ABSTRACT

Accumulating evidence suggests that gut microbiota as a critical mediator of gut-brain axis plays an important role in human health. Altered gut microbial profiles have been implicated in increasing the vulnerability of psychiatric disorders, such as autism, depression, and schizophrenia. However, the cellular and molecular mechanisms underlying the association remain unknown. Here, we modified the gut microbiome with antibiotics in newborn mice, and found that gut microbial alteration induced behavioral impairment by decreasing adult neurogenesis and long-term potentiation of synaptic transmission, and altering the gene expression profile in hippocampus. Reconstitution with normal gut flora produced therapeutic effects against both adult neurogenesis and behavioral deficits in the dysbiosis mice. Furthermore, our results show that circulating metabolites changes mediate the effect of gut dysbiosis on hippocampal plasticity and behavior outcomes. Elevating the serum 4-methylphenol, a small aromatic metabolite produced by gut bacteria, was found to induce autism spectrum disorder (ASD)-like behavior impairment and hippocampal dysfunction. Together our finding demonstrates that early-life gut dysbiosis and its correlated metabolites change contribute to hippocampal dysfunction and behavior impairment, hence highlight the potential microbiome-mediated therapies for treating psychiatric disorders.

摘要

越来越多的证据表明，肠道微生物群作为肠脑轴的关键介质在人类健康中发挥着重要作用。改变的肠道微生物特征与增加精神疾病的易感性有关，例如自闭症、抑郁症和精神分裂症。然而，这种关联背后的细胞和分子机制仍然未知。在这里，我们用抗生素对新生小鼠的肠道微生物组进行了修饰，发现肠道微生物的改变通过减少成年神经发生和突触传递的长期增强以及改变海马中的基因表达谱来诱导行为障碍。用正常的肠道菌群重建对生态失调小鼠的成年神经发生和行为缺陷产生了治疗作用。此外，我们的研究结果表明，循环代谢物的变化介导了肠道菌群失调对海马可塑性和行为结果的影响。发现升高血清 4-甲基苯酚（一种由肠道细菌产生的小芳香代谢物）会诱发自闭症谱系障碍 (ASD) 样行为障碍和海马功能障碍。我们的发现共同表明，生命早期肠道菌群失调及其相关代谢物的变化会导致海马功能障碍和行为障碍，因此突出了微生物组介导的治疗精神疾病的潜在疗法。被发现会诱发自闭症谱系障碍（ASD）样行为障碍和海马功能障碍。我们的发现共同表明，生命早期肠道菌群失调及其相关代谢物的变化会导致海马功能障碍和行为障碍，因此突出了微生物组介导的治疗精神疾病的潜在疗法。被发现会诱发自闭症谱系障碍（ASD）样行为障碍和海马功能障碍。我们的发现共同表明，生命早期肠道菌群失调及其相关代谢物的变化会导致海马功能障碍和行为障碍，因此突出了微生物组介导的治疗精神疾病的潜在疗法。