A healthy gut might well be the key to a long and healthy life. But with trillions of bacteria and hundreds of species of microbe all interacting with your gut in unique and interdependent ways, understanding gut health is a vast and complex challenge.
A healthy gut might well be the key to a long and healthy life. But with trillions of bacteria and hundreds of species of microbe all interacting with your gut in unique and interdependent ways, understanding gut health is a vast and complex challenge.
“Gut health is really important,” says Martina Poletti. “It’s not just about gut problems, but many others related to it, such as skin problems and mental health.”
Poletti is a PhD student in the Korcsmaros Group at EI, who is working with colleagues - including senior cellular microbiologist Dr Isabelle Hautefort and fellow PhD student Agatha Treveil - on unraveling the complexities of our gut microbes, and the interactions they have with our own bodies.
Together, they are combining some of the latest technologies - patient-derived organoids, network biology, and machine learning - to answer long-standing questions that could improve the lives of many millions of people.
“600 000 people in the UK suffer from IBD,” says Poletti, “and many drugs don’t work for them, so it’s important to understand what’s going on.”
IBD - or Inflammatory Bowel Disease - describes a range of symptoms characterised by inflammation of the gut (see info box below), which are broadly grouped into two main conditions: Crohn’s disease (CD) and ulcerative colitis (UC).
“Crohn’s affects the top of the large intestine - the colon - and the last part of the small intestine. By comparison, people with ulcerative colitis have inflammation at the end of their colon - the rectum - and this usually progresses upwards,” says Hautefort. “Certain new drugs can reduce the inflammation associated with IBD but, for the majority of patients, this effect soon subsides.
“Unfortunately, that means there’s no cure for any of these lifelong chronic diseases - they’re multi-factoral, very complex, and differ between patients even if they display the same symptoms. It’s absolutely essential we understand why.”
One of the key factors being investigated is our food. “With western lifestyles and diets, general gut health is declining and a lot of immune-related diseases are increasing, including IBD and eczema,” explains Treveil, who is coming to the end of a successful PhD, with a first author publication and an award for best conference talk (among a whopping field of 1100) already to her name.
“To get to the bottom of this, you have to go to the basics: the interactions in the gut with bacteria, our immune system, and food. The list of things that can affect your gut is endless.”
“Gut health is really important, it’s not just about gut problems, but many others related to it, such as skin problems and mental health.”
Inflammatory bowel disease (IBD) is defined as “chronic gut inflammation due to an inappropriate immune response to the gut microbiota in genetically susceptible hosts”.
The overarching symptom of ulcerative colitis (UC) and Crohn’s disease (CD), two major types of IBD, is chronic inflammation of the gastrointestinal tract, which can lead to significant damage and illness. During inflammatory flare-ups, patients can suffer a range of debilitating symptoms, including: abdominal pain, cramps or tummy swelling, frequent passing of recurrently bloody stools, weight loss and extreme tiredness.
In both conditions, an exaggerated immune reaction causes a person’s body defences to fight against their own gut microbiota - the microbes living in the human gut. A disrupted or impaired microbiota is frequently associated with each disease - a condition known as dysbiosis.
Scientists are working to unravel the causes of these auto-immune diseases, which appear to have many triggers and compounding factors which are difficult to disentangle.
It’s important to understand how we can prevent diseases, rather than just treat them. That’s where I see this research going. How we can prevent people getting IBD in the first place, and how simple lifestyle changes can improve people’s gut health.
A walk down the supermarket dairy aisle will yield a variety of products claiming to boost a healthy gut. Yoghurts laden with probiotics are a frequent sight. But are these actually beneficial?
“There is increasing evidence that some bacteria, when we’re healthy, promote health and gut health in particular,” says Hautefort. “There’s a lot of hope that, once we understand more about diseases like IBD, we can understand how to use those healthy microbes to help restore the balance through microbial therapy, rather than drugs or - in the worst case - surgery.”
Poletti and Treveil - who both also work with the Lindsay Hall lab at the Quadram Institute - have spent much of their PhDs working on a particular group of microbes known as bifidobacteria, which make up most of a newborn’s natural gut microbiota. These bacteria are commonly used as probiotics alongside other common types of bacteria such as Lactobacilli.
“There’s a lot of evidence that [bifidobacteria] can benefit gut health, but we don’t know a lot about how.” says Treveil. “We’re trying to take that to a basic level to understand how bifido interacts with the gut lining at the host cell level, both in health and disease.”
Poletti is developing an experimental model to look at the effect of bifidobacteria on different types of cells in the lining of the gut. In particular, her research focuses on special gut cells that affect the composition of our microbiome, called Paneth cells. She’s using intestinal organoids - a very useful piece of technology that allows us to model what happens in the gut.
