Morphine, the microbiome, and fatty acids: short chains make a big link in opioid reward.
Morphine, the microbiome, and fatty acids: short chains make a big link in opioid reward.
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吗啡、微生物组和脂肪酸：短链在阿片类药物奖励中发挥着重要作用。
DOI：
10.1038/s41386-021-01093-4
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Day,JeremyJ
中科院分区：
文献类型：
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作者：
Tuscher,JenniferJ;Day,JeremyJ
几个世纪以来，人们已经认识到胃肠道对情绪和心理健康的影响，过去十年的积累结果支持肠道细菌(统称为肠道微生物组)在大脑健康和疾病的许多方面发挥关键作用[1]。虽然微生物群-脑相互作用的机制基础很复杂，但新出现的证据表明，肠道微生物区系产生多种具有基因调控潜力的脑穿透代谢物，例如表观遗传修饰的辅助因子[2-4]。这一观察结果有可能将肠道微生物区系的差异与多种神经精神疾病中观察到的基因表达和染色质模式失调联系起来，包括严重抑郁症、应激相关疾病和药物滥用[5]。尽管细菌代谢物最近被牵连到肠道-大脑相互作用的协调中[2]，但支持特定因素在复杂的动机行为和药物诱导的转录重新编程中的直接作用的证据仍然有限。在本期《神经精神药理学》中，Hofford等人[6]利用口服抗生素击倒模型(ABX；一种通过饮用水输送的抗生素鸡尾酒)探索了肠道微生物群多样性和组成在吗啡条件性位置偏爱(CPP)和运动敏化中的作用。作者首次表明，口服抗生素降低了细菌的复杂性，改变了细菌门的相对比例，包括菲米库斯细菌的减少。这种常见的肠道微生物群在健康个体中发现，并已知产生短链脂肪酸(SCFA)(如丁酸盐)，这些脂肪酸既作为组蛋白去乙酰化酶抑制剂，又被进一步代谢为组蛋白乙酰化的辅助因子。值得注意的是，细菌多样性的丧失与肠道细菌产生的至少两种单链脂肪酸-丁酸盐和丙酸盐水平的下降有关。接下来，这篇手稿报告说，微生物群的枯竭削弱了吗啡运动敏化，并取消了吗啡CPP，这是衡量药物行为影响的常用指标。更引人注目的是，当饮用水中添加SCFAs时，吗啡CPP完全恢复，这表明了吗啡奖赏的可逆控制以及SCFAs在这一过程中的必要性。鉴于SCFAs通过表观遗传调节在基因调控中具有已知的作用，Hofford和他的同事接下来探索了反复服用吗啡后，口服ABX是否也改变了伏隔核(与药物奖励有关的关键大脑区域)的转录变化。与行为学观察一致，微生物组的耗尽导致了显著不同的对吗啡的转录反应，正如RNA-Seq所测量的那样。虽然在对照和ABX条件下，许多基因都被吗啡类似地改变，但微生物组的枯竭也导致了额外的吗啡调节的变化，主要是在与组蛋白修饰和染色质动力学相关的功能类别上。此外，SCFA补充恢复了ABX在几个基因上诱导的转录变化，包括以前被认为在药物反应中重要的可诱导转录因子(例如，即刻早期基因Egr2和Egr4)。因此，就像微生物群枯竭对行为的影响一样，当饮食中的SCFA被取代时，至少对吗啡诱导的基因表达变化的部分影响是可逆的。同时，这些发现标志着继续探索肠道-大脑相互作用对吗啡作用调控的基本第一步。然而，还有许多其他问题仍然存在。对于…来说
Influences of the gastrointestinal tract on mood and mental health have been recognized for centuries, and accumulating results over the past decade have supported a key role for gut bacteria (collectively known as the gut microbiome) in many aspects of brain health and disease [1]. While the mechanistic underpinnings of microbiome-brain interactions are complex, emerging evidence suggests that gut microbiota produce multiple brain-penetrant metabolites with gene regulatory potential, such as co-factors for epigenetic modifications [2–4]. This observation has the potential to link differences in gut microbiota to dysregulated gene expression and chromatin patterns that are observed in multiple neuropsychiatric disorders, including major depression, stressrelated conditions, and substance abuse [5]. Although bacterial metabolites have recently been implicated in the orchestration of gut-brain interactions [2], evidence supporting a direct role for specific factors in complex motivated behaviors and drug-induced transcriptional reprogramming remains limited. In this issue of Neuropsychopharmacology, Hofford et al.[6] explored the contribution of gut microbiome diversity and composition in morphine conditioned place preference (CPP) and locomotor sensitization using an oral antibiotic knockdown model (Abx; an antibiotic cocktail delivered via drinking water). The authors first show that oral antibiotic administration reduced bacterial complexity and altered the relative proportion of bacterial phyla, including decreases in Firmicutes bacteria. This common gut microbiome phylum is found in healthy individuals and is known to generate short-chain fatty acids (SCFAs)(such as butyrate), which act both as histone deacetylase inhibitors and are further metabolized into co-factors for acetylation of histone proteins. Notably, loss of bacterial diversity was associated with decreased levels of at least two SCFAs produced by gut bacteria—butyrate and propionate. Next, the manuscript reports that microbiome depletion blunts morphine locomotor sensitization and abolishes morphine CPP, commonly used measures of behavioral effects of drugs. Even more strikingly, morphine CPP was completely restored when drinking water was supplemented with SCFAs, demonstrating reversible control of morphine reward as well as necessity for SCFAs in this process. Given that SCFAs have a known role in gene regulation via epigenetic modulation, Hofford and colleagues next explored whether oral Abx also alters transcriptional changes in the nucleus accumbens (a key brain region linked to drug reward) following repeated morphine administration. Consistent with behavioral observations, microbiome depletion resulted in a dramatically distinct transcriptional responses to morphine, as measured with RNA-seq. While a number of genes were similarly altered by morphine in both control and Abx conditions, microbiome depletion also resulted in additional morphine-regulated changes, largely in functional categories related to histone modification and chromatin dynamics. In addition, SCFA replenishment restored transcriptional changes induced by Abx at several genes, including inducible transcription factors previously identified to be important in drug responses (eg, the immediate early genes Egr2 and Egr4). Thus, like the behavioral effects of microbiome depletion, at least some effects on morphine-induced gene expression changes are reversible when SCFAs are replaced in the diet.Together, these findings mark a fundamental first step for continued exploration of gut-brain interactions in the regulation of morphine action. However, many additional questions remain. For …