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Gut microbiota-derived succinate aggravates acute lung injury after intestinal ischaemia/reperfusion in mice
Yi-Heng Wang1,2,3, Zheng-Zheng Yan1,3, Si-Dan Luo1
1Department of Anaesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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.
Insights
Gut bacteria produce succinate, which worsens acute lung injury (ALI) after intestinal ischemia/reperfusion (I/R). Blocking succinate receptor 1 (Sucnr1) mitigates this lung injury, offering a new therapeutic target for critical care.
Area of Science:
- Microbiology and Immunology
- Gastroenterology and Pulmonology
- Metabolomics
Background:
- Acute lung injury (ALI) is a severe complication following intestinal ischemia/reperfusion (I/R).
- The gut microbiota significantly influences the gut-lung axis, impacting systemic inflammation and organ injury.
- Microbial metabolites, such as succinate, are increasingly recognized for their role in modulating host responses.
Purpose of the Study:
- To investigate the role of succinate, a gut microbiota metabolite, in the development of intestinal I/R-induced ALI.
- To elucidate the mechanisms by which succinate contributes to lung injury.
- To identify succinate as a potential therapeutic target for ALI.
Main Methods:
- Analysis of gut and lung microbiota composition using 16S rRNA gene sequencing in a mouse model of intestinal I/R.
- Measurement of succinate levels in germ-free and antibiotic-treated mice.
- Evaluation of succinate's effects on alveolar macrophages and epithelial cells, including studies using succinate receptor 1 (Sucnr1)-deficient mice and siRNA knockdown.
Main Results:
- Succinate accumulated in the lungs post-intestinal I/R, originating from the gut microbiota.
- Succinate promoted alveolar macrophage polarization and alveolar epithelial apoptosis, exacerbating lung injury.
- Blocking Sucnr1 or its signaling pathway (PI3K-AKT/HIF-1α) ameliorated succinate-induced lung injury in vitro and in vivo.
Conclusions:
- Gut microbiota-derived succinate exacerbates intestinal I/R-induced ALI via Sucnr1-dependent macrophage activation.
- Succinate emerges as a novel therapeutic target for mitigating gut-derived ALI in critically ill patients.
- Targeting the succinate-Sucnr1 axis offers a promising strategy for managing post-I/R lung injury.