“Intestinal organoids are like a mini gut,” says Poletti, who recently won an international video competition in which she demonstrated her work on organoids. “You can grow them in the lab and they’re very useful because they have the same structure and cell types of the gut.”
These organoids can be derived from a patient’s own cells, which opens up possibilities for a personalised medicine approach. Patients who are having an endoscopy, for example, can agree for some of their intestinal cells to be donated and used to make organoid research models.
“We can grow organoids in vitro and then get detailed information about how gut cells work - it might be genetic changes associated with a disease, or how certain medications affect inflammation.
“Working with organoids from patients - and specific cells in those organoids - we can see where normal functions are altered compared to a healthy gut at a level that was not possible a few years ago,” says Hautefort.
As an expert and pioneer of research into gut organoids, Hautefort sees great potential for revolutionising patient care and biomedical studies. “With organoid models, generated at a patient specific level, we are going to be able to see - for each patient - how normal function can be restored.”
You might have heard the terms microbiome and microbiota. These are often used interchangeably in popular media to describe all of the microbes living in the gut, for example. However, we’re really referring to slightly different things:
Microbiota refers to the community of microorganisms living in a certain environment. That could be the gut, but it could also be the skin, a river, a tree, or even a dishcloth.
Microbiome refers to the DNA sequences that belong to all of the microorganisms living in a certain environment. Not only does this tell us what species are present in the microbiota, but also the genes and other parts of DNA which give us much more information about how these organisms interact with the host (such as human gut cells). These genes might be responsible for digesting certain nutrients in food, such as fibres, or - in the case of Salmonella - for infecting our intestines.
Considering all of the compounding factors associated with gut health, and the highly variable nature of IBD, that is no easy task. That’s why Treveil is taking a computational approach.
“We use network biology a lot, which is where we try to understand the interactions between molecules in the cell [and between different cells] using networks,” says Treveil. “In doing that you can integrate different types of data from different sources, and look at that together as a system.
“To integrate environmental factors becomes a lot harder because measuring them is hard. Measuring what people eat is inherently difficult, but I think we’ll see more and more of that.”
Poletti says that one way around this is to measure changes in the microbiome - the DNA sequences of bacteria and other microbes living in the gut: an area being tackled by colleagues in the Hildebrand Group who have recently secured a €1.5m ERC grant to that end. “We can now measure the microbiome of a person - and that could reflect the diet, or some environmental factors, such as the use of antibiotics,” she explains.
"We know that there is a big difference between the microbiome of a person who has taken antibiotics or not, especially early in life, and we can then correlate that with disease outcome, or even the proteome or transcriptome data - and that could give us an idea of what’s happening.
“Even a lot of common drugs like paracetamol can change the microbiome quite significantly.”
When it comes to fostering a healthy gut, then, it’s not quite as easy as just quaffing an Actimel each morning and night.
“You can’t expect to eat yoghurt or probiotics and that’s it, for the rest of your life you’ll be healthy,” says Treveil. “It’s not that simple. It can still have beneficial effects while moving through your body. But many people find - if they stop taking probiotics - they will go back to the health state they were in before because the probiotics can’t find a space [in the gut].
“There’s too much else in there.”
In the end, says Poletti, “what’s important really is the balance. There are populations of bacteria that are beneficial, some that are less beneficial. In general, a diet high in fibre promotes the growth of those beneficial bacteria. They are broken down into short chain fatty acids, which have many positive effects.
“Diet can really make a big difference - even more than probiotics.”
Treveil says we have a long way to go to properly understand what’s going in the gut, but there’s a lot that science can contribute. “It’s important to understand how we can prevent diseases, rather than just treat them. That’s where I see this research going. How we can prevent people getting IBD in the first place, and how simple lifestyle changes can improve people’s gut health.”
Poletti agrees that it’s likely to be a case of prevention being better than the cure. “At the moment most drugs target inflammation. You’re solving the problem when it’s already developed, but perhaps we can find a way to prevent it, or avoid reaching that stage.”
For Hautefort, personalised medicine will be key to achieving this. “With these organoids we can create personalised models that will allow us to define patient-specific markers indicating who is at risk of developing IBD.
“We are not doing this alone. We work with clinicians, drug developing companies and those interested in the use of probiotics to tackle IBD.
“Combining our scientific approaches with clinical data coming from global IBD centres, a UK-wide consortium, and industry, we have a better chance of learning more and discovering better ways to help people.”
This article refers to BBSRC-UKRI-funded, cross-institutional work. Group leader Dr Tamas Korcsmaros is employed by both Earlham Institute and Quadram Institute (QI), working closely with fellow joint-appointee Dr Falk Hildebrand and other collaborators including QI’s Dr Lindsay Hall.
Agatha Treveil and Martina Poletti are both PhD students on the Norwich Research Park Doctoral Training Programme.
