Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Stanford Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, USA.
BMC Med. 2021 Jan 20;19(1):13. doi: 10.1186/s12916-020-01885-3.
Much progress has been made in mapping genetic abnormalities linked to amyotrophic lateral sclerosis (ALS), but the majority of cases still present with no known underlying cause. Furthermore, even in families with a shared genetic abnormality there is significant phenotypic variability, suggesting that non-genetic elements may modify pathogenesis. Identification of such disease-modifiers is important as they might represent new therapeutic targets. A growing body of research has begun to shed light on the role played by the gut microbiome in health and disease with a number of studies linking abnormalities to ALS.
The microbiome refers to the genes belonging to the myriad different microorganisms that live within and upon us, collectively known as the microbiota. Most of these microbes are found in the intestines, where they play important roles in digestion and the generation of key metabolites including neurotransmitters. The gut microbiota is an important aspect of the environment in which our bodies operate and inter-individual differences may be key to explaining the different disease outcomes seen in ALS. Work has begun to investigate animal models of the disease, and the gut microbiomes of people living with ALS, revealing changes in the microbial communities of these groups. The current body of knowledge will be summarised in this review. Advances in microbiome sequencing methods will be highlighted, as their improved resolution now enables researchers to further explore differences at a functional level. Proposed mechanisms connecting the gut microbiome to neurodegeneration will also be considered, including direct effects via metabolites released into the host circulation and indirect effects on bioavailability of nutrients and even medications.
Profiling of the gut microbiome has the potential to add an environmental component to rapidly advancing studies of ALS genetics and move research a step further towards personalised medicine for this disease. Moreover, should compelling evidence of upstream neurotoxicity or neuroprotection initiated by gut microbiota emerge, modification of the microbiome will represent a potential new avenue for disease modifying therapies. For an intractable condition with few current therapeutic options, further research into the ALS microbiome is of crucial importance.
在绘制与肌萎缩侧索硬化症（ALS）相关的遗传异常图谱方面已经取得了很大进展，但大多数病例仍然没有已知的根本原因。此外，即使在具有共同遗传异常的家族中，也存在明显的表型变异性，这表明非遗传因素可能会改变发病机制。鉴定这些疾病修饰因子很重要，因为它们可能代表新的治疗靶点。越来越多的研究开始揭示肠道微生物组在健康和疾病中的作用，许多研究将异常与 ALS 联系起来。
微生物组是指属于生活在我们体内和体表的无数不同微生物的基因，统称为微生物群。这些微生物大多数存在于肠道中，在那里它们在消化和产生关键代谢物（包括神经递质）方面发挥着重要作用。肠道微生物组是我们身体运作环境的一个重要方面，个体间的差异可能是解释 ALS 中不同疾病结果的关键。已经开始研究疾病的动物模型和患有 ALS 的人的肠道微生物组，揭示了这些群体中微生物群落的变化。本综述将总结目前的知识体系。将重点介绍微生物组测序方法的进步，因为它们分辨率的提高使研究人员能够在功能水平上进一步探索差异。还将考虑将肠道微生物组与神经退行性变联系起来的机制，包括通过释放到宿主循环中的代谢物直接影响以及对营养物质甚至药物的生物利用度的间接影响。
肠道微生物组的分析有可能为迅速发展的 ALS 遗传学研究增加环境因素，并使研究朝着针对这种疾病的个体化医学迈进一步。此外，如果肠道微生物群引发的上游神经毒性或神经保护作用有确凿的证据，那么微生物组的修饰将代表疾病修饰治疗的潜在新途径。对于一种目前治疗方法有限的棘手疾病，进一步研究 ALS 微生物组至关重要。
