BACKGROUND Recent evidence has linked the gut microbiome to host behavior via the gut-brain axis [1-3]; however, the underlying mechanisms remain unexplored. Here, we determined the links between host genetics, the gut microbiome and memory using the genetically defined Collaborative Cross (CC) mouse cohort, complemented with microbiome and metabolomic analyses in conventional and germ-free (GF) mice. RESULTS A genome-wide association analysis (GWAS) identified 715 of 76,080 single-nucleotide polymorphisms (SNPs) that were significantly associated with short-term memory using the passive avoidance model. The identified SNPs were enriched in genes known to be involved in learning and memory functions. By 16S rRNA gene sequencing of the gut microbial community in the same CC cohort, we identified specific microorganisms that were significantly correlated with longer latencies in our retention test, including a positive correlation with Lactobacillus. Inoculation of GF mice with individual species of Lactobacillus (L. reuteri F275, L. plantarum BDGP2 or L. brevis BDGP6) resulted in significantly improved memory compared to uninoculated or E. coli DH10B inoculated controls. Untargeted metabolomics analysis revealed significantly higher levels of several metabolites, including lactate, in the stools of Lactobacillus-colonized mice, when compared to GF control mice. Moreover, we demonstrate that dietary lactate treatment alone boosted memory in conventional mice. Mechanistically, we show that both inoculation with Lactobacillus or lactate treatment significantly increased the levels of the neurotransmitter, gamma-aminobutyric acid (GABA), in the hippocampus of the mice. CONCLUSION Together, this study provides new evidence for a link between Lactobacillus and memory and our results open possible new avenues for treating memory impairment disorders using specific gut microbial inoculants and/or metabolites. Video Abstract.

中文翻译：

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小鼠微生物组与记忆之间的遗传和代谢联系。

背景技术最近的证据已经通过肠道脑轴将肠道微生物组与宿主行为联系起来[1-3]。但是，其潜在机制仍待探索。在这里，我们确定了宿主遗传学，肠道微生物组和记忆之间的联系，使用了基因定义的协作十字（CC）小鼠队列，并辅以常规和无菌（GF）小鼠中的微生物组和代谢组学分析。结果全基因组关联分析（GWAS）使用被动回避模型确定了76,080个单核苷酸多态性（SNP）中的715个，它们与短期记忆显着相关。鉴定出的SNP富含已知参与学习和记忆功能的基因。通过同一CC队列中肠道微生物群落的16S rRNA基因测序，我们在保留测试中发现了与较长潜伏期显着相关的特定微生物，包括与乳酸杆菌的正相关性。与未接种或经大肠杆菌DH10B接种的对照相比，用单个乳杆菌（罗伊氏乳杆菌F275，植物乳杆菌BDGP2或短乳杆菌BDGP6）接种GF小鼠可显着改善记忆。非靶向代谢组学分析显示，与GF对照小鼠相比，乳酸菌定殖小鼠的粪便中包括乳酸在内的几种代谢物的含量明显更高。此外，我们证明了饮食中的乳酸治疗可以增强传统小鼠的记忆力。从机理上讲，我们发现接种乳酸杆菌或乳酸治疗均可显着增加神经递质的水平，小鼠海马中的γ-氨基丁酸（GABA）。结论总之，本研究为乳杆菌与记忆之间的联系提供了新的证据，我们的结果为使用特定的肠道微生物接种剂和/或代谢物治疗记忆障碍的疾病开辟了可能的新途径。录像摘要。