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Bacteroides Fragilis Exacerbates T2D Vascular Calcification by Secreting Extracellular Vesicles to Induce M2
Cong Chen1,2, Zhengfeng Liang3, Yuqi He1
1The First Affiliated Hospital, Department of Laboratory Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
Abstract:
Vascular calcification (VC) in type 2 diabetes (T2D) poses a serious threat to the life and health of patients. However, its pathogenesis remains unclear, resulting in a lack of effective treatment for the root cause. It is found that both intestinal Bacteroides fragilis (BF) and peripheral M2 monocytes/macrophages are significantly elevated in patients with T2D VC. M2 macrophages are identified as a significant risk factor for T2D VC. Both BF and their extracellular vesicles (EV) promote T2D VC and facilitate macrophage M2 polarization. Macrophages clearance significantly antagonized BF EV-induced T2D VC in mice. Mechanistically, EV-rich double-stranded DNA (dsDNA) activates stimulator of interferon response cGAMP interactor 1 (Sting), promotes myocyte enhancer factor 2D (Mef2d) phosphorylation, upregulates tribbles pseudokinase 1 (Trib1) expression, and induces macrophage M2 polarization. Concurrently, Mef2d activated by the EV targets and upregulates the expression of pro-calcification factor Serpine1, thereby exacerbating T2D VC. Clinical studies have shown that Serpine1 is significantly elevated in the peripheral blood of patients with T2D VC and is closely associated with T2D VC. In summary, this study reveals that intestinal BF promotes Trib1 expression through the EV-Sting-Mef2d pathway to induce macrophage M2 polarization and upregulates serpin family E member 1 (Serpine1) expression, thereby aggravating T2D VC. The findings provide a new theoretical and experimental bases for optimizing the strategies for prevention and treatment of T2D VC.
Insights
Intestinal bacteria Bacteroides fragilis (BF) and their extracellular vesicles (EV) worsen type 2 diabetes vascular calcification (T2D VC) by promoting M2 macrophage polarization and increasing Serpine1 levels.
Area of Science:
- Cardiovascular Research
- Microbiology
- Immunology
Background:
- Vascular calcification (VC) is a major complication in type 2 diabetes (T2D), with unclear pathogenesis and limited effective treatments.
- Elevated levels of intestinal Bacteroides fragilis (BF) and M2 macrophages are observed in T2D patients with VC.
- M2 macrophages are identified as a significant risk factor for T2D-associated VC.
Purpose of the Study:
- To elucidate the role of intestinal BF and their extracellular vesicles (EV) in the pathogenesis of T2D VC.
- To investigate the molecular mechanisms by which BF-EVs induce M2 macrophage polarization and promote VC.
- To identify potential therapeutic targets for T2D VC.
Main Methods:
- Analysis of BF and M2 macrophage levels in T2D VC patients.
- In vivo studies using mouse models to assess the impact of BF-EVs on VC and macrophage clearance.
- Mechanistic studies involving dsDNA, Sting, Mef2d, Trib1, and Serpine1 in macrophage polarization and VC induction.
Main Results:
- BF and their EVs promote T2D VC and M2 macrophage polarization.
- Macrophage clearance significantly reduced BF EV-induced T2D VC in mice.
- BF EVs activate the EV-dsDNA-Sting-Mef2d-Trib1 pathway, inducing M2 polarization and upregulating Serpine1, exacerbating T2D VC.
Conclusions:
- Intestinal BF, via their EVs, promote T2D VC through the EV-dsDNA-Sting-Mef2d-Trib1 pathway, leading to M2 macrophage polarization and increased Serpine1 expression.
- This study provides novel insights into the pathogenesis of T2D VC and identifies potential therapeutic targets.
- Targeting BF or the identified molecular pathway may offer new strategies for T2D VC prevention and treatment.
