Impaired oxidative stress responses in the intestine in PSC-UC
Awarded to Dr Nicholas Ilott, University of Oxford
The total grant awarded is £15,000
Duration of award: 18 months
Research title: Impaired oxidative stress responses in the intestine in PSC-UC
Summary
PSC Support has awarded £15,000 to Dr Nicholas Ilott to uncover markers of ‘stress’ in cells in the small (intestine) in people with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). He will do this by using “proteomics” – a way of studying all the proteins in a tissue sample. This will be the first study to assess protein levels in the small intestine in people with both PSC and UC.
Identifying protein changes in PSC-UC could reveal new insights into how the liver and the intestine interact with each other and affect cancer risk in PSC. Dr Ilott also aims to understand the role of gut microbes in this process and how they might be modified to produce new treatments for PSC.
What will Dr Ilott do?
Dr Ilott will take intestinal biopsies from 15 people who have PSC with ulcerative colitis (PSC-UC), 15 people with ulcerative colitis alone (UC) and 15 healthy individuals. He’ll perform proteomic analysis (analysis of all proteins in the tissue samples) to identify proteins that are increased and decreased specifically in PSC-UC with a particular focus on caretaker proteins.
Why is this study important?
This is a new area of PSC research and will be the first study to assess protein levels in the small intestine in people with PSC-UC, people with UC and healthy individuals.
This research could reveal new insights into how the liver and the intestine interact with each other in PSC. This could lead to the development of new ways to stop cell damage in this disease. For example, this research might show that it is possible to control the amount of damage to the intestine by changing the types of bacteria that are present. This could be achieved by changing people’s diet to promote good bacteria that prevent cells becoming damaged.
The details
Thank you to Dr Ilott for providing this excellent explanation:
PSC is a disease of the liver that is currently not well understood. The liver is of vital importance for health as it can be thought of as a filter system for the blood, removing toxic substances and allowing nutrients to pass to the rest of the body. Part of the role of the liver is to deliver substances to the intestine that are beneficial for health.
In people with PSC, the liver is damaged because of inflammation - and this inflammation causes the liver to not function effectively and chemicals that are beneficial to the intestine are not delivered. This creates problems in the intestine and can result in people with PSC also developing inflammatory bowel disease (IBD).
Likewise, the intestine is capable of delivering things back to the liver and this includes bacteria. Bacteria are usually thought of as being bad, but the intestine is home to trillions of bacteria that live harmlessly and can even be helpful.
This collection of bacteria (and also viruses and fungi) is called the microbiome and scientists are currently fascinated with how the microbiome is able to influence health and disease.
It is currently thought that the microbiome is important in PSC. This is because even though most bacteria in the intestine are harmless, if certain bacteria manage to travel to the liver they can cause harm such as inflammation.
It might be that people with PSC are more likely to have bacteria travel from the intestine to the liver because they have problems in the intestine. Problems in the intestine may also increase the risk of colon cancer.
We want to study changes in the intestine that may be part of the way in which bacteria are able to leave the intestine and travel to the liver, as well as increase the chances of developing colon cancer.
Before we can begin to understand how the liver and the intestine are affected in diseases such as PSC, we have to understand how they usually work together in a healthy way.
No organ works alone in the body and the liver and intestine are no exception. In fact, both the liver and the intestine are part of the same system (the digestive system) and they work together to control the breakdown of food and delivery of nutrients around the body.
And here’s how.
You can think of the intestine - which is composed of both the small and large intestine - as being the latter part of a long tube that runs from your mouth to your anus. Essentially this is a transport route for food that enters your mouth.
Along the way, the food is mushed up by organs like the stomach. The resulting food mush is passed on to the next point of its tubular journey, the small intestine.
Now this is an important bit. The small intestine is where absorption happens. Absorption is the process through which the good bits of the food mush are taken from the middle of the tube and into the surrounding tissue.
These good bits (the nutrients) can then enter the bloodstream for distribution to the eagerly awaiting rest-of-the-body where they can be put to good use.
But where does the liver fit into all this?
Well, the liver is important for two parts of this process:
Firstly, it produces digestive juices that it delivers to the small intestine through a tube called the bile duct (yes, we have a lot of tubes). These juices help to break down the mush and release the nutrients for absorption in the small intestine.
Once inside the small intestine tissue, nutrients enter the blood and go to the liver. So, the liver receives the good bits of the food mush that it helped to break down in the first place! Once received, the liver can filter the blood, removing anything harmful and leaving the rest. It then acts like Royal Mail and distributes the wonderful nutrient-rich blood onwards to the rest of the body!
So that’s it, a happy tale of digestion. Or is it...
While this seems like a simple process, there are some additional things to consider. The mush that is produced and transported through the intestine is home to tiny organisms including bacteria. This collection of micro-organisms is called the intestinal microbiome and it is a good thing that it’s there.
Many of these bacteria help to break down food and produce chemicals that keep us healthy. But they are not really supposed to go into intestinal tissue, they need to stay in the mush.
