[en] [en] 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.
Disciplines :
Microbiology
Author, co-author :
Mao, Jian-Hua; Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
Kim, Young-Mo; Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
Zhou, Yan-Xia; Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA ; Marine College, Shandong University, Weihai, 264209, China
Hu, Dehong; Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
Zhong, Chenhan; Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
Chang, Hang; Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
Brislawn, Colin J; Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
Fansler, Sarah; Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
Langley, Sasha; Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
Wang, Yunshan; Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA ; Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, 250033, Shandong, China
Celniker, Susan E; Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
Threadgill, David W; Department of Veterinary Pathobiology, A&M University, College Station, Texas, USA ; Department of Molecular and Cellular Medicine Texas, A&M University, College Station, Texas, USA
WILMES, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Systems Ecology
Orr, Galya; Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
Metz, Thomas O; Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
Jansson, Janet K; Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA. Janet.Jansson@pnnl.gov
Snijders, Antoine M; Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA. AMSnijders@lbl.gov
Office of Naval Research Global Lawrence Berkeley National Laboratory Pacific Northwest National Laboratory
Funding text :
This work was primarily supported by the Office of Naval Research under ONR contract N0001415IP00021 (J.J.). Additional support was provided by the Lawrence Berkeley National Laboratory Directed Research and Development (LDRD) program funding (J.H.M. and A.M.S.). Partial support was also provided under the Microbiomes in Transition (MinT) Initiative as part of the Laboratory Directed Research and Development Program at PNNL. Metabolomic measurements, fluorescence microscopy, and mRNA FISH analyses were performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the US DOE OBER and located at PNNL in Richland, Washington. PNNL and LBNL are multiprogram national laboratories operated by Battelle for the DOE under contract DE-AC05-76RLO 1830 and the University of California for the DOE under contract DE AC02-05CH11231, respectively.
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