<br>细菌纳米囊泡作为介导疼痛超敏反应的界间信号部分,ACS Nano

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细菌纳米囊泡作为介导疼痛超敏反应的界间信号部分
ACS Nano ( IF 15.8 ) Pub Date : 2025-01-16 , DOI: 10.1021/acsnano.4c10529
Sameh Almousa ₁ , Susy Kim ₁ , Ashish Kumar ₁ , Yixin Su ₁ , Sangeeta Singh ₁ , Shalini Mishra ₁ , Miriam M Fonseca ₂ , Hilal A Rather ₁ , E Alfonso Romero-Sandoval ₂ , Fang-Chi Hsu _{3,

4} , Rakesh Singh ₅ , Hariom Yadav ₆ , Santosh Mishra _{7,

8} , Gagan Deep _{1,

4,

9}

Affiliation

Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, United States.
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, United States.
Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, United States.
Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, United States.
Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
USF Center for Microbiome Research, Microbiomes Institute, University of South Florida Morsani College of Medicine, Tampa, Florida 33612, United States.
Comparative Pain Research and Education Center, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27607, United States.
Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina 27607, United States.
Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, United States.

肠道菌群失调会导致多种病理，但肠道菌群介导的对全身和远处反应影响的机制在很大程度上仍然难以捉摸。本研究旨在确定纳米细菌细胞外囊泡（bEV）在饮食诱导的肥胖（DIO）肠道菌群失调模型中介导异常性疼痛，即疼痛超敏反应中的作用。通过结合超速离心和免疫沉淀的方法，从瘦（bEV^Lean）和 DIO （bEV^DIO）小鼠的粪便中富集 bEV，然后广泛分析纯度和细菌特性。接下来，在小鼠体内或静脉内注射 bEV 以评估疼痛敏感性。通过灌肠将荧光标记的 bEVs 注射到小鼠体内以评估生物分布。通过阵列、免疫表型分析、显微镜检查、NF-κB 活化和细胞摄取测定分析 bEV 对免疫细胞和炎症的影响。结果显示，在野生型小鼠中施用 bEV^DIO 复制了在 DIO 小鼠中观察到的机械和热刺激异常性疼痛表型。重要的是，这种效果在 TRPA1/TRPV1 双重敲除小鼠中受到了影响。生物分布分析显示 bEV 进入体循环，随后定位在远处。多项分析表明，bEV^DIO 暴露主要通过调节先天免疫系统引发全身炎症。这种炎症机制涉及 bEV 表面的 LPS，激活 TLR2 和 TLR4 相关通路，使用 TLR2 和 TLR4 抑制剂和剃除 bEV 表面蛋白证实了这一点。有趣的是，bEV^DIO 的细胞摄取增强取决于涉及 LPS 和 bEV 上的蛋白质以及单核细胞上的 TLR2/TLR4 的相互作用。这些发现阐明了 bEV 作为与肠道菌群失调相关的异常性疼痛和炎症的关键介质的作用，这是迄今为止未被探索的作用。

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Bacterial Nanovesicles as Interkingdom Signaling Moieties Mediating Pain Hypersensitivity

Gut dysbiosis contributes to multiple pathologies, yet the mechanisms of the gut microbiota-mediated influence on systemic and distant responses remain largely elusive. This study aimed to identify the role of nanosized bacterial extracellular vesicles (bEVs) in mediating allodynia, i.e., pain hypersensitivity, in a diet-induced obesity (DIO) gut dysbiosis model. bEVs were enriched from the feces of lean (bEV^Lean) and DIO (bEV^DIO) mice by an approach combining ultracentrifugation and immunoprecipitation and then extensively analyzed for purity and bacterial characteristics. Next, bEVs were injected, either intraplantarly or intravenously, in mice to assess pain sensitivity. Fluorescence-labeled bEVs were injected in mice by enema to assess biodistribution. The effect of bEV on immune cells and inflammation was analyzed by array, immunophenotyping, microscopy, NF-κB activation, and cellular uptake assays. Results showed that bEV^DIO administration in wild-type mice replicated the allodynia phenotype observed in DIO mice for both mechanical and thermal stimuli. Importantly, this effect was compromised in TRPA1/TRPV1 double-knockout mice. Biodistribution analyses showed bEV entry into systemic circulation with subsequent localization at distant sites. Multiple analyses revealed that bEV^DIO exposure incited systemic inflammation, primarily through modulating the innate immune system. This inflammatory mechanism involved LPS on the bEV surface, activating TLR2- and TLR4-related pathways, as confirmed using TLR2 and TLR4 inhibitors and shaving bEV surface proteins. Interestingly, the enhanced cellular uptake of bEV^DIO was contingent on interactions involving LPS and proteins on bEVs and TLR2/TLR4 on monocytes. These findings illuminate the hitherto unexplored role of bEV as pivotal mediators of allodynia and inflammation linked to gut dysbiosis.

更新日期：2025-01-16

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