Eradication of Small Intestinal Bacterial Overgrowth in the Cystic Fibrosis Mouse Reduces Mucus Accumulation

Abstract

Mucus accumulation in cystic fibrosis (CF) is involved in blockage of the distal small intestine. Because expression of mucin genes and mucus secretion can be increased by infection and previous work indicated that small intestinal bacterial overgrowth occurs in CF, we tested whether reduction of bacterial load by antibiotic treatment would reduce mucin gene expression and mucus accumulation in the CF mouse small intestine. CF transmembrane conductance regulator null (cftr (tm1UNC)) and wild type littermates were treated with ciprofloxacin and metronidazole for 3 weeks. Muc2 and Muc3 gene expression were measured by quantitative reverse-transcriptase polymerase chain reaction. Periodic acid Schiff (PAS) staining and morphometry were used to measure the size of mucus droplets within goblet cells and dilation of the intestinal crypt lumen, as estimates of mucus secretion and accumulation. Antibiotic treatment did not significantly affect Muc2 and Muc3 gene expression in CF mice. In untreated CF mice, the crypt lumen was almost sevenfold wider than wild type. Antibiotic treatment of CF mice reduced the intensity of PAS crypt lumen staining, and the lumen width was decreased by approximately 25%. The area occupied by PAS-positive material in goblet cells was significantly greater in tissues from antibiotic treated mice. Eradication of bacterial overgrowth in CF mice significantly decreased mucus secretion and accumulation in intestinal crypts without an effect on mucin gene expression. It is proposed that bacterial overgrowth stimulates mucus secretion, which contributes to its accumulation in the small intestine. Control of bacterial overgrowth is expected to reduce mucus accumulation and may improve intestinal function and overall health in CF.