Restoration of luminal fluidity & microbiota in the CF gut - 2
Research type
Research Study
Full title
Restoration of luminal fluidity and microbiota in the CF gut (CFGI-SRC)
IRAS ID
245934
Contact name
Soraya Shirazi-Beechey
Contact email
Sponsor organisation
University of Liverpool
Duration of Study in the UK
3 years, 0 months, 1 days
Research summary
Research Summary
This research aims to investigate new approaches to improve gut health in cystic fibrosis (CF).
Slowed movement in the CF gut frequently leads to constipation and blockage (termed distal intestinal obstructive syndrome; DIOS), which requires hospital treatment and sometime surgery. The cause of DIOS is not entirely known, but is associated with dehydration and thickening of bowel contents resulting from inherited defects in the protein CFTR, a route for chloride (one part of salt) secretion by cells lining the intestine. To date, attempts to restore CFTR function in the gut with drugs have met with limited success for most cases of CF. An alternative and innovative approach for increasing gut fluidity and prevent DIOS is to reduce sodium and water absorption by cells lining the gut. In the proposed research, we will test this idea using licenced drugs and peptides,which already known to modulate sodium and water absorption by the gut cells. We will apply cutting-edge techniques to CF mouse models and intestinal biopsies and lab-grown mini-guts (termed “organoids”) produced from the gut biopsies of individuals with CF affected by DIOS. Once the best therapy for DIOS has been identified, we will plan a large clinical trial to robustly test this new treatment. Thus, this work will inform the development of an effective new treatment for gut blockage in CF.Summary of Results
Many cystic Fibrosis (CF) patients suffer from severe abdominal symptoms, including intestinal discomfort caused by slowed bowel movement and blockage (distal intestinal obstructive syndrome; DIOS). These conditions develop because the CF gut generally contains less fluid than normal, resulting in a thickening of its contents. Treating these gut complications is one of the top priorities in CF treatment. One of our aims was to find ways to increase the fluid content of the CF gut, that can be used in all CF patients, regardless of which CFTR mutation they carry. In this project we have determined whether the licenced drugs linaclotide, lubiprostone and tenapanor can block the intestinal sodium transporter named NHE3, improving intestinal luminal fluidity in mice with cystic fibrosis and in organoids (mini guts) prepared from CF human intestinal biopsies (carried out by co-investigators in the Netherlands). For this purpose, human intestinal organoids were differentiated to absorptive cells that contain high levels of NHE3. The effects of linaclotide, lubiprostone and tenapanor on NHE3 activity were assessed. All 3 drugs blocked NHE3 activity in the human organoids, but tenapanor was most effective, blocking NHE3 activity by >90%. These results suggest that tenapanor treatment may improve intestinal luminal fluidity in CF, and provide the basis for future clinical trials with using tenapanor . In support of this findings, we have also shown that blocking NHE3 function in CF mice intestine by these drugs increases fluidity and alkalinity of the intestinal content, and that a long-term administration of tenapanor reduces the incidence of intestinal blockage in CF mice. We have also demonstrated that there is disruption of immune system in CF mice intestine brought about by intestinal blockage. We also aimed to identify, if there are changes in the intestinal bacteria in CF intestine, and if these changes may influence intestinal function. We have shown that the lining of the intestine of CF mice as well as one CF human studied is populated with pathogenic bacteria, and that these bacteria alter the number of cells lining the intestine. They cause significant decreases in the number of cells that carry out vital functions such as absorption of nutrients, secretion of anti-bacterial compounds, and secretion of gut hormones that regulate nutrient absorption and insulin secretion. In contrast they trigger increases in the number of cells that secrete mucus exacerbate thickening of dehydrated intestinal content. Our results suggest that these effects of pathogenic bacteria on the host intestine contributes to development of intestinal disease in CF, the findings which may allow the design of appropriate therapies.
REC name
North West - Liverpool Central Research Ethics Committee
REC reference
18/NW/0406
Date of REC Opinion
16 Jul 2018
REC opinion
Further Information Favourable Opinion