Effects of laxative and N-acetylcysteine on mucus accumulation, bacterial load, transit, and inflammation in the cystic fibrosis mouse small intestine

Abstract

De Lisle RC, Roach E, Jansson K. Effects of laxative and N-acetylcysteine on mucus accumulation, bacterial load, transit, and inflammation in the cystic fibrosis mouse small intestine. Am J Physiol Gastrointest Liver Physiol 293: G577-G584, 2007. First published July 5, 2007; doi:10.1152/ajpgi.00195.2007.-The accumulation of mucus in affected organs is characteristic of cystic fibrosis (CF). The CF mouse small intestine has dramatic mucus accumulation and exhibits slower interdigestive intestinal transit. These factors are proposed to play cooperative roles that foster small intestinal bacterial overgrowth (SIBO) and contribute to the innate immune response of the CF intestine. It was hypothesized that decreasing the mucus accumulation would reduce SIBO and might improve other aspects of the CF intestinal phenotype. To test this, solid chow-fed CF mice were treated with an osmotic laxative to improve gut hydration or liquid-fed mice were treated orally with N-acetylcysteine (NAC) to break mucin disulfide bonds. Treatment with laxative or NAC reduced mucus accumulation by 43% and 50%, respectively, as measured histologically as dilation of the intestinal crypts. Laxative and NAC also reduced bacterial overgrowth in the CF intestine by 92% and 63%, respectively. Treatment with laxative normalized small intestinal transit in CF mice, whereas NAC did not. The expression of innate immune response-related genes was significantly reduced in laxative-treated CF mice, whereas there was no significant effect in NACtreated CF mice. In summary, laxative and NAC treatments of CF mice reduced mucus accumulation to a similar extent, but laxative was more effective than NAC at reducing bacterial load. Eradication of bacterial overgrowth by laxative treatment was associated with normalized intestinal transit and a reduction in the innate immune response. These results suggest that both mucus accumulation and slowed interdigestive small intestinal transit contribute to SIBO in the CF intestine.small intestinal bacterial overgrowth MICE that lack the expression of the cystic fibrosis (CF) transmembrane conductance regulator (Cftr) gene have a severe intestinal phenotype with many of the problems that occur in human CF patients. These include the accumulation of mucus, intestinal obstruction, slowed small intestinal transit, small intestinal bacterial overgrowth (SIBO), inflammation, and failure to thrive (4 -6, 30). Of these changes, bacterial overgrowth is of interest because it can be responsible for the majority of the other aspects of the intestinal phenotype (22, 34).Secreted gel-forming mucins, mainly Muc2 in the intestine, bind bacteria and help carry them aborally for efficient clearance from the small intestine. When mucus clearance is impaired, bacteria can proliferate in the mucus and may use it as an energy source (36). Mucus accumulation in the CF intestine is in part due to the dehydrated, acidic environment as well as the altered glycosylation of mucins (38, 40), which may increase the viscosity of mucus. Our labora...

Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

“…This may explain why a greater number of lipid and energy metabolism genes were altered in the double knockouts. Regarding the absence of an inflammatory response in the CF models studied here, it has been shown that inflammation in Peptamen-treated CF mice is due to bacterial overgrowth and that this did not occur in Colyte-treated CF mice (9). Although Cftr Ϫ/Ϫ Nhe3 ϩ/Ϫ and double-null mice were smaller than wild-type controls at weaning, by 8 wk of age there was no significant difference in body weight.…”

“…In contrast, our histological analyses (Figs. 5 and 7) revealed no evidence of increased inflammation in the small intestine of CF mice carrying a null mutation in the Nhe3 gene, and a previous study found little evidence of inflammation in Colyte-treated CF mice (9). To search for molecular evidence of inflammation, we compared expression levels of genes involved in immune and inflammatory responses for the CF models in the present study to the levels observed in a previous study (42) of CF mice maintained on a Peptamen liquid diet.…”

Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator–dependent bicarbonate secretion

“…Moreover, it has been recognized, but unexplained, for decades that relatively pure samples of several mucus-containing CF secretions harbor elevated calcium concentrations (55)(56)(57)(58). Interestingly, intestinal crypt mucus and Paneth cell granules (which were found to accumulate in intestinal crypts in CF as does mucus) showed increased clearance and dissolution when CF mice were fed on a diet with HCO 3 --rich polyethylene glycol laxative (59,60).…”

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

“…In the present study, goblet cell function during stimulated exocytosis was investigated using WT and Cftr-KO mouse intestine. The Cftr-KO mouse recapitulates the major aspects of human CF intestinal disease, including goblet cell hyperplasia, adherent secreted mucus, low-grade bowel inflammation, and overt obstructive disease that is prevented by osmotic laxative maintenance therapy (2,(31)(32)(33)(34). Real-time evaluation of the degranulation process was possible through the use of small intestinal organoids (enteroids), which provide visual access to the longitudinal axis of mature goblet cells within the native setting of the crypt/lower villus, i.e., surrounded by enterocytes and other cell lineages of the intestinal epithelium (35,36).…”