Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Canada.
Gut Microbes. 2023 Jan-Dec;15(1):2188874. doi: 10.1080/19490976.2023.2188874.
Abdominal pain is common in patients with gastrointestinal disorders, but its pathophysiology is unclear, in part due to poor understanding of basic mechanisms underlying visceral sensitivity. Accumulating evidence suggests that gut microbiota is an important determinant of visceral sensitivity. Clinical and basic research studies also show that sex plays a role in pain perception, although the precise pathways are not elucidated. We investigated pain responses in germ-free and conventionally raised mice of both sexes, and assessed visceral sensitivity to colorectal distension, neuronal excitability of dorsal root ganglia (DRG) neurons and the production of substance P and calcitonin gene-related peptide (CGRP) in response to capsaicin or a mixture of G-protein coupled receptor (GPCR) agonists. Germ-free mice displayed greater in vivo responses to colonic distention than conventional mice, with no differences between males and females. Pretreatment with intracolonic capsaicin or GPCR agonists increased responses in conventional, but not in germ-free mice. In DRG neurons, gut microbiota and sex had no effect on neuronal activation by capsaicin or GPCR agonists. While stimulated production of substance P by DRG neurons was similar in germ-free and conventional mice, with no additional effect of sex, the CGRP production was higher in germ-free mice, mainly in females. Absence of gut microbiota increases visceral sensitivity to colorectal distention in both male and female mice. This is, at least in part, due to increased production of CGRP by DRG neurons, which is mainly evident in female mice. However, central mechanisms are also likely involved in this process.
腹痛是胃肠道疾病患者的常见症状，但腹痛的病理生理学机制尚不清楚，部分原因是对内脏敏感性的基本机制了解不足。越来越多的证据表明，肠道微生物群是内脏敏感性的重要决定因素。临床和基础研究也表明，性别在疼痛感知中起作用，尽管确切的途径尚不清楚。我们研究了无菌和常规饲养的雌雄小鼠的疼痛反应，并评估了对结直肠扩张的内脏敏感性、背根神经节 (DRG) 神经元的兴奋性以及对辣椒素或 G 蛋白偶联受体 (GPCR) 激动剂混合物的物质 P 和降钙素基因相关肽 (CGRP) 的产生。无菌小鼠对结肠扩张的体内反应大于常规小鼠，雌雄小鼠之间没有差异。常规饲养的小鼠经结肠内给予辣椒素或 GPCR 激动剂预处理可增加反应，但无菌饲养的小鼠无此反应。在 DRG 神经元中，肠道微生物群和性别对辣椒素或 GPCR 激动剂激活神经元没有影响。虽然 DRG 神经元中辣椒素或 GPCR 激动剂刺激的物质 P 产生相似，且无性别差异，但 CGRP 的产生在无菌小鼠中更高，主要在雌性小鼠中。肠道微生物群的缺失增加了雌雄小鼠对结直肠扩张的内脏敏感性。至少部分原因是 DRG 神经元中 CGRP 的产生增加，这主要在雌性小鼠中明显。然而，中枢机制也可能参与这一过程。
