Lactobacillus rhamnosus GG and butyrate supplementation in rats with bone cancer reduces mechanical allodynia and increases expression of μ-opioid receptor in the spinal cord.
Lactobacillus rhamnosus GG and butyrate supplementation in rats with bone cancer reduces mechanical allodynia and increases expression of μ-opioid receptor in the spinal cord.
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DOI：
10.3389/fnmol.2023.1207911
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发表时间：
2023
影响因子：
4.8
通讯作者：
Song, Xue-Jun
中科院分区：
文献类型：
--
作者：
Yuan, Wenxi;Xiao, Jie;Liao, Huabao;Xie, Zhiyuan;Zhao, Yiran;Li, Cheng;Zhou, Keying;Song, Xue-Jun
关键词：
慢性癌痛是晚期癌症患者最难以忍受的症状之一。癌症疼痛的治疗仍然面临着重大挑战。在这里，我们报告通过益生菌调整肠道微生物群可以减轻大鼠的骨癌疼痛（BCP）。 BCP模型是通过将肿瘤细胞植入(TCI)到大鼠胫骨来产生的。连续饲喂鼠李糖乳杆菌 GG (LGG) 用于调节肠道微生物群。评估了机械性异常疼痛、骨质破坏、粪便微生物群以及初级背根神经节（DRG）和脊髓背角（DH）的神经化学变化。 LGG 补充剂（109 CFU/大鼠/天）可延迟 BCP 的产生 3-4 天，并在 TCI 后的前 2 周内显着减轻机械性异常性疼痛。 TCI 后第 8 天补充 LGG 后，TCI 诱导的 DH 中促炎细胞因子 TNF-α 和 IL-β 以及 TCI 诱导的胫骨骨质破坏均显着减少。同时，我们发现补充 LGG 除了抑制 TCI 引起的疼痛外，还导致 DH 中 μ-阿片受体 (MOR) 的表达显着增加，但 DRG 中却没有。 LGG 补充剂显着增强吗啡的镇痛作用。此外，补充 LGG 导致粪便和血清中丁酸盐水平增加，DH 中组蛋白脱乙酰酶 2 (HDAC2) 表达减少。以 100 mg/kg 的剂量单独用丁酸钠溶液喂养 TCI 大鼠，可减轻疼痛，并减少 DH 中的 HDAC2 表达和增加 MOR 表达。当我们用补充 LGG 或丁酸钠的 TCI 大鼠血清处理细胞时，在 Neuro-2a 细胞中也观察到 MOR 表达增加和 HDAC2 减少。这项研究提供的证据表明，用益生菌 LGG 重塑肠道微生物群可以延缓癌症疼痛的发作。丁酸-HDAC2-MOR通路可能是LGG镇痛作用的潜在机制。这些发现揭示了一种有效、安全和非侵入性的癌症疼痛控制方法，并支持补充益生菌对 BCP 患者的临床意义。
Chronic cancer pain is one of the most unbearable symptoms for the patients with advanced cancer. The treatment of cancer pain continues to possess a major challenge. Here, we report that adjusting gut microbiota via probiotics can reduce bone cancer pain (BCP) in rats. The model of BCP was produced by tumor cell implantation (TCI) to the tibia in rats. Continuous feeding of Lactobacillus rhamnosus GG (LGG) was used to modulate the gut microbiota. Mechanical allodynia, bone destruction, fecal microbiota, and neurochemical changes in the primary dorsal root ganglion (DRG) and the spinal dorsal horn (DH) were assessed. LGG supplementation (109 CFU/rat/day) delayed the production of BCP for 3–4 days and significantly alleviated mechanical allodynia within the first 2 weeks after TCI. TCI-induced proinflammatory cytokines TNF-α and IL-β in the DH, and TCI-induced bone destruction in the tibia were both significantly reduced following LGG supplementation examined on day 8 after TCI. Meanwhile, we found that LGG supplementation, in addition to inhibiting TCI-induced pain, resulted in a significantly increased expression of the μ-opioid receptor (MOR) in the DH, but not in the DRG. LGG supplementation significantly potentiated the analgesic effect of morphine. Furthermore, LGG supplementation led to an increase in butyrate levels in the feces and serum and a decrease in histone deacetylase 2 (HDAC2) expression in the DH. Feeding TCI-rats with sodium butyrate solution alone, at a dose of 100 mg/kg, resulted in decreased pain, as well as decreased HDAC2 expression and increased MOR expression in the DH. The increased expression of MOR and decreased HDAC2 were also observed in neuro-2a cells when we treated the cells with serum from TCI rats with supplementation of LGG or sodium butyrate. This study provides evidence that reshaping the gut microbiota with probiotics LGG can delay the onset of cancer pain. The butyrate-HDAC2-MOR pathway may be the underlying mechanism for the analgesic effect of LGG. These findings shed light on an effective, safe, and non-invasive approach for cancer pain control and support the clinical implication of probiotics supplementation for patients with BCP.
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影响因子：
13.9
作者：
Corder G;Castro DC;Bruchas MR;Scherrer G
通讯作者：
Scherrer G
影响因子：
2.1
作者：
Hippe, Berit;Zwielehner, Jutta;Haslberger, Alexander G.
通讯作者：
Haslberger, Alexander G.
影响因子：
82.9
作者：
Rousseaux, Christel;Thuru, Xavier;Desreumaux, Pierre
通讯作者：
Desreumaux, Pierre
影响因子：
7.6
作者：
Horvath, A.;Dziechciarz, P.;Szajewska, H.
通讯作者：
Szajewska, H.
DOI：
10.1073/pnas.0711891105
发表时间：
2008-02-12
影响因子：
11.1
作者：
Amaral, F. A.;Sachs, D.;Teixeira, M. M.
通讯作者：
Teixeira, M. M.