PSC and IBD
Nearly three-quarters of people with primary sclerosing cholangitis (PSC) have a form of inflammatory bowel disease (IBD) such as ulcerative colitis (UC). Although the cause of PSC is unknown, its association with IBD has generated several theories that include an exaggerated immune response, a reaction to abnormal gut bacteria and changes in the composition of bile in the gut.
PSC-IBD is different to IBD alone
However, IBD in patients with PSC (PSC-IBD) appears to behave differently compared to those with ulcerative colitis (UC) alone. Patients with PSC-IBD appear to be at greater risk of colon cancer and need for bowel surgery. Indeed, there is very little overlap in the changes seen at a genetic level between PSC-IBD and UC. Furthermore, we have previously shown that the gut bacteria in patients with PSC-IBD are different to that seen in UC alone.
This made us wonder if the mechanisms that drive inflammation in the bowel in people with PSC are different to that seen in people with UC alone.
What did the researchers do?
We conducted a study where we obtained biopsies from the colon during colonoscopy in patients with PSC-IBD, UC alone and people with no underlying disease. We were then able to conduct a highly in depth analysis of expression of genes at a tissue level, the activity of the immune cells and gut bacteria in the colonic tissue.
What did the team find out?
PSC-IBD and UC alone: similarities
As PSC-IBD and UC are primarily diseases that are a result of an overactive immune response, we unsurprisingly found that the genes associated with activation of the immune system were similar in these two groups.
PSC-IBD and UC alone: differences
However, fascinatingly, we discovered that the genes that were being expressed by the cells in the colon were very different in PSC-IBD compared to UC alone. This suggested that the possible mechanisms that lead to inflammation in the colon were different in PSC-IBD compared to IBD alone.
Detailed analyses of these genes suggested that the pathways that control the levels of bile acid in the colon were in a state of overdrive in PSC-IBD. This we believe is possibly to be a result of a combination of genetically determined problems with genes that maintain a balance in bile acid levels as well as a significantly greater amount of availability of bile acids in the colon.
We discovered that the bacteria attached to the bowel in patients with PSC-IBD were very different to those with UC and healthy individuals. These bacteria had genes that were associated with converting bile acids into a form that can be absorbed into the colonic tissue.
These novel findings raise several important questions in helping us understand reasons why patients with PSC get colonic inflammation and if these distinctions in the gut bacteria have anything to do with it.
Balance of bile acid levels
Bile acids are produced by the liver and released into the small bowel primarily in order to help digest fat. Most of these bile acids get reabsorbed once they reach the end of the small bowel, with a small proportion entering the large bowel (colon). Here colonic bacteria help convert bile acids into a form that can be absorbed by the colon. Bile acids are generally toxic to cells and can cause damage to tissue, therefore our body maintains its composition in a very balanced way.
In PSC this balance appears to be lost and may be a result of changes within gut bacteria in the colon.
There is early evidence to suggest that an oral antibiotic called vancomycin that works only within the bowel treats the inflammation in the colon in PSC-IBD. Moreover, oral vancomycin appears to be effective in improving some of the liver enzymes in PSC.
Faecal Microbiota Transplantation (FMT)
A recent trial in a small group of patients demonstrated that a single infusion faecal microbiota transplantation (FMT) improved liver enzymes in a subset of patients and was associated with changes in the composition of bile acid in the colon.
Faecal transplantation is when a doctor transplants specially prepared stool from a healthy donor into another person. A single infusion faecal transplantation is when the procedure is done only once.
These findings collectively suggest that bacteria appear to play a key role in the development of PSC and PSC-IBD, possibly by interfering with the bile acid balance. It is now more important than ever to explore if and how modifying gut bacteria through therapies such as oral vancomycin, FMT and next generation probiotics can help us treat PSC.
By Dr Nabil Quraishi, University of Birmingham, UK (@NabilQuraishi on Twitter)