Cracking the code of gut-brain communication

Cell communication within the gut is a language that Professor Damien Keating is striving to interpret – not only to improve knowledge of gastroenterological health but also because the gut holds great secrets about how the rest of our body behaves, including our brain.

As Deputy Director of the Flinders Health and Medical Research Institute and Head of the Gut Sensory Systems research group, Professor Keating is leading research into gut cells and the gut-brain axis. This is a multifaceted system, with the nuances of so many interconnecting variable components and influences adding profound complexity to these studies.

“My research is focused on understanding how cells send chemical signals to each other and how this is implicated in health and disease,” he says. “The more I investigate, the more it keeps leading to other connections, which keeps opening up new possibilities and avenues of research to explore.”

It’s frontier science that requires bold, unconventional investigations – and a key that needs to be unlocked is the function and behaviour of gut endocrine cells.

“Our gut wall is mostly lined with epithelial cells, similar to skin cells, but there are also other cell types in the gut wall and about 1% of these are called enteroendocrine cells. There are about 15 sub-types of these enteroendocrine cells, and the small intestine has the highest rate of cell turnover in the human body, so it is an incredibly dynamic environment to study,” explains Professor Keating.

“It’s a completely unique environment for our body to deal with. Our gut wall is essentially exposed to the outside world through this hole that runs through our entire body – via what we eat and drink, via the bacteria that live within the gut microbiome and release substances, and all this has an effect on how these cells are created and behave.”

Part of this work involves a study of serotonin – the happy hormone that affects our mood and behaviour – which is typically classified as a neuro-transmitter, but is also a regulator of normal gut function and is an important driver of metabolism and metabolic diseases, including obesity and type 2 diabetes.

Professor Keating’s investigations have shown that individual cells producing serotonin in the intestines change under high-fat diet conditions and are increased in human obesity. He believes this leads to not only intestinal disruption but exacerbates metabolic problems and may even have mental health ramifications. Such findings open up the possibility of diverting attention away from the brain to the gut in the search for some mental health solutions.

Professor Keating made a conscious decision a decade ago to specialise on studying cells in the gut, inspired to work in collaboration with Flinders University colleagues on novel research ideas. “I realised that these cells were very much under-studied, especially when compared with other endocrine cells, and I had an opportunity to work with other gastrointestinal research teams at Flinders. Part of these collaborations has meant we could undertake our studies with human gut tissue and embark on a whole series of world-first studies.”

Such studies are plugging into new explorations of metabolic disorders including diabetes and obesity. This includes demonstrating that sugars, including glucose, trigger the release of specific types of gut hormones, some of which activate insulin secretion after a meal that brings down blood glucose levels, while others send signals to our brain to tell us to stop eating.

Professor Keating is also studying how enteroendocrine cells activate nearby neurons that then affect how our gut contracts, and how they can dictate painful gut disorders such as constipation and diarrhoea.

He wants to delve deeper, to examine how the microbiome interacts with these cells and can change some of the gut hormones, and investigate the symbiotic relationship between gut bacteria and their human hosts.

This all connects with ongoing work to explore the gut-brain axis, comprising the behaviour of nerves that run from the brain into the gut, with nerve endings located very close to enteroendocrine cells. The gut-brain axis therefore affects higher brain function, in both conscious and unconscious ways.

Professor Keating wants to discover how nerve endings close to enteroendocrine cells can be linked to a raft of human health disorders – from thermal control to heart rate and blood pressure, but also to mood and mental health disorders.

“The signals being sent to the brain from the gut could be affected by the food we eat, but could also be affected by environmental factors – things such as pollution or stress – because the outside world has access to, and affects, these cells,” he says.

“It opens up a whole new area of exploration. If we can understand how these signals work, then we can explore how they lead to or modify specific human health disorders – and lead us towards new ways of treating these disorders.”

The big next step is to identify gut-brain links to higher brain functions, through understanding what triggers nerves that then produce reactions in the brain. Professor Keating believes this could unlock an improved understanding of mental health disorders.

“It’s a gigantic exploration which provides my team with the opportunity to focus on the ‘blue sky’ ideas and to consider the bigger picture about the impact of what we study. This means focusing on collaborations that are already great strengths here at Flinders – and also to identify world leaders in the field and work with them to get answers to some of our really big questions,” says Professor Keating.

“Our investigations so far have produced remarkable results – but there is so much more exciting work ahead of us. It’s as though we have pulled a thread, and so much more is unravelling than we ever anticipated.”