Recent evidence points to the gut microbiota as a regulator of brain and behavior, although it remains to be determined if gut bacteria play a role in chronic pain. The endocannabinoid system is implicated in inflammation and chronic pain processing at both the gut and central nervous system (CNS) levels. In the present study, we used low Vitamin D dietary intake in mice and evaluated possible changes in gut microbiota, pain processing and endocannabinoid system signaling. Vitamin D deficiency induced a lower microbial diversity characterized by an increase in Firmicutes and a decrease in Verrucomicrobia and Bacteroidetes. Concurrently, vitamin D deficient mice showed tactile allodynia associated with neuronal hyperexcitability and alterations of endocannabinoid system members (endogenous mediators and their receptors) at the spinal cord level. Changes in endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were also observed in the duodenum and colon. Remarkably, the anti-inflammatory anandamide congener, palmitoylethanolamide, counteracted both the pain behaviour and spinal biochemical changes in vitamin D deficient mice, whilst increasing the levels of Akkermansia, Eubacterium and Enterobacteriaceae, as compared with vehicle-treated mice. Finally, induction of spared nerve injury in normal or vitamin D deficient mice was not accompanied by changes in gut microbiota composition. Our data suggest the existence of a link between Vitamin D deficiency - with related changes in gut bacterial composition - and altered nociception, possibly via molecular mechanisms involving the endocannabinoid and related mediator signaling systems.

中文翻译：

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维生素 D 缺乏介导的慢性疼痛中肠道微生物群和内源性大麻素系统的变化

最近的证据表明肠道微生物群是大脑和行为的调节器，尽管肠道细菌是否在慢性疼痛中起作用仍有待确定。内源性大麻素系统与肠道和中枢神经系统 (CNS) 水平的炎症和慢性疼痛处理有关。在本研究中，我们在小鼠中使用低维生素 D 膳食摄入量，并评估了肠道微生物群、疼痛处理和内源性大麻素系统信号传导的可能变化。维生素 D 缺乏导致微生物多样性降低，其特征是厚壁菌门增加，疣微菌门和拟杆菌门减少。同时，缺乏维生素 D 的小鼠表现出与神经元过度兴奋和脊髓水平的内源性介质系统成员（内源性介质及其受体）的改变相关的触觉异常性疼痛。在十二指肠和结肠中也观察到内源性大麻素（anandamide 和 2-花生四烯酸甘油）水平的变化。值得注意的是，与载体处理的小鼠相比，抗炎 anandamide 同源物棕榈酰乙醇酰胺可以抵消维生素 D 缺乏小鼠的疼痛行为和脊柱生化变化，同时增加阿克曼氏菌、真杆菌和肠杆菌科的水平。最后，在正常或缺乏维生素 D 的小鼠中诱导神经损伤并未伴随肠道微生物群组成的变化。我们的数据表明维生素 D 缺乏（与肠道细菌组成的相关变化）和伤害感受改变之间存在联系，可能是通过涉及内源性大麻素和相关介质信号系统的分子机制。