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Developmental Biology - Brain Development

Genetics, Gut Microbiome & Memory

A new study traces molecular connections between genetics, gut microbiome and memory in a mouse bred to resemble human diversity...

A team of researchers from two US Departments of Energy national laboratories, have found new evidence of tangible connections between our gut and brain. They have identified lactate as a key memory-boosting molecular messenger. Lactose is a molecule produced by all species of one gut microbe.

The work was published April 17 in the journal BMC Microbiome.

"Our study shows that the microbiome might partner with genetics to affect memory," said Janet Jansson, a microbial ecologist at Pacific Northwest National Laboratory and a corresponding author of the study.

Scientists know that mice fed microbes called probiotics, experience positive benefits. These microbes produce molecules which travel through blood acting as chemical messengers to influence other parts of the body, including the brain. The microbiome's impact on memory is a very active research area now with more than 100 papers published in the last five years on links between common probiotics and memory.

However, it wasn't clear which specific microorganisms and microbial molecular messengers influence memory until now.
"The challenge is that a mouse's unique genetic makeup and environmental conditions also impact its memory and microbiome. To know if a microbial molecule influenced memory, we needed to understand the interaction between genetics and the microbiome."

Antoine Snijders PhD, Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA and co-corresponding author.

Mouse Genetics Influence Memory, Gut Microbiome

Before hunting for molecules that might be involved with memory improvement, Jansson, Snijders and their colleagues needed to determine how genetics influence memory.

They started with a collection of mice called the Collaborative Cross, breeding 29 different strains of mice to mimic the genetic and physical diversity of a human population. This includes mice of different sizes, coat colors and disposition (as in: timid or bold). Researchers also know the genome sequences of each mouse strain.

First, they gave each strain of mice a memory test. Then screened each strain for genetic variations, correlating these variations to the memory test results. This allowed them to identify two sets of genes associated with memory. One was a new set of candidate genes for influencing cognition; the other set being genes already known.

Next, they analyzed the gut microbiome of each mouse strain to make microbial connections between genetics and memory links they had already identified in four families of microbes associated with improved memory.
The most common of those was a species of Lactobacillus, L. reuteri.

To test this association, the researchers fed L. reuteri to germ-free mice without any gut microbes and then tested the mice's memory — and saw a significant improvement relative to germ-free mice not fed microbes.

They found the same improvement when they fed germ-free mice one of two other Lactobacillus species.
"While a link between Lactobacillus and memory has previously been reported, we also found it independently in this unbiased genetic screen.

These results suggest genetic variation in large part controls memory, as well as the differences in the composition of the gut microbiome across [mouse] strains."

Antoine Snijders PhD

Diet, Probiotics Boost Memory

Finally, the researchers wanted to identify which microbe-related molecules might be involved with memory enhancement. They analyzed stool, blood and brain tissue from germ-free mice fed a specific species of Lactobacillus. Lactate was one of the common metabolic molecular byproducts — and is also a molecule that all Lactobacillus strains produce.
The team fed lactate to mice previously identified to have poor memory and noticed that their memory improved. Mice fed lactate or Lactobacillus microbes also had increased levels of gamma-aminobutyric acid (GABA), a molecular messenger linked to memory formation in their brains.

To see if the same molecular mechanism might also apply to humans, researchers contacted Paul Wilmes at the University of Luxembourg. Wilmes had developed a tiny chip that mimics where microbes interact with human intestinal tissue.
When Wilmes and his colleagues tested L. reuteri on this chip, they saw how lactate produced by the microbes traveled through human gut tissue. This indicates lactate could enter the bloodstream and potentially travel to the brain.

"While this research strengthens the idea that diet, genetics, and behaviors — like memory — are connected, further work is needed to show if Lactobacillus can improve memory in humans," Jansson is quick to add.

Snijders agrees, adding how it might be possible one day to use probiotics to improve memory in targeted populations, such as people with learning disabilities and neurodegenerative disorders.

Recent evidence has linked the gut microbiome to host behavior via the gut–brain axis [1,2,3]; 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.

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.

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.

Jian-Hua Mao, Young-Mo Kim, Yan-Xia Zhou, Dehong Hu, Chenhan Zhong, Hang Chang, Colin Brislawn, Sasha Langley, Yunshan Wang, B. Y. Loulou Peisl, Susan E. Celniker, David W. Threadgill, Paul Wilmes, Galya Orr, Thomas O. Metz, Janet K. Jansson and Antoine M. Snijders

The authors would like to thank Gabriela Fuentes-Creollo and Frank Ponce for maintenance and breeding of germ-free and gnotobiotic mice, Kenneth Wan and Benjamin Booth for assistance in 16S rRNA gene sequencing, and Emma L. Schymanski for technical assistance with HuMiX experiments

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 multi-program 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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May 29 2020   Fetal Timeline   Maternal Timeline   News

Illustration of the connection between brain and microbes in the gut.
Courtesy of Nathan Johnson/Pacific Northwest National Laboratory - PNNL.

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