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Plastic brains and gastrointestinal strains: The microbiota–gut–brain axis as a modulator of cellular plasticity and cognitive function (commentary on Darch et al., 2021)
European Journal of Neroscience ( IF 3.4 ) Pub Date : 2021-06-14 , DOI: 10.1111/ejn.15348
Carolina Gubert 1 , Anthony J. Hannan 1, 2
Affiliation  

The last decade has witnessed rapid advances in DNA sequencing technologies and bioinformatic approaches, leading to fast and cost-effective phylogenetic identification of microbial communities and gut microbiota in particular. These breakthroughs have been revolutionary for different fields, from ecology and agriculture to biological and medical sciences. Remarkably, the communication between these trillions of microorganisms, the gut they inhabit and the brain has been found to be both extensive and dynamically bidirectional. The microbiota–gut–brain axis has been associated with mechanisms mediating neurodevelopment, behaviour, cognition and many neurological and psychiatric disorders (Cryan et al., 2019). This extra level of complexity has been revealed with respect to brain function and dysfunction and fits into a broader conceptualisation of the centrality of bidirectional brain–body interactions in health and disease. Does this mean that more neuroscientists should consider the role of the microbiota–gut–brain axis in their studies of brain structure and function? A new study in this issue of EJN adds weight to this argument, particularly for those who study learning, memory and associated cellular plasticity.

Darch et al. (2021) provided new insights into the role of the microbiome as a potential modulator of synaptic plasticity in the hippocampus of adult mice. They evaluated the electrophysiological properties of hippocampal slices from germ-free (GF) adult mice (C57/Bl6 wild types at 8–12 weeks of age), raised in the absence of microbiota, in comparison with their conventionally (Conv) raised counterparts. While the GF mice showed normal basal synaptic excitability and presynaptic function, postsynaptic long-term potentiation (LTP) was altered in GF male (but not female) mice, demonstrating sex-dependent changes in synaptic plasticity in the absence of microbiota (keeping in mind that GF mice lack microbes in all parts of their body, not just the gut). However, the hippocampal CA1 neurons of these GF mice showed enhanced dendritic input–output coupling (both sexes), suggesting a compensatory hyperexcitability. In summary, Darch et al. (2021) uncover a sex-specific alteration in dendritic signalling and associated synaptic plasticity in the hippocampus of mice induced by the absence of microbiota.

These findings have implications for how we might understand the regulation of synaptic plasticity and associated learning and memory mechanisms. These new results suggest a role of the microbiome in modulating aspects of hippocampal plasticity and LTP in particular. This is not totally surprising since direct and indirect modulation of the gut microbiome (by far the most abundant microbiome in mice and humans) has been already linked with cellular plasticity, learning, memory and other aspects of cognition (Cryan et al., 2019; Davidson et al., 2018). Interestingly, the gut microbiome has been even suggested to be a contributor to individual differences in cognition, with evolutionary consequences that benefit both host and microbial populations (Davidson et al., 2018). Furthermore, this capacity for gut microbiota to modulate such aspects of neural cell function and cognition has the potential to provide a missing link between the effects of environmental interventions such as exercise, diet and stress, on brain health and disease (Gubert et al., 2020). Such environmental factors have been shown to modulate gut microbiota, as well as have impacts on the brain, and therefore, it is possible that some such environmental stimuli could modify brain health and disease via the microbiota–gut–brain axis (Gubert et al., 2020).

While Darch et al. (2021) did not reveal specific molecular and cellular mechanisms involved in the effect of the lack of gut microbiota on hippocampal cellular plasticity, they found a sexual dysmorphism in their observed changes, with males being more affected. This sexual dimorphism raises new questions, including the potential role of sex hormones and associated receptor signalling, that should drive further studies. The investigation of sex-related differences, or sexual dimorphism, in the context of the gut microbiome, is a relatively new field, but it is growing rapidly. Sex seems to affect gut microbiota composition over the entire lifespan while affecting species diversity and, importantly, disease susceptibility (Valeri & Endres, 2021).

