Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba, 260-8670, Japan.
Department of Sustainable Health Science, Chiba University Center for Preventive Medical Sciences, Chiba, 263-8522, Japan.
Eur Arch Psychiatry Clin Neurosci. 2022 Oct;272(7):1297-1309. doi: 10.1007/s00406-022-01437-1. Epub 2022 Jun 6.
Increasing epidemiological evidence shows that the use of cannabis during adolescence could increase the risk for psychosis in adulthood. However, the precise mechanisms underlying long-lasting cannabis-induced risk for psychosis remain unclear. Accumulating evidence suggests the role of gut microbiota in the pathogenesis of psychiatric disorders. Here, we examined whether gut microbiota plays a role in the risk for psychosis of adult after exposure of cannabinoid (CB) receptor agonist WIN55,212-2 during adolescence. Repeated administration of WIN55,212-2 (2 mg/kg/day) during adolescence (P35-P45) significantly increased the expression of Iba1 (ionized calcium-binding adapter molecule 1) in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of adult mice after administration of lipopolysaccharide (LPS: 0.5 mg/kg). In contrast, there were no changes in blood levels of pro-inflammatory cytokines between the two groups. Although alpha-diversity and beta-diversity of gut microbiota were no differences between the two groups, there were several microbes altered between the two groups. Interestingly, there were significant correlations between the relative abundance of microbiota and Iba1 expression in the mPFC and NAc. Furthermore, there were also significant correlations between the relative abundance of microbiota and several metabolites in the blood. These findings suggest that gut microbiota may play a role in the microglial activation in the mPFC and NAc of adult mice after repeated WIN55,212-2 exposure during adolescence. Therefore, it is likely that gut-microbiota-microglia crosstalk might play a role in increased risk for psychosis in adults with cannabis use during adolescence.
越来越多的流行病学证据表明，青少年时期使用大麻会增加成年后患精神病的风险。然而，长期吸食大麻导致精神病风险的确切机制仍不清楚。越来越多的证据表明，肠道微生物群在精神疾病的发病机制中起作用。在这里，我们研究了在青春期暴露于大麻素（CB）受体激动剂 WIN55,212-2 后，肠道微生物群是否在成年后患精神病的风险中起作用。青春期（P35-P45）反复给予 WIN55,212-2（2mg/kg/天）可显著增加成年后给予脂多糖（LPS：0.5mg/kg）时内侧前额叶皮质（mPFC）和伏隔核（NAc）中 Iba1（离子钙结合接头分子 1）的表达。相比之下，两组之间的促炎细胞因子的血液水平没有变化。尽管两组之间的肠道微生物群的 alpha 多样性和 beta 多样性没有差异，但两组之间有几种微生物发生了变化。有趣的是，mPFC 和 NAc 中微生物群的相对丰度与 Iba1 表达之间存在显著相关性。此外，微生物群的相对丰度与血液中的几种代谢物之间也存在显著相关性。这些发现表明，肠道微生物群可能在青春期反复暴露于 WIN55,212-2 后成年小鼠的 mPFC 和 NAc 中小胶质细胞激活中起作用。因此，肠道微生物群-小胶质细胞相互作用可能在青少年使用大麻后成年患精神病风险增加中起作用。
