Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes with no effective drug currently. Quercetin is a natural bio-flavonoid widely distributed in the human diet. As an effective antioxidant for reactive oxygen species (ROS) protection, quercetin’s protective effects against diabetes, inflammation, and nerve damage have been extensively documented. However, the mechanism of its neuroprotective function and the link to the gut microbiota remains to be elucidated.

The present study investigated the relationship between the therapeutic effect and the modulation of gut microbiota of quercetin in DPN rats. The current results indicate that quercetin might exert a peripheral neuroprotective effect in DPN rats by modulating the gut microbial dysbiosis through decreasing the abundance of potential pathogenic bacterias, such as f_Porphyromonadaceae, f_Oxalobacteraceae, g_Oxalobacter and g_Klebsiella, which were positively correlated with DPN phenotypes and ROS production levels; while enriching the potential ‘probiotics’ bacterial taxa, such as p_Actinobacteria and c_Actinobacteria, which were negatively correlated with DPN phenotypes and ROS production levels. These target microbiota species might help ameliorate the oxidant stress that caused myelin and axon damage accompanied with up-regulated amyloid precursor protein (APP) and ionized calcium binding adaptor molecule 1 (Iba1) expressions and down-regulated percentage of contactin-associated protein (Caspr)-expressing paranodes in the sciatic nerves of DPN rats. Meanwhile, the balanced gut microbiota might help improve protein gene product 9.5 (PGP9.5)-positive intraepidermal nerve fiber densities in the plantar skin of DPN rats. The protected sciatic nerves and increased intraepidermal nerve fiber densities might contribute to the improved peripheral nerve functions after quercetin treatment.

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.