Yang Junpeng, Lv Xin, Xu Ya, Huang Fenglian, Yang Xueli, Shi Xiaoyang, Zhao Lingyun, Liang Chenghong, Wang Danyu, Fang Yuanyuan, Tang Shasha, Liu Yalei, Wang Limin, Deng Xinru, Wang Xiaobing, Yuan Huijuan
Department of Endocrinology, Henan Provincial Key Medicine Laboratory of Intestinal Microecology and Diabetes, Henan Provincial People's Hospital, Zhengzhou, Henan, China.
Department of Endocrinology, Henan Provincial Key Medicine Laboratory of Intestinal Microecology and Diabetes, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Front Cell Infect Microbiol. 2025 Sep 2;15:1599954. doi: 10.3389/fcimb.2025.1599954. eCollection 2025.
Painful diabetic peripheral neuropathy (PDPN) is closely linked to cognitive dysfunction. The gut microbiota plays a pivotal role in the pathophysiology of diabetic neuropathy, but its contribution, along with related metabolites, to PDPN complicated by cognitive impairment remains poorly understood. This study aimed to explore the characteristics of gut microbiota and metabolites in / mice with PDPN and concomitant cognitive impairment, and to investigate the underlying mechanisms.
Male homozygous / mice and their littermate / mice used as the research subjects. Thermal hyperalgesia and mechanical allodynia tests were applied to assess pain phenotypes, while the Morris water maze test was used to evaluate cognitive function. Immunohistochemistry was employed to measure intraepidermal nerve fiber density and nerve fiber markers, and Western blot analysis was used to detect pro-inflammatory cytokine levels. 16S rRNA gene sequencing of the V3-V4 regions was applied to analyze the gut microbiota structure, and LC-MS was used to analyze fecal metabolites.
At 12 weeks of age, / mice exhibited PDPN and cognitive deficits. The gut microbiota composition differed between the two groups, with LEfSe analysis identifying 38 key amplicon sequence variants (ASVs) enriched in / mice and 39 ASVs more abundant in / mice. Meanwhile, 398 metabolites that were significantly different between the two groups. Bidirectional mediation models indicated that Dl-lactate positively mediated the relationship between specific microbiota ( (ASV243) and (ASV149)) and thermal latency. In contrast, polygalic acid negatively mediated the relationship between and escape latency, as well as between and thermal latency. These microbiota and metabolite changes were associated with elevated proinflammatory cytokine levels in the dorsal root ganglion (DRG) and hippocampus, respectively.
This study highlights the intricate relationship between gut microbiota, metabolites, and both PDPN and cognitive dysfunction in / mice. It also provides insights into potential mechanisms underlying the pathophysiology of these comorbidities, suggesting that modulation of the gut microbiota and its metabolites may offer new therapeutic strategies.
疼痛性糖尿病周围神经病变（PDPN）与认知功能障碍密切相关。肠道微生物群在糖尿病神经病变的病理生理学中起关键作用，但其对合并认知障碍的PDPN的贡献以及相关代谢产物仍知之甚少。本研究旨在探讨合并PDPN和认知障碍的小鼠肠道微生物群和代谢产物的特征，并研究其潜在机制。
将雄性纯合/小鼠及其同窝/小鼠作为研究对象。采用热痛觉过敏和机械性异常性疼痛测试来评估疼痛表型，同时使用莫里斯水迷宫测试来评估认知功能。采用免疫组织化学法测量表皮内神经纤维密度和神经纤维标志物，并用蛋白质免疫印迹分析检测促炎细胞因子水平。应用V3-V4区域的16S rRNA基因测序分析肠道微生物群结构，并用液相色谱-质谱联用仪分析粪便代谢产物。
12周龄时，/小鼠表现出PDPN和认知缺陷。两组的肠道微生物群组成不同，通过线性判别分析效应大小（LEfSe）分析确定，/小鼠中有38个关键扩增子序列变体（ASV）富集，/小鼠中有39个ASV更为丰富。同时，两组之间有398种代谢产物存在显著差异。双向中介模型表明，D-乳酸正向介导特定微生物群（（ASV243）和（ASV149））与热潜伏期之间的关系。相反，聚半乳糖醛酸负向介导与逃避潜伏期之间的关系，以及与热潜伏期之间的关系。这些微生物群和代谢产物的变化分别与背根神经节（DRG）和海马体中促炎细胞因子水平升高有关。
本研究突出了/小鼠肠道微生物群、代谢产物与PDPN和认知功能障碍之间的复杂关系。它还为这些合并症病理生理学的潜在机制提供了见解，表明调节肠道微生物群及其代谢产物可能提供新的治疗策略。
