Table 2_Gut microbiota and ALS: cause, consequence or correlation? - a systematic review.docx

BackgroundGut microbiome disturbances have been proposed as contributors to amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disorder characterised by motor neuron loss, extra-motor symptoms, and rapid progression. Mechanistic links between dysbiosis, epithelial and blood–brain barrier dysfunction, metabolic imbalance, and immune activation have been suggested, but causality remains unresolved. We conducted a systematic review to evaluate the evidence supporting microbiome involvement in ALS pathogenesis.
MethodsWe searched PubMed, Medline, Embase, Scopus, Semantic Scholar, and Google Scholar (Nov 23, 2025) for human and ALS-relevant animal studies assessing bacterial microbiota, gut or blood–brain barrier integrity, microbial metabolites, or immune pathways. No language or date restrictions were applied. Studies were screened according to predefined criteria, and quality was assessed using QUADAS-2. Owing to the heterogeneity of study designs and sequencing approaches, findings were synthesised narratively.
Findings61 of 2,397 studies met inclusion criteria. Across human cohorts, ALS was consistently associated with reduced microbial diversity, shifts in key taxa, and disruption of microbial pathways regulating short-chain fatty acids, nicotinamide metabolism, and inflammatory signalling. Several mechanistic animal studies demonstrated that microbiota manipulation, through antibiotics, faecal microbiota transfer, or supplementation with protective taxa, modulated motor function, microglial activation, gut permeability, and survival, indicating that dysbiosis can influence disease trajectories. Conversely, longitudinal human data showed that dysbiosis often emerged alongside worsening physical function, gastrointestinal dysmotility, weight loss, and changes in dietary intake, suggesting secondary effects of disease progression. Integrative multi-omics studies linked microbial alterations with systemic cytokine profiles, metabolic stress pathways, and CNS immune phenotypes, reinforcing a bidirectional gut–brain axis. However, the predominance of cross-sectional designs and small sample sizes substantially limits causal inference.
InterpretationCurrent evidence supports a model in which gut dysbiosis interacts with ALS via barrier failure, metabolic disruption, and immune dysregulation, but does not establish dysbiosis as a primary cause of disease. Preclinical findings highlight microbiome-derived mechanisms with disease-modifying potential, yet human data largely indicate association rather than initiation. Clarifying temporal relationships will require longitudinal, multi-modal studies, integration with pre-symptomatic cohorts, and controlled interventional trials. Microbiome-targeted therapies remain a promising but unproven avenue for ALS.

背景
肠道菌群失调被认为是肌萎缩侧索硬化症（amyotrophic lateral sclerosis, ALS）的潜在致病因素。ALS是一种以运动神经元丢失、非运动症状及快速进展为特征的多系统神经退行性疾病。目前已有研究提出菌群失调、上皮屏障与血脑屏障（blood–brain barrier）功能障碍、代谢失衡及免疫激活之间的潜在机制关联，但二者的因果关系仍未明确。本研究开展了一项系统综述，以评估支持微生物组参与ALS发病机制的相关证据。
方法
针对评估细菌菌群、肠道或血脑屏障完整性、微生物代谢物或免疫通路的人类及ALS相关动物研究，我们于2025年11月23日检索了PubMed、Medline、Embase、Scopus、Semantic Scholar及谷歌学术数据库。本研究未设置语言及时间限制。研究按照预先设定的标准进行筛选，并采用QUADAS-2工具评估研究质量。由于各研究的设计方案与测序方法存在异质性，本综述采用叙述性方法对研究结果进行整合。
结果
2397项研究中共有61项符合纳入标准。在人类队列研究中，ALS始终与微生物多样性降低、关键分类群丰度改变，以及调控短链脂肪酸（short-chain fatty acids）、烟酰胺（nicotinamide）代谢与炎症信号通路的微生物通路紊乱相关。多项机制性动物研究表明，通过抗生素、粪便菌群移植（faecal microbiota transfer）或补充保护性分类群来调控微生物组，可改善运动功能、抑制小胶质细胞激活、改善肠道通透性并延长生存期，提示菌群失调可影响疾病进程。反之，纵向人类研究数据显示，菌群失调通常伴随运动功能恶化、胃肠道动力障碍、体重下降及膳食摄入改变，提示菌群失调可能是疾病进展的继发效应。整合性多组学研究将微生物组改变与全身细胞因子谱、代谢应激通路及中枢神经系统（central nervous system, CNS）免疫表型关联起来，进一步证实了双向肠-脑轴的存在。但由于多数研究为横断面设计且样本量较小，极大限制了因果推断的可靠性。
解读
现有证据支持如下模型：肠道菌群失调通过屏障功能障碍、代谢紊乱及免疫失调与ALS发生发展相互作用，但尚未证实菌群失调是疾病的原发诱因。临床前研究结果凸显了微生物组相关机制具有改变疾病进程的潜力，但人类研究数据大多仅显示二者存在关联，而非菌群失调为疾病起始因素。明确二者的时间关联需开展纵向多模态研究、纳入症状前队列研究，并进行对照干预试验。针对微生物组的治疗策略仍是ALS治疗中极具前景但尚未被证实的方向。