Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
Brain Behav Immun. 2023 Nov;114:311-324. doi: 10.1016/j.bbi.2023.08.020. Epub 2023 Aug 30.
The pathophysiology of autism spectrum disorder (ASD) involves genetic and environmental factors. Mounting evidence demonstrates a role for the gut microbiome in ASD, with signaling via short-chain fatty acids (SCFA) as one mechanism. Here, we utilize mice carrying deletion to exons 4-22 of Shank3 (Shank3) to model gene by microbiome interactions in ASD. We identify SCFA acetate as a mediator of gut-brain interactions and show acetate supplementation reverses social deficits concomitant with alterations to medial prefrontal cortex (mPFC) transcriptional regulation independent of microbiome status.
Shank3 and wild-type (Wt) littermates were divided into control, Antibiotic (Abx), Acetate and Abx + Acetate groups upon weaning. After six weeks, animals underwent behavioral testing. Molecular analysis including 16S and metagenomic sequencing, metabolomic and transcriptional profiling were conducted. Additionally, targeted serum metabolomic data from Phelan McDermid Syndrome (PMS) patients (who are heterozygous for the Shank3 gene) were leveraged to assess levels of SCFA's relative to ASD clinical measures.
Shank3 mice were found to display social deficits, dysregulated gut microbiome and decreased cecal levels of acetate - effects exacerbated by Abx treatment. RNA-sequencing of mPFC showed unique gene expression signature induced by microbiome depletion in the Shank3 mice. Oral treatment with acetate reverses social deficits and results in marked changes in gene expression enriched for synaptic signaling, pathways among others, even in Abx treated mice. Clinical data showed sex specific correlations between levels of acetate and hyperactivity scores.
These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.
自闭症谱系障碍（ASD）的病理生理学涉及遗传和环境因素。越来越多的证据表明肠道微生物组在 ASD 中起作用，短链脂肪酸（SCFA）信号传导是一种机制。在这里，我们利用携带 Shank3 外显子 4-22 缺失的小鼠来模拟 ASD 中的基因-微生物组相互作用。我们确定 SCFA 醋酸盐作为肠-脑相互作用的介质，并表明醋酸盐补充剂可逆转社交缺陷，同时改变内侧前额叶皮层（mPFC）转录调节，而与微生物组状态无关。
Shank3 和野生型（WT）同窝仔鼠在断奶后分为对照组、抗生素（Abx）组、醋酸盐组和 Abx+醋酸盐组。六周后，动物进行行为测试。进行分子分析，包括 16S 和宏基因组测序、代谢组学和转录组学分析。此外，还利用 Phelan McDermid 综合征（PMS）患者（Shank3 基因杂合子）的靶向血清代谢组学数据来评估 SCFA 相对于 ASD 临床指标的水平。
Shank3 小鼠表现出社交缺陷、肠道微生物组失调和盲肠中醋酸盐水平降低——抗生素治疗加剧了这些影响。mPFC 的 RNA 测序显示，Shank3 小鼠的微生物组耗竭诱导了独特的基因表达特征。口服醋酸盐治疗可逆转社交缺陷，并导致基因表达显著变化，富集突触信号等通路，即使在 Abx 处理的小鼠中也是如此。临床数据显示，醋酸盐水平与多动评分之间存在性别特异性相关性。
这些结果表明肠道微生物组和神经活性代谢物醋酸盐在调节 ASD 样行为中起关键作用。
