Millie Garg

The Enigmatic Gut in Cystic Fibrosis: Linking Inflammation, Dysbiosis, and the Increased Risk of Malignancy

Purpose of ReviewIntestinal inflammation, dysbiosis, and increased gastrointestinal malignancy risks are well-described in patients with cystic fibrosis (CF). However, there is limited understanding of their pathophysiology. This review aims to discuss these issues and assess potential links between them.Recent FindingsEvidence of links between intestinal inflammation and dysbiosis (an imbalance in intestinal microbial populations) exist. Recent studies have demonstrated reduction in intestinal inflammation with probiotic administration. Both bacterial dysbiosis and gut inflammation contribute to the suboptimal nutritional status seen in children with CF. Short-chain fatty acids may be reduced in the gut lumen as a result of bacterial imbalances and may promote inflammation. Inflammation and bacterial dysbiosis in CF may also contribute to emerging adult complications such as gastrointestinal malignancy. An increase in carcinogenic microbes and reduction in microbes protective against cancer have been found in CF, linking bacterial dysbiosis and cancer. Murine studies suggest the CF gene, cystic fibrosis transmembrane conductance regulator (CFTR) gene, itself may be a tumour suppressor gene.SummaryThe pathophysiology of interactions among intestinal inflammation, dysbiosis, and malignancy in CF is not clearly understood and requires further research.

Age-dependent variation of fecal calprotectin in cystic fibrosis and healthy children

BACKGROUND Fecal calprotectin may be used as a non-invasive method to assess the effect of novel therapies on the gut in cystic fibrosis (CF). METHOD Stools from CF patients and healthy controls (HC) (0-10years old) were prospectively collected for evaluation of temporal trends. RESULTS 130 CF samples (64 subjects) and 114 HC samples (101 subjects) were collected. Overall, fecal calprotectin levels were different in CF patients and HC from 0 to 10years (P=0.0002). Fecal calprotectin in CF was significantly lower than HC from 0 to 1years (P=0.03) and demonstrated an upward trajectory until 4years. From >4 to 10years calprotectin was consistently higher in CF patients compared with HC (P=0.007). CONCLUSIONS Fecal calprotectin levels in children with CF and HC were age-dependent and had distinct trajectories. Careful interpretation of calprotectin is required if used in drug trials for CF, particularly in children less than 4years old.

Age-related levels of fecal M2-pyruvate kinase in children with cystic fibrosis and healthy children 0 to 10 years old

BACKGROUND The pathogenesis of gut inflammation, bacterial dysbiosis and increased rates of malignancy in CF is unclear. Fecal M2-pyruvate kinase (M2-PK) is a biomarker indicative of cellular proliferation that may be raised in intestinal malignancy and inflammation. Biomarkers, including M2-PK, may be useful in assessing effects of novel therapies on the gastrointestinal tract. METHODS M2-PK was measured in stools collected from patients with CF and HC (0-10years). Linear mixed model analysis was used. RESULTS M2-PK levels did not significantly change in children with CF (36 patients, 77 samples) (P=0.998) or HC (45 patients, 45 samples) (P=0.21), over the age range 0-10years. Patients with CF had elevated M2-PK compared to HC (median [IQR; range]: 10.7 [5.7-28.6; 1.0-239.1] (n=77) vs. 1.0 [1.0-1.0; 1.0-50.0] (n=45) U/mL, respectively; P=0.001). CONCLUSIONS Fecal M2-PK was elevated in children with CF compared with HC during infancy and throughout childhood suggesting abnormalities in the CF gut exist in early life.