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Research Article: Causal relationship between gut microbiota and diabetic neuropathy: a Mendelian randomization and 16S rRNA sequencing analysis

Date Published: 2025-09-25

Abstract:
Evidence suggests a link between gut microbiota and diabetes mellitus, yet the specific role in diabetic peripheral neuropathy (DPN) remains elusive. The study aims to explore the association through Mendelian randomization and 16S rRNA gene sequencing analysis. Mendelian randomization (MR) analysis was employed to investigate the causal association between gut microbiota and diabetic neuropathy. Diabetes mellitus (DM) and DPN mice models were developed via high-fat diet (HFD) feeding followed by intraperitoneal streptozotocin (STZ) administration at 30 mg/kg (DM group) or 60 mg/kg (DPN group). The occurrence of diabetic neuropathy was determined by evaluating pain-related behavioral parameters in mice. Additionally, fecal samples from mice and patients with diabetic neuropathy were collected, and 16S rRNA sequencing was performed to analyze the composition of gut microbiota. Mendelian randomization analysis identified 14 gut microbiota species exhibiting a causal relationship with diabetic neuropathy. In animal studies, diabetic neuropathy mice exhibited decreased mechanical pain thresholds and reduced thermal withdrawal latency. Sequencing analyses further revealed significant alterations in gut microbiota composition in both DPN mice and DPN patients compared to control group. This study integrates Mendelian randomization analysis with 16S rRNA fecal assessments from animal models and clinical patients, revealing that gut microbiota imbalances may contribute to diabetic neuropathy development and providing novel insights for its prevention and therapeutic strategies.

Introduction:
Diabetes mellitus (DM) is a global epidemic, affecting an estimated 536.6 million people in 2021, with projections indicating a rise to 783.2 million people by2045 ( 1 , 2 ).Diabetic peripheral neuropathy (DPN), affecting about 50% among diabetic patients ( 3 , 4 ), manifests as debilitating pain and sensory loss, drastically reducing quality of life and imposing substantial healthcare costs—up to 4.2 times higher than diabetes without DPN ( 5 , 6 ). Currently, the treatment options for diabetic neuropathy are…

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