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Published on: December 18, 2010
ASTRAGALOSIDE Ⅳ MODULATES GUT MACROPHAGES M1/M2 POLARIZATION BY RESHAPING GUT MICROBIOTA AND SHORT CHAIN FATTY ACIDS
Tao Yang, Shuhua Xie1, Lei Cao
1Department of Anesthesiology, Tianjin Union Medical Center, Tianjin, China.
Abstract:
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 short chain fatty acids (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. NLRP3 inflammasome 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.
Insights
Astragaloside intravenous (AS-IV) protects against sepsis-induced gut damage by restoring gut microbiota and short-chain fatty acids (SCFAs). This treatment modulates macrophage polarization and reduces NLRP3 inflammasome activation, improving intestinal barrier function.
Area of Science:
- Immunology
- Microbiology
- Gastroenterology
Background:
- Sepsis-induced gut impairment involves M1 macrophage inflammation.
- The protective mechanisms of astragaloside intravenous (AS-IV) in sepsis are not fully understood.
- Gut microbiota and short-chain fatty acids (SCFAs) play roles in maintaining gut homeostasis.
Purpose of the Study:
- To investigate the effects of AS-IV on gut macrophage polarization in sepsis.
- To explore the roles of gut microbiota and SCFAs in AS-IV's protective effects against septic gut damage.
- To elucidate the underlying molecular mechanisms involving the NLRP3 inflammasome.
Main Methods:
- Mice were treated with AS-IV before cecal ligation and puncture (CLP) to induce sepsis.
- Gut macrophages polarization, gut microbiota composition (16S rRNA sequencing), and SCFA levels were analyzed.
- In vitro models using Caco-2 and THP-1 cells were employed to study butyrate's effects.
- NLRP3 inflammasome activation was assessed in both in vivo and in vitro settings.
Main Results:
- CLP induced M1 macrophage polarization, gut inflammation, barrier dysfunction, and NLRP3 inflammasome activation.
- AS-IV treatment reversed M1/M2 macrophage polarization, reduced inflammation and barrier injury, and restored gut microbiota diversity.
- AS-IV increased fecal butyrate levels, and these benefits were mimicked by fecal microbiota transplantation or butyrate supplementation.
- Butyrate administration mitigated sepsis-induced damage in vitro, but these effects were blocked by NLRP3 overexpression.
Conclusions:
- AS-IV ameliorates sepsis-induced gut inflammation and barrier dysfunction.
- The protective effects of AS-IV are mediated by modulating gut macrophage polarization, restoring gut microbiota, and increasing SCFAs.
- AS-IV likely restrains NLRP3 inflammasome activation through these mechanisms, offering a therapeutic strategy for sepsis-related gut injury.
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