Amelioration of intestinal disease severity in cystic fibrosis mice is associated with improved chloride secretory capacity

The variability in intestinal disease severity in patients with cystic fibr osis (CF) has bean associated with the expression of secondary modifier gen es. The locus containing these modifier genes in CF patients is syntenic wi th a modifier locus previously associated with survival in CF transmembrane conductance regulator-knockout mice. These previous studies showed that th e proportion of CF mice that survive weaning (mildly affected mice) versus those that succumb to obstruction of the small intestine (severely affected ) is related to their genetic background and the expression of modifier gen es. In the present work, we show that the basal transepithelial chloride tr ansport measured across jejuna obtained from mice of mixed generic backgrou nds segregates into two groups, some mice having low and others having high , near normal chloride transport. Further, we report that the segregation o f mice with respect to intestinal chloride transport correlates with their predicted segregation on the basis of genotype at the "modifier locus." The se findings support the hypothesis that intestinal disease modification in CF mice correlates with improved chloride transport through non-CF transmem brane conductance regulator chloride channels.