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

TitleGut microbial metabolite hyodeoxycholic acid targets the TLR4/MD2 complex to attenuate inflammation and protect against sepsis
Authors
Keywordsgut microbiota
hyodeoxycholic acid
sepsis
Toll-like receptor 4
Issue Date2023
Citation
Molecular Therapy, 2023, v. 31, n. 4, p. 1017-1032 How to Cite?
AbstractSepsis, 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.
Persistent Identifierhttp://hdl.handle.net/10722/342265
ISSN
2023 Impact Factor: 12.1
2023 SCImago Journal Rankings: 3.736
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLi, Jiaxin-
dc.contributor.authorChen, Yuqi-
dc.contributor.authorLi, Rui-
dc.contributor.authorZhang, Xianglong-
dc.contributor.authorChen, Tao-
dc.contributor.authorMei, Fengyi-
dc.contributor.authorLiu, Ruofan-
dc.contributor.authorChen, Meiling-
dc.contributor.authorGe, Yue-
dc.contributor.authorHu, Hongbin-
dc.contributor.authorWei, Rongjuan-
dc.contributor.authorChen, Zhenfeng-
dc.contributor.authorFan, Hongying-
dc.contributor.authorZeng, Zhenhua-
dc.contributor.authorDeng, Yongqiang-
dc.contributor.authorLuo, Haihua-
dc.contributor.authorHu, Shuiwang-
dc.contributor.authorCai, Shumin-
dc.contributor.authorWu, Feng-
dc.contributor.authorShi, Nengxian-
dc.contributor.authorWang, Zhang-
dc.contributor.authorZeng, Yunong-
dc.contributor.authorXie, Ming-
dc.contributor.authorJiang, Yong-
dc.contributor.authorChen, Zhongqing-
dc.contributor.authorJia, Wei-
dc.contributor.authorChen, Peng-
dc.date.accessioned2024-04-17T07:02:33Z-
dc.date.available2024-04-17T07:02:33Z-
dc.date.issued2023-
dc.identifier.citationMolecular Therapy, 2023, v. 31, n. 4, p. 1017-1032-
dc.identifier.issn1525-0016-
dc.identifier.urihttp://hdl.handle.net/10722/342265-
dc.description.abstractSepsis, 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.-
dc.languageeng-
dc.relation.ispartofMolecular Therapy-
dc.subjectgut microbiota-
dc.subjecthyodeoxycholic acid-
dc.subjectsepsis-
dc.subjectToll-like receptor 4-
dc.titleGut microbial metabolite hyodeoxycholic acid targets the TLR4/MD2 complex to attenuate inflammation and protect against sepsis-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.ymthe.2023.01.018-
dc.identifier.pmid36698311-
dc.identifier.scopuseid_2-s2.0-85150834010-
dc.identifier.volume31-
dc.identifier.issue4-
dc.identifier.spage1017-
dc.identifier.epage1032-
dc.identifier.eissn1525-0024-
dc.identifier.isiWOS:001064892700001-

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