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Pregnancy-induced changes to the gut microbiota drive macrophage pyroptosis and exacerbate septic inflammation

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机构: [1]Department of Obstetrics and Gynecology, First People’s Hospital of Foshan, Foshan 528000, China [2]School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China [3]Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China [4]Institute of Ecological Science, School of Life Science, South China Normal University, Guangzhou 510631, China [5]School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China [6]Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China [7]Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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The physiological and immune changes that occur during pregnancy are associated with worsened disease outcomes during infection and sepsis. How these perturbations exacerbate inflammation has not been explored. Here, using antibiotic treatment and fecal microbial transfers, we showed that sepsis susceptibility is driven by pregnancy-induced changes to gut microbiome in mice and humans. Integrative multiomics and genetically engineered bacteria revealed that reduced Parabacteroides merdae (P. merdae) abundance during pregnancy led to decreased formononetin (FMN) and increased macrophage death. Mechanistically, FMN inhibited macrophage pyroptosis by suppressing nuclear accumulation of hnRNPUL2 and subsequent binding to the Nlrp3 promoter. Treatment with FMN or deletion of murine hnRNPUL2 protected against septic inflammation. Intestinal abundances of P. merdae and FMN inversely correlated with the progression of septic patients. Our data reveal a microbe-immune axis that is disrupted in pregnant septic hosts, highlighting the potential of the FMN-hnRNPUL2-NLRP3 axis in providing promising therapeutic strategies for sepsis.Copyright © 2023 Elsevier Inc. All rights reserved.

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大类 | 1 区 医学
小类 | 1 区 免疫学
最新[2025]版:
大类 | 1 区 医学
小类 | 1 区 免疫学
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第一作者机构: [1]Department of Obstetrics and Gynecology, First People’s Hospital of Foshan, Foshan 528000, China [2]School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
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通讯机构: [2]School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China [3]Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
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