Multi-Omics Insights into the Gut-Spinal Cord Axis: Paeoniflorin Mitigates Diabetic Neuropathic Pain in Rats through Microbial-Metabolic Crosstalk

IF 7.3 1区农林科学 Q1 FOOD SCIENCE & TECHNOLOGY

Food Science and Human Wellness Pub Date : 2025-11-01 DOI:10.26599/fshw.2025.9250837

Yuning Liu, Zhi Ming, Shuaiying Jia, Su Yao, Kun Wu, Wei Yan, Jingyan Lin

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引用次数: 1

Abstract

Painful Diabetic Neuropathy (PDN), a common chronic complication of diabetes, is closely associated with glymphatic system dysfunction and neuroinflammation. This study is the first to explore the mechanism of Paeoniflorin (PF) in treating PDN from the perspective of the gut-spinal cord axis. By establishing a streptozotocin (STZ)/high-fat diet-induced PDN rat model and integrating metagenomics, untargeted metabolomics, and microbial depletion techniques, we demonstrated that PF significantly improved mechanical paw withdrawal threshold (PWT), alleviated insulin resistance, and reduced spinal pro-inflammatory cytokine levels (IL-1β, IL-6, TNF-α) in PDN rats. Dynamic Magnetic resonance imaging (MRI) revealed that PF restored spinal glymphatic metabolic function, evidenced by enhanced gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) clearance and aquaporin-4 (AQP4) polarization remodeling. Immunofluorescence confirmed that PF suppressed astrocyte activation (total GFAP fluorescence intensity decreased by 61.86% in the PF group vs. PDN group) and restored AQP4 polarity at perivascular endfeet (polarization rate increased from 31.8% to 59.3%). These therapeutic effects were completely reversed by antibiotic intervention (ABX+PF group), highlighting the critical role of gut microbiota. Metagenomic analysis showed that PF enriched short-chain fatty acid (SCFA)-producing genera (Bifidobacterium and Faecalibacterium), activating the tricarboxylic acid (TCA) cycle and arginine metabolism. Metabolomics identified PF-mediated upregulation of anti-inflammatory metabolites (e.g., MGMG 18:2 and N-Acetyl-4-O-acetylneuraminic acid) and suppression of dehydroepiandrosterone sulfate (DHEA-S) synthesis. Our findings demonstrate that PF alleviates PDN by remodeling the gut microbiota-metabolite network, repairing intestinal barrier integrity, and regulating AQP4-dependent waste clearance in the spinal glymphatic system, providing novel therapeutic targets. This study elucidates the regulatory role of the gut-spinal cord axis in PDN and offers a paradigm for investigating "microbiota-host" interactions of low-bioavailability herbal components.

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肠道-脊髓轴的多组学研究：芍药苷通过微生物-代谢串扰减轻大鼠糖尿病神经性疼痛

疼痛性糖尿病神经病变（pain Diabetic Neuropathy， PDN）是糖尿病常见的慢性并发症，与淋巴系统功能障碍和神经炎症密切相关。本研究首次从肠脊髓轴的角度探讨芍药苷（Paeoniflorin， PF）治疗PDN的机制。通过建立链脲佐菌素(STZ)/高脂饮食诱导的PDN大鼠模型，并整合元基因组学、非靶向代谢组学和微生物消耗技术，我们发现PF显著改善PDN大鼠的机械爪戒断阈值（PWT），减轻胰岛素抵抗，降低脊髓促炎细胞因子（IL-1β、IL-6、TNF-α）水平。动态磁共振成像（MRI）显示，PF可以恢复脊髓淋巴代谢功能，这可以通过增强钆-二乙烯三胺五乙酸（Gd-DTPA）清除和水通道蛋白-4 （AQP4）极化重塑来证明。免疫荧光证实，PF抑制星形胶质细胞活化（PF组GFAP总荧光强度比PDN组降低61.86%），恢复血管周围终足AQP4极性（极化率从31.8%增加到59.3%）。抗生素干预（ABX+PF组）完全逆转了这些治疗效果，突出了肠道微生物群的关键作用。宏基因组分析表明，PF富含短链脂肪酸（SCFA）产生属（双歧杆菌和Faecalibacterium），激活三羧酸（TCA）循环和精氨酸代谢。代谢组学鉴定了nf介导的抗炎代谢物（如MGMG 18:2和n -乙酰-4- o -乙酰神经氨酸）的上调和硫酸脱氢表雄酮（DHEA-S）合成的抑制。我们的研究结果表明，PF通过重塑肠道微生物群代谢物网络、修复肠道屏障完整性和调节脊髓淋巴系统中aqp4依赖性废物清除来缓解PDN，提供了新的治疗靶点。本研究阐明了肠-脊髓轴在PDN中的调节作用，并为研究低生物利用度草药成分的“微生物-宿主”相互作用提供了一个范例。

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来源期刊

Food Science and Human Wellness Agricultural and Biological Sciences-Food Science

CiteScore

8.30

自引率

5.70%

发文量

审稿时长

28 days

期刊介绍： Food Science and Human Wellness is an international peer-reviewed journal that provides a forum for the dissemination of the latest scientific results in food science, nutriology, immunology and cross-field research. Articles must present information that is novel, has high impact and interest, and is of high scientific quality. By their effort, it has been developed to promote the public awareness on diet, advocate healthy diet, reduce the harm caused by unreasonable dietary habit, and directs healthy food development for food industrial producers.