Journal Article

Gut microbiota-derived acetic acids promoted sepsis-induced acute respiratory distress syndrome by delaying neutrophil apoptosis through FABP4

Xuan, Weixia, Cao, Bin, Wu, Xu, Zhang, Xulong, Jia, Huayun, Zheng, Longcheng, Zhang, Xiaoju

2024

Overview

In patients with sepsis, neutrophil apoptosis tends to be inversely proportional to the severity of sepsis, but its mechanism is not yet clear. This study aimed to explore the mechanism of fatty acid binding protein 4 (FABP4) regulating neutrophil apoptosis through combined analysis of gut microbiota and short-chain fatty acids (SCFAs) metabolism. First, neutrophils from bronchoalveolar lavage fluid (BALF) of patients with sepsis-induced acute respiratory distress syndrome (ARDS) were purified and isolated RNA was applied for sequencing. Then, the cecal ligation and puncture (CLP) method was applied to induce the mouse sepsis model. After intervention with differential SCFAs sodium acetate, neutrophil apoptosis and FABP4 expression were further analyzed. Then, FABP4 inhibitor BMS309403 was used to treat neutrophils. We found CLP group had increased lung injury score, lung tissue wet/dry ratio, lung vascular permeability, and inflammatory factors IL-1β, TNF-α, IL-6, IFN-γ, and CCL3 levels in both bronchoalveolar lavage fluid and lung tissue. Additionally, FABP4 was lower in neutrophils of ARDS patients and mice. Meanwhile, CLP-induced dysbiosis of gut microbiota and changes in SCFAs levels were observed. Further verification showed that acetic acids reduced neutrophil apoptosis and FABP4 expression via FFAR2. Besides, FABP4 affected neutrophil apoptosis through endoplasmic reticulum (ER) stress, and neutrophil depletion alleviated the promotion of ARDS development by BMS309403. Moreover, FABP4 in neutrophils regulated the injury of RLE-6TN through inflammatory factors. In conclusion, FABP4 affected by gut microbiota-derived SCFAs delayed neutrophil apoptosis through ER stress, leading to increased inflammatory factors mediating lung epithelial cell damage.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Acetates - pharmacology / Acetic acid / acute respiratory distress syndrome / Alveoli / Animals / Apoptosis / Apoptosis - drug effects / Biochemistry / Biomedical and Life Sciences / Biomedicine / Biphenyl Compounds / Bronchoalveolar Lavage Fluid / Bronchus / Cecum / Cell Biology / digestive system / Disease Models, Animal / Dysbacteriosis / dysbiosis / Endoplasmic reticulum / Epithelial cells / Epithelium / Fatty acid-binding protein / Fatty Acid-Binding Proteins - genetics / Fatty Acid-Binding Proteins - metabolism / Fatty acids / Fatty Acids, Volatile - metabolism / Fatty Acids, Volatile - pharmacology / Female / Gastrointestinal Microbiome - drug effects / Gene sequencing / Gut microbiota / Humans / Inflammation / Injury analysis / interleukin-6 / Intestinal microflora / intestinal microorganisms / Lavage / Leukocytes (neutrophilic) / Life Sciences / Lung - metabolism / Lung - microbiology / Lung - pathology / Lungs / Male / metabolism / Mice / Mice, Inbred C57BL / Microbiota / Microorganisms / Middle Aged / Neutrophils / Neutrophils - metabolism / Original / Original Article / permeability / Pyrazoles / Respiratory distress syndrome / Respiratory Distress Syndrome - drug therapy / Respiratory Distress Syndrome - etiology / Respiratory Distress Syndrome - metabolism / Respiratory Distress Syndrome - microbiology / Respiratory Distress Syndrome - pathology / RNA / Sepsis / Sepsis - complications / Sepsis - metabolism / Sepsis - microbiology / Sepsis - pathology / Sodium acetate / Tumor necrosis factor-α / γ-Interferon