PB0847 - Gut microbial metabolite butyrate reduces the susceptibility to septic DIC via inhibiting the caspase-11/ GSDMD-dependent macrophage pyroptosis

Monday, June 24, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Ying ying Li, Graduate

student
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)

Co-Author(s)

ZW

Zhong Wu

student
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)
MX

Min Xu

student
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)
ZC

Zhaozhao Chen

doctoral student
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)
LL

Lili Luo

PhD
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wuhan, Hubei, China (People's Republic)
HM

Heng Mei

PhD
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
wuhan, Hubei, China (People's Republic)
YH

Yu Hu

PhD
Institution of Hematology, Wuhan Union Hospital, Tongji medical college, Huazhong University of Science and Technology
wuhan, Hubei, China (People's Republic)

Background: Disseminated intravascular coagulation (DIC) is a common and main life-threating complication in sepsis. We observed a different predisposition to DIC in mouse model of sepsis, but the mechanism remains unknown.

Aims: To explore the mechanisms responsible for susceptibility to septic DIC.

Methods: Cecal ligation and puncture (CLP) was used to induce sepsis. Feces were collected before CLP to detect intestinal flora composition by 16s RNA and gut microbial metabolite by metabolome. FMT was performed to study the role of gut microbiota and its metabolites in susceptibility to septic DIC. Macrophage pyroptosis were comprehensively assessed by IL-1β secretion levels, lactate dehydrogenase activity and non-viable apoptotic cell defined by flow cytometry.

Results: After CLP, mice that died within 24h were defined as the DIC-sensitive (Sen), and those that survived over 7 days were defined as the DIC-resistant (Res). Sen mice were more likely to develop DIC and multiple organ failure than Res mice. The relative abundance of butyric-producing bacteria firmicutes and the concentration of butyrate in Res mice were significantly higher than those in Sen mice. Butyrate can effectively decrease the mortality of DIC, improve coagulation dysfunction and alleviate multiple organ damage. Interestingly, the susceptibility to septic DIC can be transmitted through intestinal flora. Mechanistically, the proportion of peritoneal macrophage pyroptosis, plasma levels of IL-1β and LDH in Sen mice were statistically higher than that in Res mice, and butyrate could reduce these indicators and downregulate the expression of histone deacetylase 3 (HDAC3). Butyrate, HDAC3 inhibitors and caspase11 inhibitor reduced the proportion of pyroptosis cells characterized by swell and rupture, IL-1β level and LDH release, thereby inhibiting pyroptosis of macrophages.

Conclusion(s): Butyrate, a metabolite of intestinal flora, negatively regulates the activation of the caspase-11/ GSDMD pathway in macrophages by down-regulating the activity of HDAC3, thereby inhibiting the occurrence and development of DIC in sepsis.