Gut Microbiota and Its Metabolites Promote Painful Diabetic Peripheral Neuropathy Complicated with Cognitive Dysfunction in Mice

Junpeng YANG^1,2,3Xin Lv³Ya Xu¹Fenglian Huang¹Xueli Yang^1,2,3Xiaoyang Shi^1,2,3Lingyun Zhao^1,2Chenghong Liang^1,2Danyu Wang^1,2,3Yuanyuan Fang^1,2,3Shasha Tang^1,2,3Yalei Liu^1,2,3Limin Wang^1,2,3Xinru Deng^1,2,3Xiaobing Wang^1,2,3Huijuan Yuan^1,2,3*

• ¹Department of Endocrinology, Henan Provincial People's Hospital, Zhengzhou, China
• ²Department of Endocrinology, People’s Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
• ³Department of Endocrinology, People’s Hospital of Henan University, Zhengzhou, China

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 db/db mice with PDPN and concomitant cognitive impairment, and to investigate the underlying mechanisms. At 12 weeks of age, db/db 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 db/db mice and 39 ASVs more abundant in db/m 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 (Muribaculaceae (ASV243) and Ruminococcus (ASV149)) and thermal latency. In contrast, polygalic acid negatively mediated the relationship between Muribaculaceae and escape latency, as well as between Ruminococcus 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 db/db 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.