早期生活压力诱发的肠道-大脑表型的恢复力和合并症的性别特异性肠道微生物群特征

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress Pub Date : 2024-11-01 DOI:10.1016/j.ynstr.2024.100686

Lars Wilmes , Valentina Caputi , Thomaz F.S. Bastiaanssen , James M. Collins , Fiona Crispie , Paul D. Cotter , Timothy G. Dinan , John F. Cryan , Gerard Clarke , Siobhain M. O'Mahony

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引用次数: 0

摘要

背景早期生活压力引起的肠道-大脑轴沟通途径和肠道微生物群生态系统的改变已被广泛描述为压力诱发疾病的病理生理学中的关键因素。然而，应激诱导的肠道微生物群改变在生命早期的表现程度，以及在成年期对不同肠道-大脑表型的性别特异性易感性的贡献程度尚未确定。方法对雌雄Sprague-Dawley大鼠后代进行母鼠分离（从出生后第2-12天，每天3小时）。断奶前收集粪便样本，进行肠道微生物群 16S rRNA 测序和代谢组学分析。成年后，分别使用结肠直肠胀气和强迫游泳测试评估内脏痛敏感性和负价行为。对行为数据进行了两步聚类分析，以确定数据集中的分组情况。结果母体分离导致内脏超敏性增加，同时成年后负价行为的增加趋势与性别有关。聚类分析揭示了数据集中的四个聚类，它们代表了不同的病理生理领域，让人联想到早期生活压力的行为后果：1.适应力强；2.疼痛；3.行动不便；4.合并症。这些群组中每个群组的生命早期肠道微生物群在多样性、属级丰度差异和功能模块方面都显示出不同的变化。我们的研究首次发现了不同的表型，这些表型由生命早期压力诱发的肠道-大脑功能障碍的易感性或恢复力所定义。生命早期的肠道微生物群在每个群中都显示出性别依赖性改变，这些改变先于成年期的特定行为表型。未来的研究需要确定早期生活压力诱导的肠道微生物群变化之间的因果关系，并了解导致成年后表现出不同行为表型的轨迹。

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Sex specific gut-microbiota signatures of resilient and comorbid gut-brain phenotypes induced by early life stress

Background

Alterations in gut-brain axis communication pathways and the gut microbiota ecosystem caused by early life stress have been extensively described as critical players in the pathophysiology of stress-induced disorders. However, the extent to which stress-induced gut microbiota alterations manifest in early life and contribute to the sex-specific susceptibility to distinct gut-brain phenotypes in adulthood has yet to be defined.

Methods

Male and female Sprague-Dawley rat offspring underwent maternal separation (3h/day from postnatal day 2–12). Faecal samples were collected before weaning for gut microbiota 16S rRNA sequencing and metabolomic analysis. Visceral pain sensitivity and negative valence behaviours were assessed in adulthood using colorectal distension and the forced swim test respectively. Behavioural data were processed in a two-step cluster analysis to identify groupings within the dataset. Multi-omics analysis was carried out to investigate if the microbial signatures following early life stress were already defined according to the membership of the adult behavioural phenotypes.

Results

Maternal separation resulted in increased visceral hypersensitivity while showing a trend for a sex-dependent increase in negative valence behaviour in adulthood. The cluster analysis revealed four clusters within the dataset representing distinct pathophysiological domains reminiscent of the behavioural consequences of early-life stress: 1. resilient, 2. pain, 3. immobile and 4. comorbid. The early life gut microbiota of each of these clusters show distinct alterations in terms of diversity, genus level differential abundance, and functional modules. Multi-omic integrations points towards a role for different metabolic pathways underlying each cluster-specific phenotype.

Conclusion

Our study is the first to identify distinct phenotypes defined by susceptibility or resilience to gut-brain dysfunction induced by early life stress. The gut microbiota in early life shows sex-dependent alterations in each cluster that precede specific behavioural phenotypes in adulthood. Future research is warranted to determine the causal relationship between early-life stress-induced changes in the gut microbiota and to understand the trajectory leading to the manifestation of different behavioural phenotypes in adulthood.

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来源期刊

Neurobiology of Stress Biochemistry, Genetics and Molecular Biology-Biochemistry

CiteScore

9.40

自引率

4.00%

发文量

审稿时长

48 days

期刊介绍： Neurobiology of Stress is a multidisciplinary journal for the publication of original research and review articles on basic, translational and clinical research into stress and related disorders. It will focus on the impact of stress on the brain from cellular to behavioral functions and stress-related neuropsychiatric disorders (such as depression, trauma and anxiety). The translation of basic research findings into real-world applications will be a key aim of the journal. Basic, translational and clinical research on the following topics as they relate to stress will be covered: Molecular substrates and cell signaling, Genetics and epigenetics, Stress circuitry, Structural and physiological plasticity, Developmental Aspects, Laboratory models of stress, Neuroinflammation and pathology, Memory and Cognition, Motivational Processes, Fear and Anxiety, Stress-related neuropsychiatric disorders (including depression, PTSD, substance abuse), Neuropsychopharmacology.