Gut microbial metabolite hyodeoxycholic acid targets the TLR4/MD2 complex to attenuate inflammation and protect against sepsis

Jiaxin Li, Yuqi Chen, Rui Li, Xianglong Zhang, Tao Chen, Fengyi Mei, Ruofan Liu, Meiling Chen, Yue Ge, Hongbin Hu, Rongjuan Wei, Zhenfeng Chen, Hongying Fan, Zhenhua Zeng, Yongqiang Deng, Haihua Luo, Shuiwang Hu, Shumin Cai, Feng Wu, Nengxian ShiZhang Wang, Yunong Zeng, Ming Xie, Yong Jiang, Zhongqing Chen*, Wei Jia*, Peng Chen*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

8 Citations (Scopus)

Abstract

Sepsis, a critical condition resulting from the systemic inflammatory response to a severe microbial infection, represents a global public health challenge. However, effective treatment or intervention to prevent and combat sepsis is still lacking. Here, we report that hyodeoxycholic acid (HDCA) has excellent anti-inflammatory properties in sepsis. We discovered that the plasma concentration of HDCA was remarkably lower in patients with sepsis and negatively correlated with the severity of the disease. Similar changes in HDCA levels in plasma and cecal content samples were observed in a mouse model of sepsis, and these changes were associated with a reduced abundance of HDCA-producing strains. Interestingly, HDCA administration significantly decreased systemic inflammatory responses, prevented organ injury, and prolonged the survival of septic mice. We demonstrated that HDCA suppressed excessive activation of inflammatory macrophages by competitively blocking lipopolysaccharide binding to the Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 receptor complex, a unique mechanism that characterizes HDCA as an endogenous inhibitor of inflammatory signaling. Additionally, we verified these findings in TLR4 knockout mice. Our study highlights the potential value of HDCA as a therapeutic molecule for sepsis.

Original languageEnglish
Pages (from-to)1017-1032
Number of pages16
JournalMolecular Therapy
Volume31
Issue number4
DOIs
Publication statusPublished - 5 Apr 2023

Scopus Subject Areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

User-Defined Keywords

  • gut microbiota
  • hyodeoxycholic acid
  • sepsis
  • Toll-like receptor 4

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