ASTRAGALOSIDE Ⅳ MODULATES GUT MACROPHAGES M1/M2 POLARIZATION BY RESHAPING GUT MICROBIOTA AND SHORT CHAIN FATTY ACIDS IN SEPSIS

Nov 14, 2023Shock (Augusta, Ga.)

Astragaloside IV may change gut immune cell balance by altering gut bacteria and fatty acids during sepsis

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Abstract

Astragaloside intravenous (AS-IV) treatment significantly reversed M1 macrophage polarization and reduced gut inflammation in a mouse model of sepsis.

Cecal ligation and puncture promoted M1 polarization of gut macrophages, leading to cytokine release and intestinal barrier dysfunction.
Activation of the was observed in following septic injury.
Treatment with AS-IV restored M1/M2 polarization balance in gut macrophages and decreased NLRP3 inflammasome expression.
AS-IV also improved gut microbiota diversity and increased levels of beneficial (SCFAs), including butyrate.
Fecal microbiota transplantation and exogenous butyrate supplementation produced similar protective effects on gut inflammation.

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M1 macrophage-mediated inflammation is critical in sepsis. We previously found the protective role of astragaloside intravenous (AS-IV) in sepsis-associated gut impairment, whose specific mechanism remains unknown. Gut microbiota modulates gut homeostatic balance to avoid excessive inflammation. Here, we aimed to investigate effects of AS-IV on gut macrophages polarization and potential roles of gut microbiota and (SCFAs) in septic gut damage. Mice were pretreated by AS-IV gavage for 7 days before cecal ligation and puncture. M1 polarization of gut lamina propria macrophages (LpMs) was promoted by cecal ligation and puncture, accompanied by abnormal cytokines release and intestinal barrier dysfunction. was activated in M1 LpMs. 16S rRNA sequencing demonstrated gut microbiota imbalance. The levels of acetate, propionate, and butyrate in fecal samples decreased. Notably, AS-IV reversed LpMs M1/M2 polarization, lightened gut inflammation and barrier injury, reduced NLRP3 inflammasome expression in LpMs, restored the diversity of gut microbiome, and increased butyrate levels. Similarly, these benefits were mimicked by fecal microbiota transplantation or exogenous butyrate supplementation. In Caco-2 and THP-1 cocultured model, LPS and interferon γ caused THP-1 M1 polarization, Caco-2 barrier impairment, abnormal cytokines release, and high NLRP3 inflammasome expression in THP-1 cells, all of which were mitigated by butyrate administration. However, these protective effects of butyrate were abrogated by NLRP3 gene overexpression in THP-1. In conclusion, AS-IV can ameliorate sepsis-induced gut inflammation and barrier dysfunction by modulating M1/M2 polarization of gut macrophages, whose underlying mechanism may be restoring gut microbiome and SCFA to restrain NLRP3 inflammasome activation.

Key numbers

butyrate increased

Increase in butyrate levels

Observed in AS-IV–treated septic mice

7-day survival rate

Survival rate improvement

Measured in septic mice after AS-IV treatment

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ASTRAGALOSIDE Ⅳ MODULATES GUT MACROPHAGES M1/M2 POLARIZATION BY RESHAPING GUT MICROBIOTA AND SHORT CHAIN FATTY ACIDS IN SEPSIS

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