The Jackson Laboratory Genomic Medicine, 10 Discovery Way, Farmington, CT, USA.
The Jackson Laboratory Mammalian Genetics, 600 Main St, Bar Harbor, ME, USA.
Neuropharmacology. 2023 Mar 15;226:109409. doi: 10.1016/j.neuropharm.2022.109409. Epub 2022 Dec 30.
The gut microbiome is thought to play a critical role in the onset and development of psychiatric disorders, including depression and substance use disorder (SUD). To test the hypothesis that the microbiome affects addiction predisposing behaviors and cocaine intravenous self-administration (IVSA) and to identify specific microbes involved in the relationship, we performed 16S rRNA gene sequencing on feces from 228 diversity outbred mice. Twelve open field measures, two light-dark assay measures, one hole board and novelty place preference measure significantly differed between mice that acquired cocaine IVSA (ACQ) and those that failed to acquire IVSA (FACQ). We found that ACQ mice are more active and exploratory and display decreased fear than FACQ mice. The microbial abundances that differentiated ACQ from FACQ mice were an increased abundance of Barnesiella, Ruminococcus, and Robinsoniella and decreased Clostridium IV in ACQ mice. There was a sex-specific correlation between ACQ and microbial abundance, a reduced Lactobacillus abundance in ACQ male mice, and a decreased Blautia abundance in female ACQ mice. The abundance of Robinsoniella was correlated, and Clostridium IV inversely correlated with the number of doses of cocaine self-administered during acquisition. Functional analysis of the microbiome composition of a subset of mice suggested that gut-brain modules encoding glutamate metabolism genes are associated with the propensity to self-administer cocaine. These findings establish associations between the microbiome composition and glutamate metabolic potential and the ability to acquire cocaine IVSA thus indicating the potential translational impact of targeting the gut microbiome or microbial metabolites for treatment of SUD. This article is part of the Special Issue on "Microbiome & the Brain: Mechanisms & Maladies".
肠道微生物群被认为在精神疾病的发生和发展中起着关键作用，包括抑郁症和物质使用障碍（SUD）。为了验证微生物群影响成瘾易感性行为和可卡因静脉自我给药（IVSA）的假设，并确定与该关系相关的特定微生物，我们对 228 只多样性杂交小鼠的粪便进行了 16S rRNA 基因测序。12 项开阔场测量、2 项明暗箱测量、1 项洞板和新颖性位置偏好测量结果表明，可卡因 IVSA 获得（ACQ）和未获得 IVSA（FACQ）的小鼠之间存在显著差异。我们发现 ACQ 小鼠比 FACQ 小鼠更活跃、更具探索性，且恐惧程度较低。区分 ACQ 和 FACQ 小鼠的微生物丰度为 Barnesiella、Ruminococcus 和 Robinsoniella 的丰度增加，而 ACQ 小鼠的 Clostridium IV 减少。ACQ 与微生物丰度存在性别特异性相关性，ACQ 雄性小鼠的乳酸杆菌丰度降低，ACQ 雌性小鼠的 Blautia 丰度降低。Robinsoniella 的丰度与可卡因自我给药期间获得的剂量数呈正相关，Clostridium IV 呈负相关。对一小部分小鼠的微生物组组成进行功能分析表明，编码谷氨酸代谢基因的肠道-大脑模块与自我给药可卡因的倾向有关。这些发现确立了微生物组组成和谷氨酸代谢潜力与获得可卡因 IVSA 的能力之间的关联，从而表明针对肠道微生物组或微生物代谢产物治疗 SUD 的潜在转化意义。本文是“微生物组与大脑：机制与疾病”特刊的一部分。
