van de Wouw Marcel, Walsh Calum J, Vigano Giulia M D, Lyte Joshua M, Boehme Marcus, Gual-Grau Andreu, Crispie Fiona, Walsh Aaron M, Clarke Gerard, Dinan Timothy G, Cotter Paul D, Cryan John F
APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
APC Microbiome Ireland, University College Cork, Cork, Ireland; Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland.
Brain Behav Immun. 2021 Oct;97:119-134. doi: 10.1016/j.bbi.2021.07.004. Epub 2021 Jul 9.
Autism spectrum disorder (ASD) is one of the most severe developmental disorders, affecting on average 1 in 150 children worldwide. There is a great need for more effective strategies to improve quality of life in ASD subjects. The gut microbiome has emerged as a potential therapeutic target in ASD. A novel modulator of the gut microbiome, the traditionally fermented milk drink kefir, has recently been shown to modulate the microbiota and decrease repetitive behaviour, one of the hallmarks of ASD, in mice. As such, we hypothesized that kefir could ameliorate behavioural deficits in a mouse model relevant to ASD; the BTBR T Itpr3/J mouse strain. To this end, adult mice were administered either kefir (UK4) or a milk control for three weeks as treatment lead-in, after which they were assessed for their behavioural phenotype using a battery of tests. In addition, we assessed systemic immunity by flow cytometry and the gut microbiome using shotgun metagenomic sequencing. We found that indeed kefir decreased repetitive behaviour in this mouse model. Furthermore, kefir prolonged stress-induced increases in corticosterone 60 min post-stress, which was accompanied by an ameliorated innate immune response as measured by LY6C monocyte levels. In addition, kefir increased the levels of anti-inflammatory Treg cells in mesenteric lymph nodes (MLNs). Kefir also increased the relative abundance of Lachnospiraceae bacterium A2, which correlated with reduced repetitive behaviour and increased Treg cells in MLNs. Functionally, kefir modulated various predicted gut microbial pathways, including the gut-brain module S-Adenosylmethionine (SAM) synthesis, as well as L-valine biosynthesis and pyruvate fermentation to isobutanol, which all correlated with repetitive behaviour. Taken together our data show that kefir modulates peripheral immunoregulation, can ameliorate specific ASD behavioural dysfunctions and modulates selective aspects of the composition and function of the gut microbiome, indicating that kefir supplementation might prove a viable strategy in improving quality of life in ASD subjects.
自闭症谱系障碍（ASD）是最严重的发育障碍之一，全球平均每150名儿童中就有1人受其影响。迫切需要更有效的策略来改善自闭症谱系障碍患者的生活质量。肠道微生物群已成为自闭症谱系障碍潜在的治疗靶点。一种新型的肠道微生物群调节剂，即传统发酵乳饮料开菲尔，最近已被证明可以调节小鼠的微生物群，并减少自闭症谱系障碍的标志性特征之一——重复行为。因此，我们假设开菲尔可以改善与自闭症谱系障碍相关的小鼠模型中的行为缺陷；BTBR T Itpr3/J小鼠品系。为此，成年小鼠作为治疗导入期接受了为期三周的开菲尔（UK4）或牛奶对照处理，之后使用一系列测试评估它们的行为表型。此外，我们通过流式细胞术评估全身免疫，并使用鸟枪法宏基因组测序评估肠道微生物群。我们发现，在这个小鼠模型中，开菲尔确实减少了重复行为。此外，开菲尔在应激后60分钟延长了应激诱导的皮质酮增加，这伴随着通过LY6C单核细胞水平测量的先天免疫反应的改善。此外，开菲尔增加了肠系膜淋巴结（MLN）中抗炎性调节性T细胞的水平。开菲尔还增加了毛螺菌科细菌A2的相对丰度，这与MLN中重复行为的减少和调节性T细胞的增加相关。在功能上，开菲尔调节了各种预测的肠道微生物途径，包括肠道-脑模块S-腺苷甲硫氨酸（SAM）合成，以及L-缬氨酸生物合成和丙酮酸发酵生成异丁醇，所有这些都与重复行为相关。综合我们的数据表明，开菲尔调节外周免疫调节，可以改善特定的自闭症谱系障碍行为功能障碍，并调节肠道微生物群组成和功能的选择性方面，这表明补充开菲尔可能是改善自闭症谱系障碍患者生活质量的可行策略。
