Aaldijk Emma, Vermeiren Yannick
Division of Human Nutrition and Health, Chair Group of Nutritional Biology, Wageningen University & Research (WUR), Wageningen, Netherlands.
Division of Human Nutrition and Health, Chair Group of Nutritional Biology, Wageningen University & Research (WUR), Wageningen, Netherlands; Faculty of Medicine & Health Sciences, Translational Neurosciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Ageing Res Rev. 2022 Mar;75:101556. doi: 10.1016/j.arr.2021.101556. Epub 2022 Jan 3.
Alzheimer's disease (AD) is the most common cause of dementia, accounting for more than 50 million patients worldwide. Current evidence suggests the exact mechanism behind this devastating disease to be of multifactorial origin, which seriously complicates the quest for an effective disease-modifying therapy, as well as impedes the search for strategic preventative measures. Of interest, preclinical studies point to serotonergic alterations, either induced via selective serotonin reuptake inhibitors or serotonin receptor (ant)agonists, in mitigating AD brain neuropathology next to its clinical symptoms, the latter being supported by a handful of human intervention trials. Additionally, a substantial amount of preclinical trials highlight the potential of diet, fecal microbiota transplantations, as well as pre- and probiotics in modulating the brain's serotonergic neurotransmitter system, starting from the gut. Whether such interventions could truly prevent, reverse or slow down AD progression likewise, should be initially tested in preclinical studies with AD mouse models, including sufficient analytical measurements both in gut and brain. Thereafter, its potential therapeutic effect could be confirmed in rigorously randomized controlled trials in humans, preferentially across the Alzheimer's continuum, but especially from the prodromal up to the mild stages, where both high adherence to such therapies, as well as sufficient room for noticeable enhancement are feasible still. In the end, such studies might aid in the development of a comprehensive approach to tackle this complex multifactorial disease, since serotonin and its derivatives across the microbiota-gut-brain axis might serve as possible biomarkers of disease progression, next to forming a valuable target in AD drug development. In this narrative review, the available evidence concerning the orchestrating role of serotonin within the microbiota-gut-brain axis in the development of AD is summarized and discussed, and general considerations for future studies are highlighted.
阿尔茨海默病（AD）是痴呆最常见的病因，全球患者超过5000万。目前的证据表明，这种毁灭性疾病背后的确切机制是多因素的，这使得寻求有效的疾病修饰疗法变得极为复杂，也阻碍了寻找战略性预防措施。有趣的是，临床前研究指出，通过选择性5-羟色胺再摄取抑制剂或5-羟色胺受体（抗）激动剂诱导的5-羟色胺能改变，除了能缓解AD的临床症状外，还能减轻AD脑的神经病理学变化，少数人体干预试验也支持了后者。此外，大量临床前试验强调了饮食、粪便微生物群移植以及益生元和益生菌从肠道开始调节大脑5-羟色胺能神经递质系统的潜力。同样，此类干预措施是否真的能预防、逆转或减缓AD的进展，应首先在AD小鼠模型的临床前研究中进行测试，包括在肠道和大脑中进行充分的分析测量。此后，其潜在的治疗效果可在严格的人体随机对照试验中得到证实，最好是在整个阿尔茨海默病连续过程中进行，但特别是从前驱期到轻度阶段，因为在这些阶段，对这种疗法的高依从性以及有足够的显著改善空间仍然是可行的。最后，此类研究可能有助于制定一种全面的方法来应对这种复杂的多因素疾病，因为5-羟色胺及其在微生物群-肠道-脑轴中的衍生物可能作为疾病进展的潜在生物标志物，同时也是AD药物开发中有价值的靶点。在这篇叙述性综述中，总结并讨论了关于5-羟色胺在微生物群-肠道-脑轴中对AD发展的协调作用的现有证据，并强调了对未来研究的一般考虑。
