Genistein is a naturally occurring isoflavone found in soy. Genistein has been shown to increase the open probability of the most common cystic fibrosis (CF) disease-associated mutation, ∆F508-CFTR. Mice homozygous for the ∆F508 mutation are characterized with severe intestinal disease and require constant laxative treatment for survival. This pathology mimics the intestinal obstruction (meconium ileus) seen in some cystic fibrosis patients. This study tested whether dietary supplementation with genistein would reduce the dependence of the ∆F508 CF mouse model on laxatives for survival, thereby improving mortality rates. At weaning (21 days), homozygous ∆F508 mice were maintained on one of three diet regimens for a period of up to 65 days: normal diet, normal diet plus colyte, or genistein diet. Survival rates for males were as follows: standard diet (38%, n = 21), standard diet plus colyte (83%, n = 42) and genistein diet (60%, n = 15). Survival rates for females were as follows: standard diet (47%, n = 19), standard diet plus colyte (71%, n = 38), and genistein diet (87%, n = 15). Average weight of male mice fed genistein diet increased by ~2.5 g more (p = 0.006) compared to those with colyte treatment. Genistein diet did not change final body weight of females. Expression of intestinal SGLT-1 increased 2-fold (p = 0.0005) with genistein diet in females (no change in males, p = 0.722). Expression of GLUT2 and GLUT5 was comparable between all diet groups. Genistein diet reduced the number of goblet cells per micrometer of crypt depth in female (p = 0.0483), yet was without effect in males (p = 0.7267). The results from this study demonstrate that supplementation of diet with genistein for ~45 days increases the survival rate of female ∆F508-CF mice (precluding the requirement for laxatives), and genistein only improves weight gain in males.

Genistein is a naturally occurring isoflavone found in soy. Mice homozygous for the ∆F508 mutation are characterized with severe intestinal disease and require constant laxative treatment for survival. This pathology mimics the intestinal obstruction (meconium ileus) seen in some cystic fibrosis (CF) patients. We therefore tested whether dietary supplementation with genistein would reduce the dependence of the ∆F508 CF mouse model on laxatives for survival, thereby improving mortality rates. At weaning (21 days), we maintained homozygous ∆F508 mice on three diet regimens for a period of up to 65 days; normal diet, normal diet + Colyte or genistein diet. Survival rates for males were as follows: standard diet (38%), standard diet plus Colyte (83%) or genistein diet (60%). Survival rates for females were as follows: standard diet (47%), standard diet plus Colyte (71%), or genistein diet (87%).  Average weight of male mice fed genistein diet increased by ~2.5 g more compared to those with Colyte treatment. Genistein diet did not change final body weight of females. Expression of SGLT-1 increased 2-fold with genistein diet in females (no change in males). Expression of GLUT2 and GLUT5 was comparable between all diet groups. Genistein diet reduced the number of goblet cells per micometer of crypt depth in female, yet was without effect in males. We conclude that supplementation of diet with genistein for ~45 days increases the survival rate of female ∆F508-CF mice precluding the requirement for laxatives, and only improves weight gain in males.

Mice homozygous for the most common disease‐associated mutation, DF508, are characterized with severe intestinal disease and require constant laxative treatment for survival. This pathology mimics the intestinal obstruction (meconium ileus) seen in some CF patients. Genistein is a naturally occurring isoflavone found in soy. Patch clamp studies have demonstrated that genistein increases the open probability of DF508 CFTR to wild‐type (WT) levels. We evaluated whether dietary genistein alone would eliminate the need for laxatives for survival of the DF508 CF mouse, thereby improving mortality rates. At age 21 days, we maintained male and female DF508 mice on three diet regimens for 45 days; normal diet, normal diet + Colyte or 600 mg genistein/kg diet, 600G. Survival rates and body weight data were determined. At the completion of the diet study, tissues were extracted, immediately frozen at −80ºC until use and evaluated later for protein expression and histological evaluation. Survival rates for each diet group were as follows; males fed normal diet = 38% (8/21 mice), males fed normal diet + Colyte = 83% (35/42 mice), males fed 600G = 60% (9/15 mice) and females fed normal diet = 47% (9/19 mice), females fed normal diet + Colyte 71% (27/38 mice), females fed 600G = 87% (13/15 mice). Body weight at the end of the diet study was greater in males fed 600G (21.96±0.68 g, n=14) versus those males on Colyte (18.86±0.64 g, n=8). There was no change in overall weight gain in the female groups. Jejunum villi length, crypt depth and wall thickness was comparable between diet groups. Total protein expression of jejunum Na+/K+‐ATPase and NKCC1 was comparable between groups. Total expression of jejunum GLUT2 and GLUT5 were unchanged, however SGLT1 expression was significantly increased 2‐fold in females fed 600G. We are currently exploring whether liver protein expression and serum metabolic markers are modified to better elucidate the mechanism of action of 600G to improve weight in males and to improve survival rate in females. We conclude that feeding DF508 female mice 600G genistein‐diet abolished the dependence upon laxatives for survival. These studies could have implications in reducing the sex‐dependent differences in the age of survival of CF female patients.Support or Funding InformationSupported by Soy Health Research Program and MWU intramural funds (LA).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.