Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, Florence, 50134, Italy.
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Morgagni 50, Florence, 50134, Italy.
Acta Neuropathol Commun. 2024 Nov 6;12(1):174. doi: 10.1186/s40478-024-01877-x.
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, with genetic and environmental factors contributing to its complex pathogenesis. Dysregulated immune responses and altered energetic metabolism are key features, with emerging evidence implicating the gut microbiota (GM) in disease progression. We investigated the interplay among genetic background, GM composition, metabolism, and immune response in two distinct ALS mouse models: 129Sv_G93A and C57Ola_G93A, representing rapid and slow disease progression, respectively.Using 16 S rRNA sequencing and fecal metabolite analysis, we characterized the GM composition and metabolite profiles in non-transgenic (Ntg) and SOD1 mutant mice of both strains. Our results revealed strain-specific differences in GM composition and functions, particularly in the abundance of taxa belonging to Erysipelotrichaceae and the levels of short and medium-chain fatty acids in fecal samples. The SOD1 mutation induces significant shifts in GM colonization in both strains, with C57Ola_G93A mice showing changes resembling those in 129 Sv mice, potentially affecting disease pathogenesis. ALS symptom progression does not significantly alter microbiota composition, suggesting stability.Additionally, we assessed systemic immunity and inflammatory responses revealing strain-specific differences in immune cell populations and cytokine levels.Our findings underscore the substantial influence of genetic background on GM composition, metabolism, and immune response in ALS mouse models. These strain-specific variations may contribute to differences in disease susceptibility and progression rates. Further elucidating the mechanisms underlying these interactions could offer novel insights into ALS pathogenesis and potential therapeutic targets.
肌萎缩侧索硬化症（ALS）是一种破坏性的神经退行性疾病，其特征是运动神经元的进行性丧失，遗传和环境因素促成了其复杂的发病机制。失调的免疫反应和改变的能量代谢是关键特征，越来越多的证据表明肠道微生物群（GM）与疾病进展有关。我们研究了两种不同的 ALS 小鼠模型（129Sv_G93A 和 C57Ola_G93A）中遗传背景、GM 组成、代谢和免疫反应之间的相互作用，分别代表快速和缓慢的疾病进展。使用 16S rRNA 测序和粪便代谢物分析，我们描述了非转基因（Ntg）和两种品系的 SOD1 突变小鼠的 GM 组成和代谢物图谱。我们的结果揭示了 GM 组成和功能的菌株特异性差异，特别是在属于 Erysipelotrichaceae 的分类群的丰度和粪便样本中短链和中链脂肪酸的水平方面。SOD1 突变在两种菌株中都引起 GM 定植的显著变化，C57Ola_G93A 小鼠的变化类似于 129Sv 小鼠，可能影响疾病的发病机制。ALS 症状进展不会显著改变微生物群组成，表明其稳定性。此外，我们评估了系统免疫和炎症反应，揭示了免疫细胞群体和细胞因子水平的菌株特异性差异。我们的研究结果强调了遗传背景对 ALS 小鼠模型中 GM 组成、代谢和免疫反应的巨大影响。这些菌株特异性差异可能导致疾病易感性和进展率的差异。进一步阐明这些相互作用的机制可能为 ALS 发病机制和潜在治疗靶点提供新的见解。
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