The intestinal microbiota plays an important role in regulating brain functions and behaviour. Microbiota-dependent changes in host physiology have been suggested to be key contributors to psychiatric conditions. However, specific host pathways modulated by the microbiota involved in behavioural control are lacking. Here, we assessed the role of the aryl hydrocarbon receptor (Ahr) in modulating microbiota-related alterations in behaviour in male and female mice after antibiotic (Abx) treatment. Mice of both sexes were treated with Abx to induce bacterial depletion. Mice were then tested in a battery of behavioural tests, including the elevated plus maze and open field tests (anxiety-like behaviour), 3 chamber test (social preference), and the tail suspension and forced swim tests (despair behaviour). Behavioural measurements in the tail suspension test were also performed after microbiota reconstitution and after administration of an Ahr agonist, β-naphthoflavone. Gene expression analyses were performed in the brain, liver, and colon by qPCR. Abx-induced bacterial depletion did not alter anxiety-like behaviour, locomotion, or social preference in either sex. A sex-dependent effect was observed in despair behaviour. Male mice had a reduction in despair behaviour after Abx treatment in both the tail suspension and forced swim tests. A similar alteration in despair behaviour was observed in Ahr knockout mice. Despair behaviour was normalized by either microbiota recolonization or Ahr activation in Abx-treated mice. Ahr activation by β-naphthoflavone was confirmed by increased expression of the Ahr-target genes Cyp1a1, Cyp1b1, and Ahrr. Our results demonstrate a role for Ahr in mediating the behaviours that are regulated by the crosstalk between the intestinal microbiota and the host. Ahr represents a novel potential modulator of behavioural conditions influenced by the intestinal microbiota.

肠道微生物群在调节大脑功能和行为方面起着重要作用。宿主生理的微生物群依赖性变化被认为是导致精神疾病的关键因素。然而，缺乏由参与行为控制的微生物群调节的特定宿主途径。在这里，我们评估了芳烃受体 (Ahr) 在调节抗生素 (Abx) 治疗后雄性和雌性小鼠的微生物群相关行为改变中的作用。两种性别的小鼠都用 Abx 处理以诱导细菌消耗。然后在一系列行为测试中对小鼠进行测试，包括高架十字迷宫和野外测试（焦虑样行为）、3 室测试（社会偏好）以及悬尾和强迫游泳测试（绝望行为）。在微生物群重建和施用 Ahr 激动剂 β-萘黄酮后，还进行了悬尾试验中的行为测量。通过 qPCR 在大脑、肝脏和结肠中进行基因表达分析。Abx 诱导的细菌消耗并没有改变任何性别的焦虑样行为、运动或社会偏好。在绝望行为中观察到性别依赖效应。在尾悬和强迫游泳测试中，经过 Abx 治疗后，雄性小鼠的绝望行为有所减少。在 Ahr 基因敲除小鼠中观察到类似的绝望行为改变。在 Abx 治疗的小鼠中，通过微生物群重新定植或 Ahr 激活使绝望行为正常化。Ahr 靶基因的表达增加证实了 β-萘黄酮对 Ahr 的激活Cyp1a1、Cyp1b1 和 Ahrr。我们的结果证明了 Ahr 在介导由肠道微生物群和宿主之间的串扰调节的行为中的作用。Ahr 代表了受肠道微生物群影响的行为条件的新型潜在调节剂。