Dietary Geranylgeraniol Mitigates Pain-Associated Behaviors via Improving Mitochondrial Function and Colon Integrity and Suppressing Neuroinflammation in Male Diabetic Neuropathy Rats

Growing evidence highlights the links between diabetic neuropathy (DNP), gut dysbiosis, mitochondrial dysfunction and neuroinflammation in colon and bone microstructure deterioration. Geranylgeraniol (GG) shows neuroprotective and osteoprotective capacity. Our study examines GG's effects on pain-associated behaviors, glucose homeostasis, gut microbiota, mitochondrial homeostasis, and bone microstructure in DNP rats. We randomly assigned 27 male Sprague Dawley rats to three groups (<i>n</i> = 8-10/group): a control group (regular low-fat diet), a DNP group (high-fat diet + a single dose of 35 mg/kg streptozotocin), and a GG-treated DNP group (a single dose of 35 mg/kg streptozotocin + GG at 800 mg/kg in diet) for 6 weeks. Nocifensive response was assessed via the von Frey test and an open field test, and the elevated plus maze was used to assess anxio-depressive behaviors. The mRNA expression levels of tight junction protein, mitochondrial homeostasis, and neuroinflammation were measured in the colon using qRT-PCR. We collected fecal samples for microbiota composition analysis with 16S rRNA gene sequencing and analyzed by QIIME 2. All other data were analyzed via one-way ANOVA followed by post hoc Tukey's multiple comparison. <i>p</i> < 0.05 was defined as statistical significance. Our study showed GG's ability to mitigate mechanical hypersensitivity and anxio-depressive behavior in rats with DNP. GG supplementation did not improve glucose homeostasis (i.e., glucose intolerance, insulin sensitivity, pancreatic β-cell dysfunction) and bone microstructure. GG increased alpha-diversity without changing microbial abundance. DNP rats exhibited elevated Clostridium <i>sensu stricto</i> and reduced Eubacterium <i>coprostanoligenes</i>, <i>Lachnospiraceae</i>, <i>Oscillospiraceae</i>, and <i>Peptococcaceae</i> compared with controls. GG did not reverse DNP-induced gut dysbiosis but increased colonic claudin-3 (tight junction), MFN1 (mitochondria fusion), and TFAM (mitochondria biogenesis), while reducing FIS1 (mitochondria fission), GFAP (glial activation), P62 and PINK1 (mitophagy), and TNFα (inflammation). Functionally, GG reduced pain behaviors, improved intestinal integrity and mitochondrial homeostasis, increased alpha-diversity, and suppressed neuroinflammation, but did not improve glucose homeostasis or bone microstructure in obese DNP rats.