CRC Scotland & London, Eccleston Square, London, United Kingdom.
Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand.
Curr Top Med Chem. 2020;20(7):524-539. doi: 10.2174/1568026620666200131094445.
The gut and mitochondria have emerged as two important hubs at the cutting edge of research across a diverse array of medical conditions, including most psychiatric conditions. This article highlights the interaction of the gut and mitochondria over the course of development, with an emphasis on the consequences for transdiagnostic processes across psychiatry, but with relevance to wider medical conditions. As well as raised levels of circulating lipopolysaccharide (LPS) arising from increased gut permeability, the loss of the short-chain fatty acid, butyrate, is an important mediator of how gut dysbiosis modulates mitochondrial function. Reactive cells, central glia and systemic immune cells are also modulated by the gut, in part via impacts on mitochondrial function in these cells. Gut-driven alterations in the activity of reactive cells over the course of development are proposed to be an important determinant of the transdiagnostic influence of glia and the immune system. Stress, including prenatal stress, also acts via the gut. The suppression of butyrate, coupled to raised LPS, drives oxidative and nitrosative stress signalling that culminates in the activation of acidic sphingomyelinase-induced ceramide. Raised ceramide levels negatively regulate mitochondrial function, both directly and via its negative impact on daytime, arousal-promoting orexin and night-time sleep-promoting pineal gland-derived melatonin. Both orexin and melatonin positively regulate mitochondria oxidative phosphorylation. Consequently, gut-mediated increases in ceramide have impacts on the circadian rhythm and the circadian regulation of mitochondrial function. Butyrate, orexin and melatonin can positively regulate mitochondria via the disinhibition of the pyruvate dehydrogenase complex, leading to increased conversion of pyruvate to acetyl- CoA. Acetyl-CoA is a necessary co-substrate for the initiation of the melatonergic pathway in mitochondria and therefore the beneficial effects of mitochondria melatonin synthesis on mitochondrial function. This has a number of treatment implications across psychiatric and wider medical conditions, including the utilization of sodium butyrate and melatonin. Overall, gut dysbiosis and increased gut permeability have significant impacts on central and systemic homeostasis via the regulation of mitochondrial function, especially in central glia and systemic immune cells.
肠道和线粒体已成为各种医学疾病（包括大多数精神疾病）研究前沿的两个重要枢纽。本文重点介绍了肠道和线粒体在发育过程中的相互作用，强调了精神病学中转诊断过程的后果，但也与更广泛的医学状况有关。除了由于肠道通透性增加而导致循环脂多糖（LPS）水平升高外，短链脂肪酸丁酸盐的丧失也是肠道菌群失调调节线粒体功能的重要介质。反应性细胞、中枢神经胶质细胞和系统性免疫细胞也受肠道调节，部分通过对这些细胞中线粒体功能的影响。肠道驱动的反应性细胞在发育过程中的活性改变被认为是胶质细胞和免疫系统转诊断影响的重要决定因素。应激，包括产前应激，也通过肠道起作用。丁酸盐的抑制作用，加上 LPS 的升高，会导致氧化和硝化应激信号的产生，最终导致酸性鞘磷脂酶诱导的神经酰胺的激活。神经酰胺水平升高会负调节线粒体功能，直接和通过其对白天促进觉醒的食欲素和夜间促进松果腺衍生褪黑素的负影响。食欲素和褪黑素都能通过正调节线粒体氧化磷酸化来调节线粒体功能。因此，肠道介导的神经酰胺增加会对昼夜节律和线粒体功能的昼夜节律调节产生影响。丁酸盐、食欲素和褪黑素可以通过抑制丙酮酸脱氢酶复合物来正调节线粒体，从而增加丙酮酸向乙酰辅酶 A 的转化。乙酰辅酶 A 是线粒体中启动褪黑素途径的必要辅酶，因此线粒体中褪黑素合成对线粒体功能的有益影响。这对精神病学和更广泛的医学状况都有许多治疗意义，包括使用丁酸钠和褪黑素。总的来说，肠道菌群失调和肠道通透性增加通过调节线粒体功能对中枢和全身内稳态有重大影响，尤其是对中枢神经胶质细胞和系统性免疫细胞。