The intestine is usually very good at keeping members of the microbiome out, as it has a protective wall of cells that forms a barrier to separate the microbiome-filled mush from the tissue (Figure 1).
However, if bacteria do enter the tissue, they can cause problems like inflammation, that can damage the intestine. They are even able to take the same route as the nutrient-rich blood and pass to the liver.
Oh, no! I hear you cry.
Yes, this sounds worrying, but in most cases the liver can deal with these bacteria, as it contains special immune cells that can easily gobble up invading bacteria.
However, in some cases, certain bacteria can cause inflammation and damage to the liver. So, in general, it’s best to keep them out if we can!
Figure 1. The liver and intestine in PSC (Credit: Dr Nicholas Ilott)
Now that we know what is supposed to happen, we can start to understand what happens in PSC.
PSC is a disease of the liver that progresses over time. During this time, the liver loses some of its ability to transport digestive juices to the intestine because of blockages in the tubes that connect the two organs.
Having fewer digestive juices in the intestine means that nutrients aren’t absorbed as effectively. We also think that a reduced transport of digestive juices means that cells of the intestine are more likely to become damaged, which may have an impact on both the health of the liver and the intestine.
To understand this part, we need to consider what is going on inside each cell of the intestine. Here we are talking about cells that make up the barrier (see Figure 1).
Caretaker proteins
Each cell is like a little factory, using its genetic code (DNA) as a blueprint to make proteins. Each cell makes a huge number of different proteins (we’re talking 1000’s of different proteins) and each has a role to play in what the cell is doing.
Proteins that we are interested in are those that protect cells from damage. Once made by the cell, these proteins act as the caretaker of the factory, mopping up waste that can damage the cell if left uncleaned.
We think that there are fewer caretaker proteins in the intestines of people with PSC which may lead to a higher number of damaged barrier cells.
This is important because if cells in the intestine are more likely to become damaged, it means that they are more likely to die, which can leave gaps in the cell barrier of the intestine.
These gaps are quickly filled, but could still mean that people with PSC are more at risk of things passing through the intestinal barrier that are not supposed to be there.
For example, certain types of bacteria that usually live in the faeces that is passing through the intestine may be able to get through the gaps. This means that they can enter the intestine itself and be carried to the liver through blood vessels that connect these organs.
Different types of bacteria have different abilities and some of these abilities can result in inflammation of the liver.
As well as allowing bacteria into the intestine, dying cells in the intestine can send signals to other cells to grow more – in an effort to repair the gaps. This is one of the ways that cancer can begin.
Based on previous work we have done we suspect that people with PSC and intestinal inflammation are more likely to have damaged and dying cells in the intestine and one way that we want to confirm if this is true is to study the level of caretaker proteins in the intestine to see if they are changed in PSC-UC.
Dr Nicholas Ilott, Dr Emma Culver, Professor Paul Klenerman and Professor Fiona Powrie
This world-class research team from the University of Oxford is highly respected and brings a wealth of clinical and research experience, especially in PSC and in proteomics analysis, bioinformatics and immunology.
Dr Nicholas Ilott is a senior research scientist at the Kennedy Institute of Rheumatology who specialises in ‘omics analysis in PSC-UC. This includes both microbiome and host profiling as well as single-cell RNA-seq approaches from intestinal samples. He is keen to extend observations of transcriptional changes in PSC-UC to look at protein-level changes and identify novel pathways that link liver and intestinal pathogenesis in PSC.
Dr Emma Culver: Dr Culver is a consultant hepatologist and senior lecturer at the Translational Gastroenterology Unit (TGU), University of Oxford. She has extensive clinical and research experience in PSC. She has contributed significantly to our understanding of pathogenesis of sclerosing cholangiopathies including PSC, as well as the extent to which liver abnormalities present in patients with UC. Dr Culver is a vital member of the PSC clinical research community, sitting on the steering committee for UK PSC and BASL Immune Liver Disease Special Interest Group, being a member of the international PSC study group (IPSCSG) and in the PSC Support Scientific Expert Panel.
Professor Paul Klenerman: Professor Klenerman is Sidney Truelove Professor of gastroenterology at the TGU, University of Oxford. Professor Klenerman has been instrumental in driving PSC research through the application of the latest technologies such as single-cell and spatial transcriptomics as part of his collaboration in the international Human Cell Atlas (HCA) project.
Professor Fiona Powrie: Professor Powrie is director of the Kennedy Institute of Rheumatology, University of Oxford and Professor of mucosal immunology. She is expert in host-microbe interactions and mucosal immunology, particularly in the context of inflammatory bowel disease. Part of her current research explores the development of colorectal cancer in the context of bacteria and IBD.
Dr Roman Fischer: Dr Fischer is Associate professor and head of the discovery proteomics facility, University of Oxford. He has extensive experience in the analysis of the proteome derived from patient samples and has published extensively on collaborative projects that utilise these techniques.
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