Negative experiences during adolescence, such as social isolation (SI), bullying, and abuse, increase the risk of psychiatric diseases in adulthood. However, the pathogenesis of psychiatric diseases induced by these factors remain poorly understood. In adolescents, stress affects the intestinal homeostasis in the gut-brain axis. This study determined whether adolescent SI induces behavioral abnormalities by disrupting colonic function. Adolescent mice exposed to SI exhibit spatial cognitive deficits and microglial activation in the hippocampus (HIP). SI decreased the differentiation of mucin-producing goblet cells, which was accompanied by alterations in the composition of the gut microbiota, particularly the depletion of mucin-feeding bacteria. Treatment with rebamipide, which promotes goblet cell differentiation in the colon, attenuated SI-induced spatial cognitive deficits and microglial activation in the HIP and decreased cystine, a downstream metabolite of homocysteine. Treatment with cystine ameliorated SI-induced spatial cognitive deficits and increased microglial C-C motif chemokine ligand 7 (CCL7) levels in the HIP. Inhibition of CCL7 receptors by antagonists of CC motif chemokine receptors 2 (CCR2) and 3 (CCR3) in the HIP prevented spatial cognitive deficits induced by SI. Infusion of CCL7 into the HIP following microglial ablation with clodronate liposome induced spatial cognitive deficits. These findings suggest that adolescent SI decreases serum cystine levels by damaging the colonic goblet cells, resulting in spatial cognitive deficits by triggering microglial activation in the HIP. Our results indicate that increased CCL7 expression in hippocampal microglia may contribute to spatial cognitive deficits by activating CCR2 and CCR3.

青春期的负面经历，如社会孤立 （SI）、欺凌和虐待，会增加成年后患精神疾病的风险。然而，由这些因素诱导的精神疾病的发病机制仍然知之甚少。在青少年中，压力会影响肠脑轴的肠道稳态。本研究确定了青少年 SI 是否通过破坏结肠功能而诱发行为异常。暴露于 SI 的青少年小鼠在海马体 （HIP） 中表现出空间认知缺陷和小胶质细胞激活。SI 减少了产生粘蛋白的杯状细胞的分化，这伴随着肠道微生物群组成的改变，特别是粘蛋白喂养细菌的消耗。用 rebamipide 治疗，促进结肠中的杯状细胞分化，减轻了 SI 诱导的 HIP 空间认知缺陷和小胶质细胞激活，并减少了胱氨酸（同型半胱氨酸的下游代谢物）。胱氨酸治疗改善了 SI 诱导的空间认知缺陷，并增加了 HIP 中小胶质细胞 C-C 基序趋化因子配体 7 （CCL7） 水平。HIP 中 CC 基序趋化因子受体 2 （CCR2） 和 3 （CCR3） 的拮抗剂对 CCL7 受体的抑制阻止了 SI 诱导的空间认知缺陷。用氯膦酸盐脂质体进行小胶质细胞消融后，将 CCL7 输注到 HIP 中会诱导空间认知缺陷。这些发现表明，青少年 SI 通过破坏结肠杯状细胞来降低血清胱氨酸水平，通过触发 HIP 中的小胶质细胞激活导致空间认知缺陷。我们的结果表明，海马小胶质细胞中 CCL7 表达的增加可能通过激活 CCR2 和 CCR3 导致空间认知缺陷。