Protective effect of quercetin on streptozotocin-induced diabetic peripheral neuropathy rats through modulating gut microbiota and reactive oxygen species level

Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes with no effective drug currently. As a powerful antioxidant, the flavonoid quercetin has been demonstrated to have potential neuroprotective and prebiotic capacity. But the mechanism of its neuroprotective function and the link to the gut microbiota remains to be elucidated. The neuroprotective effect of quercetin was evaluated on streptozotocin(STZ)-induced DPN rats through electrophysiology, behavioristic, and pathomorphology studies. Serum and urine reactive oxygen species (ROS) production levels and fecal gut microbiota compositions were detected, and the relationship between them was analyzed by Spearman's correlation. Quercetin not only reversed the decreased mechanical withdraw thresholds and intraepidermal nerve fiber densities in DPN rats, but also improved neurological morphology of sciatic nerves, accompanied with up-regulated percentage of paranodes at paranodal junctions, and down-regulated amyloid precursor protein and ionized calcium-binding adaptor molecule 1 in DPN rats. More importantly, quercetin rescued gut dysbiosis in DPN rats by decreasing four potential pathogenic species and enriching two prebiotic species associated with DPN phenotypes and ROS production levels. Quercetin exerts neuroprotective effect and modulates gut microbiota associated with DPN phenotypes and ROS production levels in STZ-induced DPN rats, suggesting the therapeutic application of quercetin for DPN prevention and treatment.