Slowed movement of digested food through the gut frequently leads to constipation and blockages (called distal intestinal obstructive syndrome or DIOS) that require hospital treatment and even surgery in people with cystic fibrosis. Existing treatments are limited in their success.
DIOS is caused by a lack of water in the gut and slower movement in the gut. The water levels are controlled by the underactivity of the CF protein, CFTR, and overactivity of another protein called NHE3. So far, research has focussed on correcting the CFTR as a way to treat DIOS. This SRC is focussed on correcting the overactivity NHE3.
Slowed movement of digested matter in the gut of people with CF frequently leads to constipation and DIOS which requires hospital treatment and occasionally surgery. The blockages are caused by the lack of water (dehydration) in the gut and an unhealthy mix of gut bacteria affecting the movement of material in the gut.
The water balance in the gut is controlled by CFTR moving chloride ions (one part of salt) into the gut and encouraging water to move with it, and by the absorption of sodium (the other part of salt) out of the gut by a protein called NHE3, which causes the water to move out of the gut. Both CFTR and NHE3 go wrong in CF, causing the gut to become dehydrated.
Attempts to use drugs to restore CFTR function in the gut have had only limited success for most cases of cystic fibrosis. An alternative approach to increase the fluidity of contents moving through the gut and prevent DIOS is to reduce sodium and water absorption by gut-lining cells by targeting NHE3.
Indirectly, overactive NHE3 also affects the amount of movement in the gut, as it affects the levels of gut bacteria that control gut movement. By correcting NHE3 levels, researchers hope to rehydrate the gut and get it moving again.
What are the aims?
The researchers working within the SRC aim to correct the overactivity of NHE3 in two ways. Firstly by targeting NHE3 directly by looking at the effect of existing NHE3 blockers. These are drugs that exist for other conditions, but haven’t been investigated for their potential in CF before.
The second way of reducing the overactivity of NHE3 is to remove the cause of the overactivity itself. The researchers believe that this can be done by diets rich in specific chemicals. Studying the individual effects of NHE3 on DIOS, the researchers will use the knowledge gained to design a proof of principle clinical trial, paving the way for a larger trial in the future.
The individual aims of the workstreams within the SRC are given below.
- Testing the NHE3 blocker drugs in animal models of cystic fibrosis
- Testing the effects of dietary change on DIOS in animal models of cystic fibrosis
- Investigating the overactivity of NHE3 in human cells and ‘mini-guts’ or ‘organoid’ cell systems grown in the lab
- Investigating the gut bacteria in a) animal models of CF treated with NHE3 blocking drugs and different diets and b) in samples from people with CF with and without DIOS and from people who don’t have cystic fibrosis
- Designing and conducting a proof of principle clinical trial based on the results of the aims listed above
Principal Investigator (PI): Professor Soraya Shirazi-Beechey (University of Liverpool)
- Professor David Sheppard (University of Bristol)
- Professor Hugo de Jonge (Erasmus University Medical Centre)
- Professor Ursula Seidler (Hannover Medical School)
- Dr Arun Urs (Sheffield Children’s Hospital)
- Dr Louise Robson (University of Sheffield)
- Dr Paul Flanagan, Arrow Park Teaching Hospital, Wirral, Merseyside
- Dr Richmond Muimo (University of Sheffield)
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