Sex differences have also been previously described for various aspects of synaptic plasticity, including evidence for hormones acting directly and indirectly (Hyer et al., 2018). Therefore, the present results of Darch and colleagues could be followed up by investigating correlations with, and manipulations of, the oestrous cycle of the female mice, since it was demonstrated that the levels of steroids in the hippocampus fluctuate across the female cycle and sex can alter synaptic plasticity, with implications for learning and memory (Hojo & Kawato, 2018). On the other hand, in the hippocampus of males, testosterone levels also appear to modulate LTP and dendritic sprouting (Skucas et al., 2013). Therefore, sex hormones and neurosteroids, and their potential modulation of the microbiota–gut–brain axis, could provide a link between the recent findings of Darch and colleagues and sexual dimorphism of hippocampal plasticity and associated cognitive processes.

There are other questions raised by this new study (Darch et al., 2021). The authors showed sexually dimorphic impacts of microbial absence on hippocampal LTP, but within the ‘yin and yang’ of synaptic plasticity, it is unknown whether long-term depression (LTD) was also affected in the GF mice. As discussed above, future studies should carefully measure the oestrous cycle in female animals to establish whether any changes in brain function (and dysfunction) are correlated with sex hormone fluctuations. GF mice constitute a highly artificial construct, as no humans (except perhaps for very rare cases of individuals with severe immune disorders who must live in sterile ‘bubbles’, albeit with their endogenous microbiota intact) exist under such extreme conditions. Therefore, it would be of great interest to know whether oral administration of a cocktail of nonabsorbable antibiotics, to greatly deplete the gut microbiota, could have similar impacts on the animals' brains, when delivered either during specific periods of development, or in adulthood. This would also address the possibility that the brain changes in GF mice are due to the absence of not only gut microbiota but also other microbiota (which are also absent in GF animals) and associated systemic changes that are also known to modulate brain function (Pluvinage & Wyss-Coray, 2020). Furthermore, the findings in this new article (Darch et al., 2021) could be followed up with experimental manipulations, including prebiotics, probiotics and faecal-matter transfer, to establish what aspects of the missing microbiota in the GF mice, and which intermediate cellular and molecular mechanisms, led to the reported hippocampal changes.

Another question not yet addressed is whether microbiota contribute to age-related decline in these aspects of hippocampal plasticity. It was recently reported that faecal-matter transplant from aged mice into young recipient mice was able to transfer cognitive impairment and that this modulated cognition was associated with altered hippocampal proteins involved in synaptic plasticity (D'Amato et al., 2020). However, in addition to the need to replicate and extend such surprising findings, there are substantial remaining questions regarding mechanisms mediating the hippocampal changes reported in GF mice. How does the microbiome normally regulate these aspects of hippocampal function? Does microbial modulation of this aspect of brain function occur during development or adulthood? Is it via microbiota-derived molecules such as short-chain fatty acids (SCFAs) that can travel from the gut to the brain (via the bloodstream) and signal via specific receptors? Or does it depend more on communication via the vagal nerve or perhaps other intermediaries such as the immune system?

There is much still to be understood about the microbiota–gut–brain axis, in health and disease. Furthermore, there is an urgent need to better understand the relationship between such findings in laboratory animals, including rodents, and the human microbiome and its complex bidirectional relationship with nervous system development, structure and function. If we can better understand the biological mechanisms at molecular, cellular and systems levels, it may lead to novel therapeutic approaches for a wide range of devastating neurological and psychiatric disorders (Figure 1).

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FIGURE 1
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A schematic diagram illustrating how the absence of microbiota in germ-free mice could alter hippocampal synaptic plasticity and related aspects of brain function, and dysfunction. Darch and colleagues analysed hippocampal plasticity in germ-free adult mice (C57/Bl6 wild types at 8–12 weeks of age), raised in the absence of microbiota, in comparison with their conventionally raised counterparts. They found alteration in synaptic plasticity in the hippocampus of mice induced by the absence of a microbiome, with males being more affected (Darch et al., 2021). While these investigators did not reveal specific biological mechanisms involved in the effect of the lack of gut microbiota on hippocampal cellular plasticity, or the sex-specificity for this effect, this study points to the microbiota–gut–brain axis as having a central role in brain function and dysfunction. If an unhealthy gut microbiome is able to impact hippocampal plasticity, that could in turn lead to an impairment in cognition (e.g., learning and memory), and this could be involved in the pathogenesis of relevant neurological and psychiatric disorders. Therefore, if we can better understand the biological mechanisms at molecular, cellular and systems levels, it may lead to a range of novel therapeutic approaches for these devastating disorders of the brain and body. Created with BioRender.com


