Feng Liu analysed the data. All authors read and approved the paper.
Conflict of interest: The authors declare that they have no competing interests.
Support statement: This study was funded by the Key Project of National Natural Science Foundation of China (81730058), and grants from the National Natural Science Foundation of China (82172141; 82002088), the Natural Science Foundation of Hunan Province, China (2020JJ5509), and the scientific research project of Hunan Provincial Education (21C0300). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received January 14, 2021.
- Accepted October 2, 2022.
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