SCFA-GPR41/43-AMPAR/NMDAR免疫神经轴介导肠易激综合征内脏高敏感机制研究

Brain-gut axis dysfunction is associated with visceral hypersensitivity in irritable bowel syndrome (IBS). Previous studies have revealed that Microbiota-generated metabolites (Short-chain fatty acids, SCFAs) have an influence on brain function by immunological, neuroendocrine pathways. SCFAs receptors were mainly expressed on enterochromaffin cells, which are gut chemosensors that couple to sensory neural pathways. In vivo, we have found that SCFAs levels and expression of GPR43 are increased in water-avoidance stress (WAS) induced IBS mouse model with visceral hypersensitivity. Furthermore, increased expressions of excitatory glutamic amino acid neurotransmitters receptors in the central nervous system have been identified. When high FODMAP diet (ferment into SCFAs) was given, the effect was enhanced, while SCFAs levels, expressions of GPR43 and glutamic receptors were decreased and visceral hypersensitivity was improved when pseudo-germ free mice were applied. Based on previous evidence, we put forward a hypothesis that WAS induced intestinal microbiota dysbiosis, followed with SCFAs dysregulated metabolism and innervated with GPR41/43-AMPAR/NMDAR axis, leading to visceral hyperalgesia. Firstly, we intend to evaluate the condition of microbiota, SCFAs, expressions of GPR41/43 and AMPAR/NMDAR, and visceral sensitivity in WAS induced IBS mouse model. Secondly, we will use inhibitors, knock-out mice, pseudo-germ free mice, cohousing to identify the critical role of SCFA-GPR41/43-AMPAR/NMDAR axis in the development of visceral hyperalgesia in IBS. Finally, concentration gradient FODMAPs diet were applied to explore the relationship between SCFAs and visceral sensitivity. Results from our project will provide new insights in the prevention and treatment of IBS using dietetic therapy.

脑肠轴紊乱与肠易激综合征（IBS）内脏高敏感发生关系密切。研究表明肠道菌群代谢产物短链脂肪酸（SCFA）与宿主通过免疫、神经内分泌通路影响大脑功能，肠嗜铬细胞表达SCFA受体并作为肠道化学感受器与感觉神经通路偶联。我们发现由束缚应激（WAS）形成IBS内脏高敏感模型后，肠道SCFA和GPR43表达增加，伴随脑内兴奋性谷氨酸受体表达增加。给予IBS小鼠高FODMAP饮食后上述效应增强，而用伪无菌鼠则相反。故我们推测“WAS诱导肠道菌群失衡，使SCFA代谢紊乱并通过GPR41/43-谷氨酸受体轴介导IBS内脏高敏感发生”。本研究首先评价WAS诱导下小鼠肠道菌群、SCFA、GPR41/43、谷氨酸受体及内脏敏感性的改变，并运用抑制剂、基因敲除小鼠、伪无菌鼠、共饲养和高FODMAP饮食探讨SCFA-GPR41/43-谷氨酸受体轴对IBS内脏高敏感发生的作用。预期成果为IBS饮食治疗决策提供新思路。

本研究由旋毛虫造模形成感染后肠易激综合征（PI-IBS）内脏高敏感模型，PI-IBS小鼠肠道菌群发生改变，其代谢产物SCFAs表达增多，回肠末端中5HT表达增多，回肠和结肠中NMDARs表达增加，单个细胞功能分析提示岛叶和海马区神经细胞NMDARs受体激活。肠道菌群在其中的重要作用进一步由与对照组共饲养的PI-IBS小鼠和伪无菌鼠造模得到验证，这两组小鼠SCFAs和肠道5-HT表达下降，回肠和结肠中NMDARs表达较PI-IBS小鼠下降，及岛叶和海马区神经细胞NMDARs受体表达下降，内脏敏感性下降。尽管证实了肠道菌群及其产物对于PI-IBS小鼠内脏敏感性的影响，但对小鼠分别予以高FODMAPs，低FODMAPs和正常饮食干预，小鼠的内脏敏感性并未发生明显改变。