Lab-grown mini-guts crack Crohn's disease

"Mini-guts" grown from cells collected from the lining of the intestines of patients with the inflammatory bowel condition Crohn's disease are helping scientists to better understand why some people develop this chronic and disabling syndrome. Matthias Zilbauer, professor of paediatric gastroenterology at the University of Cambridge, has found changes in the level of activity of genes linked to how the gut lining cells interact with the immune system. This is down to a system called "epigenetics" and involves chemical groups being added to the DNA to alter the extent to which different genes are read. He doesn't know yet why he's seeing the changes he is, but it seems likely that the environment we're exposed to in early life plays a major role. And by "revving up" these immune -related genes, the intestinal lining cells are more likely to provoke the inflammatory damage that characterises the disease. And, of course, if we understand how the disease gets started, we're one step closer to stopping it...

Matthias - The fundamental question is whether the cells that form the inner lining of our intestine have a sort of a malfunction in patients that suffer from a specific condition called Crohn's disease, which is a form of inflammatory bowel disease. And generally speaking, it's our immune system attacking parts of our body, and in this case the gut, causing inflammation. So the unknown here is what particular role the cells of the inner lining of the gut play in this whole disease. And we used a fairly novel approach, which allows us to grow these cells in a dish after we've taken them from a real piece of gut, from these patients.

Chris - Effectively, then, you're growing a sort of mini intestine in the dish. What does that look like and how does that take us forward?

Matthias - Correct. So we are only growing that particular cell type that forms the inner lining. And they look a little bit like cauliflowers, either sort of balls or cauliflowers with tiny little finger shaped structures. And it turns out that these structures look very similar and perform similar functions than the cells do in the real gut.

Chris - How does that help though?

Matthias - Because for the first time, we are able to test the function of these cells taken from patients with the real disease and also compare that to cells that were taken from patients that do not have the disease. And this allows us to figure out if there is something wrong? And if so, what is it that goes wrong?

Chris - And do you see differences?

Matthias - Yes, we've seen quite remarkable and striking differences and that has led us to identify a specific mechanism, which is called epigenetics. And that mechanism regulates one specific function of the cell and that function, which is called MHC Class 1, is able to attract immune cells. And so this now could explain why, in these patients, when you have a cell type that recruits these cells to the gut, why that's inflamed.

Chris - In summary then, these cells that you're studying, they have some kind of change to the way that genes are being turned on and turned off in those cells, and that is affecting how they interact with the immune system. But how did they get that change to their epigenetics in the first place?

Matthias - That's exactly a key question that is still outstanding. So we believe that these epigenetic changes that led to that malfunction were there when the disease started. If we are right and that's the case, then we speculate that these changes have probably occurred earlier in life, perhaps long before the disease has manifested itself. There are lots of studies that show that our environment has changed over the last 10, 20, 30 years, and these changes seem to correlate strongly with a dramatic rise of these conditions of inflammatory bowel diseases and Crohn's disease. And so the idea is we are being exposed to different environmental factors that impact on our cell types on the way they function, and if that goes wrong, we end up with disease.

Chris - Do you think that could be shifts in the microbiome, the composition of bacteria that live in the intestine? It could be the kinds of foods we're exposed to at what ages and that kind of thing. What do you think is the influence that causes that switch to have this particular behaviour in these cells?

Matthias - So I believe it's likely to be a combination of all of these many factors. It's going to be things like the type of foods we eat, processed foods, maybe more or less meat, which all impact on the microbiome. But also things like exposure to microbes. Our environment is becoming increasingly sterile. Everything is clean. We are not being exposed to this kind of microbial world that we may have been exposed to 50 or a hundred years ago. And so our immune system is no longer trained or challenged to defend ourselves from these microbes, which it was originally designed to do.

Chris - So obviously one way to test this out would be to either reverse the changes that you have seen in your cells and see if they start to behave more like healthy cells or take healthy cells and impose those changes that you've seen in the unhealthy cells epigenetically and see if you can make them behave in an unhealthy looking way. Have you gone down that path yet?

Matthias - That's exactly the way we are going down at the moment. We are trying essentially to find out what's caused these changes because that would allow us to prevent the disease from developing in the future potentially. We believe that in order for these changes to happen, your cell type has to be in a sort of a developmental state that allows these changes to occur. And so we've got access to human foetal organoids, gut organoids, and we're exposing them to all of these factors. To microbes, to inflammatory stimuli, to certain food types, but also the interaction with other cell types, immune cells. And then see what happens. How does the epigenome change and how does that potentially alter the cell function?