Globally, around 50 million people are living with dementia, but the causes of conditions like Alzheimer’s disease are complex and not understood.

A new study in mice from the Quadram Institute and University of East Anglia has uncovered a role for intestinal mucus in ensuring optimum communication between the gut, microbiome and brain that maintains brain health and identified how alterations in this impair memory.

Mucus is a familiar annoyance as anyone who’s had a cold or cough can testify to. But this sticky goo also plays an important role in keeping us healthy, even when we’re not fighting off malignant microbes, as a protective coating for internal surfaces of the body, such as our airways and gut.

In the gut, mucus has a major influence over our health. In recent years we’ve come to realise that the microbes living in our gut, the microbiome, influence not just gut health, but also many other conditions outside the gut, including neurological disorders such as Alzheimer’s disease.

To realise these benefits the body makes mucus, which offers a habitat for the gut bacteria that make up the microbiome. Cells lining the gut produce proteins rich in sugars, called mucins, that make up the mucus gel, which gut bacteria can attach to and use as a source of nutrition. These mucins are “capped” so that only bacteria with the enzymes to break open those caps can access the core sugars. In this way the body favours the bacteria it wants to colonise the gut, and vice-versa, ensuring a mutually beneficial relationship with the microbiome.

Many health conditions have been linked to a breakdown in the balance of the microbiome, and there’s now evidence that the integrity of the mucus layer can contribute to that.  That’s because whilst the mucus hosts bacterial populations, it does so at arm’s length from the gut lining itself. If that arrangement breaks down, the gut barrier itself can be compromised. This is associated with gut conditions such as colon cancer or inflammatory bowel diseases.

A compromised gut lining will also cause problems elsewhere in the body, as it allows bacteria, and the compounds they produce, to enter the blood stream inappropriately. This affects whole-body systems including the gut-brain axis, the two-way communication between our central nervous system and the “second brain” in our digestive system. The gut-brain axis not only controls functions like appetite, but also higher cognitive functions like mood and memory.

Because of this central role in our health, there has been a lot of interest in understanding how changes in the microbiome lead to leaky gut and affect the gut-brain axis, particularly in understanding how this affects age-related decline cognitive function. But the role of the mucus in gut-brain axis hasn’t been investigated.

To start to fill this knowledge gap, glycobiologist Prof. Nathalie Juge, who leads a group in the Quadram Institute studying microbiome-mucus interactions, worked with Dr David Vauzour from the University of East Anglia, and an expert in brain ageing, cognitive decline and dietary health.

The study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UKRI, and published in the journal Scientific Reports. as part of a collection of research articles on the gut-brain axis.

The team looked at mice with alterations in mucus sugars in the colon, to see how this affected their physiology and behaviour. Using animal models is necessary because of the complexity of the way these two organ systems interact. The researchers compared them with mice that had the genes needed for normal mucus production. The mice came from the same litter to reduce external influences on their gut microbiome composition.

The mice with altered mucus sugar composition in the colon had a more permeable gut lining, supporting the idea that these molecules are important for maintaining the integrity of the gut lining as a barrier.

These mice had broadly similar microbiome composition to their normal littermates, apart from an increase in the Lactobacillaceae family of bacteria. But to understand how a microbiome is functioning you not only need to know what it’s made of, but also what it is doing. One way to do this is to look at the metabolites– the range of small molecules produced as part of bacterial metabolism. Here they found mice with altered mucus sugars in the colon had different levels of certain metabolites previously linked to Alzheimer’s disease and depression. With these mice displaying leakier guts, it’s more likely these metabolites could move to the brain or otherwise affect signalling between the gut and the brain. So, the researchers looked for evidence of this in the brain.

Section of hippocampus showing the granule cells (in green) projecting their dendrites towards the upper and lower layers. Image by Erika Coletto, the Quadram Institute.

In the hippocampus, the brain area involved in memory formation, the team observed that in the mice with alterations in colonic mucus sugars the granule cells orchestrating the formation of new neurons (neurogenesis) had an abnormal phenotype with short and disorganised dendrites – the branch-like projections from brains cells that deal with signals.

These changes seem to have had a detrimental effect on the animals’ behaviour, measured using a series of tests of their memory and recognition capacity. The deficient mice had a significant alteration in their ability to discriminate between familiar and novel objects, suggesting an impairment of their memory circuits.

Taken together, these results suggest a link between the mucus in the colon and the development of neurological conditions. We don’t yet know how the findings in mice relate to humans, but this study points to how mucus, microbes and leaky gut link to cognitive decline, and identify some of the cells and processes involved.

 “This proof-of-concept study opens up new avenues of research on how changes in our gut microbiota relates to brain function by highlighting the role of intestinal mucus and mucin glycosylation in gut-brain axis, we hope that this will lead to the development of novel strategies to promote gut and brain health across life” said Professor Nathalie Juge

Dr David Vauzour said “This work provides novel mechanistic understanding of the role of intestinal mucus in the gut-brain axis connection. Further studies are required to identify and confirm its clinical significance.”

“I am delighted to see this work published, and grateful for the collaborations which helped address some of the multiple components involved in the gut microbiota-brain axis” said Dr Erika Coletto, a former BBSRC Norwich Research Park Doctoral Training Partnership student and first author on the paper.

Reference: Role of mucin glycosylation in the gut microbiota‑brain axis of core 3 O‑glycan deficient mice. Erika Coletto, George M. Savva, Dimitrios Latousakis, Matthew Pontifex, Emmanuelle H. Crost, Laura Vaux, Andrea Telatin, Kirk Bergstrom, David Vauzour & Nathalie Juge, Scientific Reports 13, 13982 (2023). https://doi.org/10.1038/s41598-023-40497-8

This paper was part of Scientific Report’s Gut-brain axis collection edited by Gerard Clarke, Renáta Cserjési, Ceymi Doenyas & David Vauzour.