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How do microbes living in our gut modulate brain and behaviour?

25 May 2022

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Researchers from the Quadram Institute working with colleagues from the University of East Anglia have uncovered from studies in mice the role of a key member of the gut microbiota influences communication between the gut and the brain.

The study provides evidence of how bacteria living in the mucosal lining of the gut influence the brain and neurological disorders.

The gut microbiota is a complex community of bacteria, viruses and other microbes and is emerging as a key regulator of the function of not just the gut, but also other organs including the brain.

With an ageing population, extra attention is being paid to ways of maintaining mental health and preventing cognitive decline into old age. Altering the makeup of the gut microbiota, through diet or microbial therapies, is a potentially attractive way to do this, and is a matter of extensive investigations to work out which microbes provide benefits, and even more crucially the mechanisms by which they do this.

The capacity of the gut microbiota to colonise different niches within and along the gastrointestinal tract is in large part modulated by the availability of carbohydrates from the diet or from the host.

Some bacteria living in the mucosal lining of the gut can utilise host mucin glycans – sugars associated with the proteins that make up mucus that lines the gut. Due to their proximity to the host tissue, these bacteria are best placed to influence signaling to other organs such as the brain.

Mice bred to lack any gut microbes show defects in brain function and development. These “germ-free” mice show increased permeability of the blood brain barrier, dysfunction of the microglia cells that coordinate immune responses in the brain, as well as changes in neurogenesis and how brain neurons adapt (synaptic plasticity).

Transplantation of faecal microbiota into germ free mice demonstrated the role of the gut microbiota in gut-brain signaling but there is little information on how specific gut symbionts adapted to the intestinal mucus layer modulate brain function.

R. gnavus is a prevalent member of the human gut microbiota. It is an early coloniser of the infant gut which persists throughout adulthood where it plays key role in health and disease. R. gnavus has been associated with inflammatory bowel disease and an increasing number of studies reported a disproportionate representation of R. gnavus in patients suffering of neurological disorders ranging from general anxiety disorders, migraine, depression or attention deficit hyperactive disorder, although a causal effect has not been demonstrated.

Addressing this knowledge gap became the subject of Norwich Research Park DTP PhD student Dr Erika Coletto, supervised by Prof Nathalie Juge. Working with colleagues in the Juge group at the Quadram Institute and Dr David Vauzour from the University of East Anglia, she studied the role of a specific member of the gut microbiota, Ruminococcus gnavus ATCC 29149 in the communication between the gut and the brain in germ free mice.

How R. gnavus colonises the mucus niche has been extensively studied by the Juge group and they showed that the adaptation of R. gnavus to the gut is strain-dependent and associated with their capacity to forage on mucin glycans found in the lining of the gut.

In this work, published in the journal Gut Microbes, they investigated how R. gnavus in the gut can signal to the brain and influence behavior.

Using germ free, or gnotobiotic mouse models they showed how R. gnavus colonising the intestinal mucus influences brain regulation and function through activation of microglia immune system cells and neurogenesis in the hippocampus.

They also identified potential mediators of the communication between R. gnavus and the brain. Mice colonised with R. gnavus showed increased levels of metabolites, released by the bacteria from its mucin-foraging capacity and metabolites known to affect brain function, such as tryptamine, which triggers the release of the neurotransmitter serotonin in the gut.

Colonisation of germ-free mice with R. gnavus also affected the differentiation of granule cell lineage through increased activity of phagocytic microglia and synaptic plasticity. This was accompanied with changes in spatial working memory behaviour.

The study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation (UKRI).

“Working at this project was challenging, but extremely interesting and innovative” said Dr Coletto. “It gave me the opportunity to collaborate with experts in the microbiology and neurobiology field and learn more about the gut microbiota-brain axis”

“These results provide first insights into the mechanisms underpinning the association of R. gnavus with neurological disorders through the production of metabolites” said Professor Nathalie Juge.

“Further work is required to tease out which R. gnavus specific metabolites mediate these effects and the role of mucin derived glycans in this process; we are now addressing the causality of these interactions using further preclinical models including organ-on-chips.”

That information on how the microbiota influences the brain will be extremely valuable in designing potential new ways of modulating the human microbiota or other therapeutic interventions, to help offset cognitive decline and ensure we all live healthy lives as we age.

Image: Granule cells (labelled green) in the brain hippocampus are affected by R. gnavus. Credit: Quadram Institute

Reference: The role of the mucin-glycan foraging Ruminococcus gnavus in the communication between the gut and the brain, Erika Coletto, Dimitrios Latousakis, Matthew G. Pontifex, Emmanuelle H. Crost, Laura Vaux, Estella Perez Santamarina, Andrew Goldson, Arlaine Brion, Mohammad K. Hajihosseini, David Vauzour, George M Savva & Nathalie Juge (2022), Gut Microbes, 14:1, DOI: 10.1080/19490976.2022.2073784

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