中文翻译:

可塑性大脑和胃肠道菌株:微生物群-肠-脑轴作为细胞可塑性和认知功能的调节剂(Darch 等人的评论,2021 年)

过去十年见证了 DNA 测序技术和生物信息学方法的快速进步,导致对微生物群落,特别是肠道微生物群的快速和具有成本效益的系统发育鉴定。这些突破对不同领域具有革命性意义,从生态学和农业到生物和医学科学。值得注意的是,这些数以万亿计的微生物、它们栖息的肠道和大脑之间的交流被发现既广泛又动态双向。微生物群-肠-脑轴与调节神经发育、行为、认知和许多神经和精神疾病的机制有关(Cryan 等,  2019)。这种额外的复杂性已经在大脑功能和功能障碍方面得到揭示,并且符合对健康和疾病中双向脑 - 身体相互作用的中心作用的更广泛的概念化。这是否意味着更多的神经科学家应该在他们的大脑结构和功能研究中考虑微生物群-肠-脑轴的作用?本期 EJN 上的一项新研究为这一论点增添了分量,特别是对于那些研究学习、记忆和相关细胞可塑性的人。

达奇等人。( 2021)为微生物组作为成年小鼠海马突触可塑性的潜在调节剂的作用提供了新的见解。他们评估了无菌 (GF) 成年小鼠(8-12 周龄的 C57/Bl6 野生型)海马切片的电生理特性,这些小鼠在没有微生物群的情况下饲养,与常规(Conv)饲养的对应物相比。虽然 GF 小鼠显示出正常的基础突触兴奋性和突触前功能,但 GF 雄性(但不是雌性)小鼠的突触后长时程增强 (LTP) 发生了改变,表明在没有微生物群的情况下突触可塑性的性别依赖性变化(记住GF 小鼠身体的所有部位都缺乏微生物,而不仅仅是肠道)。然而,这些 GF 小鼠的海马 CA1 神经元表现出增强的树突输入-输出耦合(两性),提示代偿性过度兴奋。总之,Darch 等人。(2021 年)揭示了由缺乏微生物群引起的小鼠海马中树突信号传导和相关突触可塑性的性别特异性改变。

这些发现对我们如何理解突触可塑性的调节以及相关的学习和记忆机制具有重要意义。这些新结果表明微生物组在调节海马体可塑性和 LTP 方面的作用。这并不完全令人惊讶,因为肠道微生物组(迄今为止小鼠和人类中最丰富的微生物组)的直接和间接调节已经与细胞可塑性、学习、记忆和认知的其他方面相关联(Cryan 等人,  2019 年;戴维森等人,  2018 年)。有趣的是,肠道微生物组甚至被认为是导致个体认知差异的一个因素,其进化结果有利于宿主和微生物种群(戴维森等人,  2018 年))。此外,肠道微生物群调节神经细胞功能和认知等方面的能力有可能在环境干预(如锻炼、饮食和压力)对大脑健康和疾病的影响之间提供缺失的联系(Gubert 等,  2020 年)。这些环境因素已被证明可以调节肠道微生物群,并对大脑产生影响,因此,一些此类环境刺激可能会通过微生物群 - 肠道 - 大脑轴改变大脑健康和疾病(Gubert 等,2017)。 ,  2020 年)。

虽然 Darch 等人。( 2021 ) 没有揭示肠道微生物群缺乏对海马细胞可塑性的影响所涉及的特定分子和细胞机制,他们在观察到的变化中发现了性别畸形,男性受到的影响更大。这种性别二态性提出了新的问题,包括性激素和相关受体信号的潜在作用,应该推动进一步的研究。在肠道微生物组的背景下,对性别相关差异或性别二态性的研究是一个相对较新的领域,但它正在迅速发展。性别似乎会影响整个生命周期的肠道微生物群组成,同时影响物种多样性,重要的是,影响疾病易感性 (Valeri & Endres,  2021 )。

先前也描述了突触可塑性的各个方面的性别差异,包括激素直接和间接作用的证据(Hyer et al.,  2018)。因此,Darch 及其同事的当前结果可以通过调查与雌性小鼠发情周期的相关性和操纵来跟进,因为已经证明海马体中的类固醇水平在整个雌性周期和性别中波动改变突触可塑性,对学习和记忆有影响(Hojo & Kawato,  2018)。另一方面,在雄性海马体中,睾酮水平似乎也调节 LTP 和树突萌芽(Skucas et al.,  2013)。因此,性激素和神经类固醇,以及它们对微生物群-肠-脑轴的潜在调节,可以提供 Darch 及其同事的最新发现与海马可塑性和相关认知过程的性别二态性之间的联系。

