Liu Kexuan's team at Nanfang Hospital published important research results in top international journals in the field of respiratory

Recently, Professor Liu Kexuan's team from the Department of Anesthesiology of Nanfang Hospital published a paper entitled "Gut microbiota-derived succinate aggravates acute lung injury after intestinal" in the form of a paper in the top international respiratory journal, European Respiratory Journal (Region I of Small Respiratory Diseases, Chinese Academy of Sciences, IF=33.
795).
Ischemia/Reperfusion in MICE"
.
Dr.
Wang Yiheng and Dr.
Yan Zhengzheng of the Department of Anesthesiology are the co-first authors of the paper, Professor Liu Kexuan and Professor Li Wei are the co-corresponding authors of the paper, and Nanfang Hospital of Southern Medical University is the
first signatory of the paper.
This paper is another important breakthrough
of Professor Liu Kexuan's team after publishing high-impact research papers related to intestinal flora in international journals such as Microbiome, Br J Anaesth, and Gut Microbes.

Intestinal ischemia reperfusion (Ischemia/reperfusion, I/R) is a common clinical acute and critical condition, often occurring in trauma, infection, shock and intestinal obstruction, cardiopulmonary bypass surgery and other clinical phenomena, not only causing intestinal injury, but also due to intestinal barrier damage after dysbacteriosis and endotoxin displacement, resulting in sepsis and extraintestinal multi-organ insufficiency and even failure
.
Acute lung injury (ALI), as the most common distant organ complication of intestinal I/R, is the leading cause of
death in these patients.
So far, the pathogenesis of ALI is unclear and there are no effective prevention and treatment measures, which is one of
the scientific problems that need to be solved urgently in the field of respiratory and critical illness.
The intestinal flora and its metabolites can be involved in the development of many lung diseases by influencing immune system function, but their role in intestinal I/R induced ALI is unclear
.
In order to reveal the above problems, Professor Liu Kexuan's team replicated the mouse intestinal I/R-induced ALI model, and found through 16S rRNA microbiota sequencing analysis that intestinal I/R caused an increase in the abundance of bacteria producing succinic acid in the intestine (not the lungs), while the abundance of bacteria degrading succinic acid decreased
.
Intestinal I/R can also lead to accumulation of succinic acid in the lungs; The ratio of succinic acid content in the lungs to succinic acid producing bacteria / succinic acid degrading bacteria in the intestine [(P+T+B)/(R+O+C)] was positively correlated
。 Furthermore, the team confirmed through antibiotic clearance experiments, fecal bacteria transplantation experiments and fluorescein labeling experiments in vivo that: (1) after the intestinal I/R of pseudo-sterile mice and germ-free (GF) mice with broad-spectrum antibiotics cleared the intestinal flora, the content of succinic acid accumulated in the lungs decreased significantly, and lung inflammation and lung damage were significantly reduced; (2) The phenotype of succinic acid accumulation, lung inflammation and lung injury in the lungs of GF mice was reproduced after transplantation of intestinal I/R mice.
(3) The mice were treated with FAM-succinic acid carrying green light label, and then the intestinal I/R model was replicated, and the fluorescence signals of the intestine and lungs were enhanced, indicating that succinic acid was transferred from the intestine to the lungs
during intestinal I/R.
These studies have shown that the accumulation of succinic acid in the lungs during intestinal I/R comes from the intestinal flora, and the intestinal flora metabolite succinic acid is an important vector
for post-intestinal I/R ALI.

Through clinical verification, it was found that the plasma succinic acid level increased in the early postoperative period of cardiopulmonary bypass cardiac surgery, and the plasma succinic acid content was significantly positively correlated with the relevant indicators reflecting lung injury after cardiopulmonary bypass surgery, which further suggested that succinic acid was related to
ALI caused by intestinal I/R.

The team further explored the role and specific mechanisms
of succinic acid in ALI after intestinal I/R.
Through in vivo and in vitro intervention experiments of succinic acid, chlorophosphate liposome removal of mouse macrophages, and alveolar macrophages and alveolar epithelial cells co-culture in vitro, it was found that succinic acid can promote the M1 polarization of alveolar macrophages, leading to apoptosis and ALI of alveolar epithelial cells, and the role of succinic acid depends on the participation
of alveolar macrophages.
Finally, the team also delved into the molecular mechanisms
by which succinic acid-mediated intestinal I/R leads to ALI.
In vivo and in vitro antibody neutralization experiments with succinic acid receptor (SUCNR1) and Sucnr1 gene knockout/knockdown experiments showed that knocking out or blocking SUCNR1 could reduce ALI caused by intestinal I/R, and a series of in vitro experiments showed that succinic acid promoted alveolar macrophage polarization through its receptor SUCNR1 and downstream PI3K/AKT/HIF-1α pathway, which in turn led to apoptosis of alveolar epithelial cells and ALI
.

This study is the first to reveal the key role of the intestinal microbiota metabolite succinic acid, an important metabolite of the intestinal flora, which promotes alveolar macrophage polarization by acting on its receptor SUCNR1, which in turn leads to lung injury
.
This study not only reveals the pathogenesis of intestinal ALI from a new perspective of "intestinal flora-gut-lung axis", but also takes the lead in proposing that succinic acid is a new target for the prevention and treatment of enterogenic ALI in critically ill patients, and that it will target the regulation of intestinal flora related to succinic acid metabolism or an effective means to
prevent and treat intestinal lung injury in the future.