Nakagawa Yutaka, Yamada Shizuo
Center for Pharma-Food Research (CPFR), Division of Pharmaceutical Sciences, Graduate School of Integrative Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka, 422-8526, Japan.
Mol Cell Biochem. 2025 May;480(5):2661-2676. doi: 10.1007/s11010-024-05153-3. Epub 2024 Nov 6.
Irritable bowel syndrome is a gastrointestinal disorder due to multiple pathologies. While patients with this condition experience anxiety and depressed mood more frequently than healthy individuals, it is unclear how gastrointestinal dysfunction interacts with such neuropsychiatric symptoms. Data suggest that irritable bowel syndrome patients predominantly display a lower zinc intake, which presumably impairs enterochromaffin cells producing 5-hydroxytryptamine, gut bacteria fermenting short-chain fatty acids, and barrier system in the intestine, with the accompanying constipation, diarrhea, low-grade mucosal inflammation, and visceral pain. Dyshomeostasis of copper and zinc concentrations as well as elevated pro-inflammatory cytokine levels in the blood can disrupt blood-cerebrospinal fluid barrier function, leading to locus coeruleus neuroinflammation and hyperactivation with resultant amygdalar overactivation and dorsolateral prefrontal cortex hypoactivation as found in neuropsychiatric disorders. The dysregulation between the dorsolateral prefrontal cortex and amygdala is likely responsible for visceral pain-related anxiety, depressed mood caused by anticipatory anxiety, and visceral pain catastrophizing due to catastrophic thinking or cognitive distortion. Collectively, these events can result in a spiral of gastrointestinal symptoms and neuropsychiatric signs, prompting the progression of irritable bowel syndrome. Given that the negative feedback mechanism in regulation of the hypothalamic-pituitary-adrenal axis is preserved in a subset of neuropsychiatric cases, dorsolateral prefrontal cortex abnormality accompanied by neuropsychiatric symptoms may be a more significant contributing factor in brain-gut axis malfunction than activation of the hypothalamic corticotropin-releasing hormone system. The proposed mechanistic model could predict novel therapeutic interventions for comorbid irritable bowel syndrome and neuropsychiatric disorders.
肠易激综合征是一种由多种病理状况引起的胃肠道疾病。虽然患有这种疾病的患者比健康个体更频繁地经历焦虑和情绪低落，但尚不清楚胃肠功能障碍与这些神经精神症状是如何相互作用的。数据表明，肠易激综合征患者主要表现为锌摄入量较低，这可能会损害产生5-羟色胺的肠嗜铬细胞、发酵短链脂肪酸的肠道细菌以及肠道屏障系统，随之而来的是便秘、腹泻、低度黏膜炎症和内脏疼痛。血液中铜和锌浓度的稳态失衡以及促炎细胞因子水平的升高会破坏血脑脊髓液屏障功能，导致蓝斑神经炎症和过度激活，进而导致杏仁核过度激活和背外侧前额叶皮质低激活，这在神经精神疾病中也有发现。背外侧前额叶皮质和杏仁核之间的失调可能是与内脏疼痛相关的焦虑、预期性焦虑引起的情绪低落以及由灾难性思维或认知扭曲导致的内脏疼痛灾难化的原因。总的来说，这些事件会导致胃肠道症状和神经精神体征的恶性循环，促使肠易激综合征的进展。鉴于在下丘脑-垂体-肾上腺轴调节中的负反馈机制在一部分神经精神病例中得以保留，伴有神经精神症状的背外侧前额叶皮质异常可能比下丘脑促肾上腺皮质激素释放激素系统的激活在脑-肠轴功能障碍中是一个更重要的促成因素。所提出的机制模型可以预测针对肠易激综合征和神经精神疾病共病的新型治疗干预措施。
