背景:将肠道微生物群与社会行为联系起来的确切机制仍在研究中。我们旨在探索肠道微生物群在使用具有显性(Dom)或顺从(Sub)行为特征的选择性繁殖小鼠塑造社会行为缺陷中的作用。亚小鼠表现出社交,类似抑郁和焦虑的行为,以及全身性炎症,所有这些都是由它们受损的肠道微生物组成形成的。
方法:使用16SrRNA测序对Dom和Sub小鼠的肠道菌群组成进行了年龄依赖性比较分析,从婴儿早期到成年。Dom和下胃肠(GI)道解剖,函数,使用组织学进行免疫谱分析,RT-PCR,流式细胞术,细胞因子阵列,和葡聚糖-FITC通透性测定。使用靶向代谢组学定量Dom和Sub小鼠结肠中的短链脂肪酸(SCFA)水平。为了支持我们的发现,成年亚小鼠口服透明质酸(HA)(30mg/kg)或非甾体抗炎剂塞来昔布(16mg/kg)。
结果:我们证明,从婴儿早期开始,亚小鼠肠道微生物群缺乏免疫成熟所必需的细菌,包括乳酸菌和双歧杆菌属。此外,从出生,亚小鼠具有较厚的结肠粘蛋白层,从成年早期开始,它们的结肠长度较短,改变结肠完整性,增加肠道通透性,降低SCFA水平和减少调节性T细胞,与Dom小鼠相比。用HA治疗的成年亚小鼠的治疗干预,塞来昔布,或者两个特工,获救的亚小鼠表型。HA治疗降低亚小鼠肠道通透性,结肠长度增加,改善老鼠的社交行为缺陷。塞来昔布治疗增加社交能力,减少抑郁和焦虑样行为,结肠长度增加,和联合治疗产生与塞来昔布作为单一药物施用相似的效果。
结论:总体而言,我们的数据表明,治疗结肠炎症和降低肠道通透性可以恢复肠道生理,并在以后的生活中预防社会缺陷。这些发现为早期肠道微生物群在塑造肠道免疫中的重要性提供了重要的见解。功能,和社会行为,并可能有利于未来治疗策略的发展。
BACKGROUND: The exact mechanisms linking the gut microbiota and social behavior are still under investigation. We aimed to explore the role of the gut microbiota in shaping social behavior deficits using selectively bred mice possessing dominant (Dom) or submissive (Sub) behavior features. Sub mice exhibit asocial, depressive- and anxiety-like behaviors, as well as systemic inflammation, all of which are shaped by their impaired gut microbiota composition.
METHODS: An age-dependent comparative analysis of the gut microbiota composition of Dom and Sub mice was performed using 16S rRNA sequencing, from early infancy to adulthood. Dom and Sub gastrointestinal (GI) tract anatomy, function, and immune profiling analyses were performed using histology, RT-PCR, flow cytometry, cytokine array, and dextran-FITC permeability assays. Short chain fatty acids (SCFA) levels in the colons of Dom and Sub mice were quantified using targeted metabolomics. To support our findings, adult Sub mice were orally treated with hyaluronic acid (HA) (30 mg/kg) or with the non-steroidal anti-inflammatory agent celecoxib (16 mg/kg).
RESULTS: We demonstrate that from early infancy the Sub mouse gut microbiota lacks essential bacteria for immune maturation, including Lactobacillus and Bifidobacterium genera. Furthermore, from birth, Sub mice possess a thicker colon mucin layer, and from early adulthood, they exhibit shorter colonic length, altered colon integrity with increased gut permeability, reduced SCFA levels and decreased regulatory T-cells, compared to Dom mice. Therapeutic intervention in adult Sub mice treated with HA, celecoxib, or both agents, rescued Sub mice phenotypes. HA treatment reduced Sub mouse gut permeability, increased colon length, and improved mouse social behavior deficits. Treatment with celecoxib increased sociability, reduced depressive- and anxiety-like behaviors, and increased colon length, and a combined treatment resulted in similar effects as celecoxib administered as a single agent.
CONCLUSIONS: Overall, our data suggest that treating colon inflammation and decreasing gut permeability can restore gut physiology and prevent social deficits later in life. These findings provide critical insights into the importance of early life gut microbiota in shaping gut immunity, functionality, and social behavior, and may be beneficial for the development of future therapeutic strategies.