Genetic and metabolic links between the murine microbiome and memory

Abstract

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.

Gut microbiome partially mediates and coordinates the effects of genetics on anxiety-like behavior in Collaborative Cross mice

“…Several lines of evidence indicated an important role for the gut microbiome in behavior (reviewed in) 13 . In the absence of microbes, the brain of mice was affected and colonization of animals with specific bacterial strains could alter behavior 14 , 15 . Furthermore, children exposed to infections exhibited an increased incidence of irritable bowel syndrome, which has been associated with psychological distress 16 .…”

Gut Microbiome Composition is Associated with Age and Memory Performance in Pet Dogs

“…We selected this technique for the analysis of the gut microbiome of a group of companion dogs and examined possible links with age and cognitive performance. Based on a study in mice, we predicted that memory performance is linked to Lactobacillus [25] and that age would be associated with less diverse microbiota [21,26] and/or less abundant lactobacilli [24].…”

Dietary Components, Microbial Metabolites and Human Health: Reading between the Lines

“…GABA is a vital metabolite, which is produced by different kinds of gut bacteria like Lactobacilli , Bifidobacterium , Bacteroides and Parabacteroides [ 78 , 79 ]. It is reported that after Germ-free mice were inoculated with Lactobacilli , their memory improved, and higher levels of GABA in the hippocampus were observed [ 80 ]. As a neurotransmitter, it targets the brain directly by stimulating the vagus nerves or indirectly by the neuroendocrine mechanism, thus affecting appetite [ 81 ].…”