Gut microbiota-derived 3-indoleacetic acid confers a protection against sepsis-associated encephalopathy through microglial aryl hydrocarbon receptors - Details

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Abstract：

Background:　The　gut　microbiota　significantly　contributes　to　the　pathogenesis　of　central　nervous　system　disorders.　Among　the　bioactive　molecules　produced　by　the　gut　microbiota,　3-indoleacetic　acid　(IAA)　has　been　shown　to　attenuate　oxidative　stress　and　inflammatory　responses.　This　experiment　aimed　to　determine　the　impacts　of　IAA　on　sepsis-associated　encephalopathy　(SAE)　and　the　underlying　mechanisms.　Methods:　A　total　of　34　septic　patients　and　24　healthy　controls　were　included　in　the　analysis　of　the　clinical　correlation　between　fecal　IAA　and　septic　encephalopathy.　Fecal　microbiota　transplantation　was　used　to　verify　the　role　of　the　gut　microbiota　and　its　metabolites　in　SAE.　Male　C57BL/6　mice　aged　six　to　eight　weeks,　pre-treated　with　IAA　via　oral　gavage,　were　subjected　to　the　cecal　ligation　and　puncture　(CLP)　procedures.　This　treatment　was　administered　either　in　combination　with　an　aryl　hydrocarbon　receptor　(AhR)　antagonist,　CH223191,　or　a　CSF1R　inhibitor,　PLX3397,　to　eliminate　microglia.　Both　immunofluorescence　staining　and　enzyme-linked　immunosorbent　assays　were　used　to　evaluate　microglia　activation　and　inflammatory　cytokine　secretion.　Behavioral　assessments　were　conducted　to　quantify　neurological　deficits.　Results:　A　decreased　fecal　level　of　IAA　was　observed　in　the　patients　with　sepsis-associated　delirium　(SAD),　a　manifestation　of　SAE.　A　reduced　IAA　level　was　significantly　associated　with　worsen　clinical　outcomes.　Fecal　microbiota　transplantation　from　the　SAD　patients　induced　an　SAE-like　phenotype　in　mice,　but　supplementing　exogenous　IAA　improved　the　SAE-like　phenotype,　mediated　by　microglia.　IAA　effectively　binded　with　the　aryl　hydrocarbon　receptor　(AhR).　Furthermore,　IAA　increased　the　nuclear　activity　of　AhR　in　the　lipopolysaccharide　(LPS)-treated　microglial　cells,　leading　to　reduced　secretion　of　inflammatory　cytokines.　The　AhR　inhibitor　CH223191　counteracted　the　protective　effect　of　IAA　against　SAE　in　mice.　Conclusions:　Gut　microbiota-derived　IAA　confers　a　protection　against　SAE　by　activating　AhR　in　microglia,　improving　neuronal　and　cognitive　impairments.　Thus,　IAA　holds　the　promise　as　a　potential　therapeutic　agent　for　managing　SAE.　©　2024

Keyword：

3-indoleacetic acid Aryl hydrocarbon receptor Gut microbiota Microglia sepsis-associated encephalopathy

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[ 1 ] [Huang Z.-B.]Department of Anesthesiology, Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
[ 2 ] [Zhang G.-P.]Department of Anesthesiology, QuanZhou Orthopedic-Traumatological Hospital, Quanzhou, China
[ 3 ] [Lu C.-X.]Department of Anesthesiology, Fuzhou Second General Hospital, Fuzhou, China
[ 4 ] [Gong C.]Department of Anesthesiology, Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
[ 5 ] [Gao X.]Department of Anesthesiology, Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
[ 6 ] [Lin Y.]Department of Anesthesiology, Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
[ 7 ] [Su P.]Anesthesiology Department of Fujian Funeng Group General Hospital, Fuzhou, China
[ 8 ] [Xu W.]Department of Anesthesiology, Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
[ 9 ] [Lin Y.]Department of Anesthesiology, Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
[ 10 ] [Lin N.]Department of Anesthesiology, Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
[ 11 ] [Wu X.]Department of Anesthesiology, Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
[ 12 ] [Chen X.]Department of Anesthesiology, Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
[ 13 ] [Zheng T.]Department of Anesthesiology, Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
[ 14 ] [Zheng X.]Department of Anesthesiology, Fuzhou University Affiliated Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, China
[ 15 ] [Zheng X.]Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, China
[ 16 ] [Zheng X.]Fujian Emergency Medical Center, Fujian Provincial Key Laboratory of Critical Care Medicine, Fujian Provincial Co-Constructed Laboratory of “Belt and Road”, Fuzhou, China

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