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Increased survival of CFTR knockout mice with an oral osmotic laxative
L L Clarke1, L R Gawenis, C L Franklin
1Cardiovascular Research Center, Department of Veterinary Biomedical Sciences, University of Missouri-Columbia, 65211, USA.
Abstract:
Mouse models of cystic fibrosis that are generated by targeted disruption (knockout) of the cystic fibrosis transmembrane conductance regulator gene, cftr(-/-), typically die shortly after weaning, from intestinal obstruction/rupture caused by an inability to secrete fluid into the bowel lumen. We investigated the use of a commercial osmotic laxative, Colyte, provided continuously in the drinking water, to increase the survival of cftr(-/-) mice. Genotype analysis of 623 offspring surviving at 10 days of age yielded 28.1% cftr(+/+), 59.6% cftr(+/-), and 12.4% cftr(-/-) mice (25% predicted), suggesting that cftr(-/-) mice have a significant perinatal mortality rate. However, of the 77 cftr(-/-) mice alive at 10 days of age, >98% survived weaning and were maintained in apparent health to a minimum of 56 days of age (arbitrary age for experimentation). In intestinal bioelectric studies Colyte-treated drinking water, compared with tap water, had no significant effect on basal short-circuit current, cyclic AMP-stimulated Cl- secretion, Na+-coupled glucose absorption, or electrogenic Na+ absorption across intestinal sections from cftr(+/+ or +/-) mice. Other than a mild dilatation of the distal portion of the colon in the Colyte-treated animals, examination of jejunal and colonic sections revealed no histologic differences between the two treatments. These findings indicate that the chronic use of Colyte osmotic laxative in drinking water is an economical means of greatly increasing the survival of CFTR knockout mice without altering the major electrolyte transport processes or histomorphologic integrity of the intestine.
Insights
An osmotic laxative, Colyte, in drinking water significantly increased survival rates in cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice. This intervention allowed CFTR knockout mice to reach adulthood without impacting intestinal function.
Area of Science:
- Animal Models
- Gastroenterology
- Genetics
Background:
- Cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice typically exhibit high mortality rates post-weaning due to intestinal complications.
- Intestinal obstruction and rupture in these models result from impaired fluid secretion into the bowel lumen.
Purpose of the Study:
- To evaluate the efficacy of a commercial osmotic laxative, Colyte, in increasing the survival rate of CFTR knockout mice.
- To assess the impact of chronic Colyte administration on intestinal bioelectric properties and histology in CFTR knockout mice.
Main Methods:
- CFTR knockout mice were provided with Colyte in their drinking water.
- Genotype analysis was performed on surviving offspring.
- Intestinal bioelectric studies (short-circuit current, ion transport) and histological examinations were conducted.
Main Results:
- Colyte administration significantly increased the survival rate of CFTR knockout mice beyond weaning (>98% survival to 56 days).
- No significant alterations in basal short-circuit current, cAMP-stimulated Cl- secretion, or Na+ absorption were observed.
- Histological examination revealed no significant differences, apart from mild distal colon dilatation in treated animals.
Conclusions:
- Chronic administration of Colyte via drinking water is an effective and economical method to enhance the survival of CFTR knockout mice.
- This intervention maintains intestinal electrolyte transport and histomorphological integrity, making these mice suitable for further research.