这项新研究还提出了其他问题(Darch 等人,  2021)。作者展示了微生物缺失对海马 LTP 的性别二态性影响,但在突触可塑性的“阴阳”范围内,GF 小鼠的长期抑郁 (LTD) 是否也受到影响尚不清楚。如上所述,未来的研究应该仔细测量雌性动物的发情周期,以确定大脑功能(和功能障碍)的任何变化是否与性激素波动有关。GF 小鼠构成了高度人工的构建体,因为在这种极端条件下,没有人类存在(可能除了极少数患有严重免疫疾病的个体,他们必须生活在无菌“气泡”中,尽管其内源性微生物群完整无缺)。因此,了解口服不可吸收的抗生素混合物是否会引起极大的兴趣,大大消耗肠道微生物群,可能对动物的大脑产生类似的影响,无论是在特定的发育时期还是在成年期。这也将解决以下可能性:GF 小鼠的大脑变化不仅是由于缺乏肠道微生物群,而且是由于其他微生物群(在 GF 动物中也不存在)和相关的系统变化,这些变化也已知会调节大脑功能(Pluvinage &Wyss-Coray, 2020 年)。此外,这篇新文章(Darch 等人,  2021 年)中的发现可以通过实验操作进行跟进,包括益生元、益生菌和粪便物质转移,以确定 GF 小鼠中缺失微生物群的哪些方面,以及哪些中间体细胞和分子机制,导致报告的海马变化。

另一个尚未解决的问题是,微生物群是否会导致海马体可塑性的这些方面与年龄相关的下降。最近有报道称,将老年小鼠的粪便物质移植到年轻的受体小鼠中能够转移认知障碍,并且这种调节的认知与参与突触可塑性的海马蛋白的改变有关(D'Amato 等人,  2020 年))。然而,除了需要复制和扩展这些令人惊讶的发现之外,关于介导 GF 小鼠海马变化的机制还存在大量问题。微生物组通常如何调节海马功能的这些方面?对大脑功能这方面的微生物调节是否发生在发育或成年期?是通过微生物群衍生的分子,例如可以从肠道传播到大脑(通过血液)并通过特定受体发出信号的短链脂肪酸 (SCFA) 吗?还是它更多地依赖于通过迷走神经或其他中介(如免疫系统)进行的交流?

关于健康和疾病中的微生物群 - 肠 - 脑轴,仍有很多需要了解的地方。此外,迫切需要更好地了解实验室动物(包括啮齿动物)和人类微生物组的这些发现之间的关系及其与神经系统发育、结构和功能的复杂双向关系。如果我们能够更好地了解分子、细胞和系统水平的生物学机制,它可能会为广泛的破坏性神经和精神疾病带来新的治疗方法(图 1)。

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图1
在图形查看器中打开微软幻灯片软件
示意图说明无菌小鼠中微生物群的缺失如何改变海马突触可塑性和大脑功能和功能障碍的相关方面。Darch 及其同事分析了无菌成年小鼠(8-12 周龄的 C57/Bl6 野生型)的海马可塑性,与常规饲养的小鼠相比,它们在没有微生物群的情况下饲养。他们发现由于缺乏微生物组而导致小鼠海马体突触可塑性发生改变,雄性受到的影响更大(Darch 等人,  2021 年))。虽然这些研究人员没有揭示肠道微生物群缺乏对海马细胞可塑性的影响的具体生物学机制,或这种影响的性别特异性,但本研究指出微生物群-肠-脑轴在海马细胞可塑性中起着核心作用。脑功能和功能障碍。如果不健康的肠道微生物群能够影响海马体的可塑性,这反过来可能会导致认知障碍(例如,学习和记忆),这可能与相关神经和精神疾病的发病机制有关。因此,如果我们能够更好地了解分子、细胞和系统水平的生物学机制,可能会为这些大脑和身体的破坏性疾病带来一系列新的治疗方法。使用 BioRender.com 创建
更新日期:2021-08-17
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