Intestinal Lesions Are Associated with Altered Intestinal Microbiome and Are More Frequent in Children and Young Adults with Cystic Fibrosis and Cirrhosis

Abstract

Background and AimsCirrhosis (CIR) occurs in 5–7% of cystic fibrosis (CF) patients. We hypothesized that alterations in intestinal function in CF contribute to the development of CIR. Aims: Determine the frequency of macroscopic intestinal lesions, intestinal inflammation, intestinal permeability and characterize fecal microbiome in CF CIR subjects and CF subjects with no liver disease (CFnoLIV).Methods11 subjects with CFCIR (6 M, 12.8 yrs ± 3.8) and 19 matched with CFnoLIV (10 M, 12.6 yrs ± 3.4) underwent small bowel capsule endoscopy, intestinal permeability testing by urinary lactulose: mannitol excretion ratio, fecal calprotectin determination and fecal microbiome characterization.ResultsCFCIR and CFnoLIV did not differ in key demographics or CF complications. CFCIR had higher GGT (59±51 U/L vs 17±4 p = 0.02) and lower platelet count (187±126 vs 283±60 p = 0.04) and weight (-0.86 ± 1.0 vs 0.30 ± 0.9 p = 0.002) z scores. CFCIR had more severe intestinal mucosal lesions on capsule endoscopy (score ≥4, 4/11 vs 0/19 p = 0.01). Fecal calprotectin was similar between CFCIR and CFnoLIV (166 μg/g ±175 vs 136 ± 193 p = 0.58, nl <120). Lactulose:mannitol ratio was elevated in 27/28 subjects and was slightly lower in CFCIR vs CFnoLIV (0.08±0.02 vs 0.11±0.05, p = 0.04, nl ≤0.03). Small bowel transit time was longer in CFCIR vs CFnoLIV (195±42 min vs 167±68 p<0.001, nl 274 ± 41). Bacteroides were decreased in relative abundance in CFCIR and were associated with lower capsule endoscopy score whereas Clostridium were more abundant in CFCIR and associated with higher capsule endoscopy score.ConclusionsCFCIR is associated with increased intestinal mucosal lesions, slower small bowel transit time and alterations in fecal microbiome. Abnormal intestinal permeability and elevated fecal calprotectin are common in all CF subjects. Disturbances in intestinal function in CF combined with changes in the microbiome may contribute to the development of hepatic fibrosis and intestinal lesions.

Growth and Morbidity of Gambian Infants are Influenced by Maternal Milk Oligosaccharides and Infant Gut Microbiota

“…For these analyses, infant calprotectin levels were used as continuous values and also binned into normal (<50 mg/kg), borderline (50–120 mg/kg), and abnormal (>120 mg/kg) categories using published cutoffs333435. Multiple linear regression stepwise models were created with relative class and individual HMO and microbiota to predict infant fecal calprotectin levels at each week.…”

“…A commercial ELISA kit (Phical; CALPRO AS) was used, with the protocol adjusted for use on freeze-dried infant feces75. Calprotectin levels were also binned into three categories based on previously developed clinical diagnoses: normal (less than 50 mg/kg), borderline (50–120 mg/kg), and abnormal (greater than 120 mg/kg)333435.…”

Colonoscopic screening shows increased early incidence and progression of adenomas in cystic fibrosis

“…Stagnant mucus is associated with bacterial overgrowth in Cftr-deficient mice along with dysregulation in gene expression involved in inflammation and epithelial homeostasis [17,18]. These physical changes in the mucus layer are also associated with compositional changes in microbiota, which can further affect epithelial function [19–22]. Interestingly, the pattern of dysregulated genes associated with CFTR deficiency overlaps with that observed following deletion of Kcnq1, which encodes for a potassium channel that is linked to CFTR function and is another tumor suppressor gene associated with gastrointestinal malignancies [23].…”

Neonatal Gastrointestinal and Respiratory Microbiome in Cystic Fibrosis: Potential Interactions and Implications for Systemic Health

“…33 Dysbiosis is attributable to antibiotics, altered mucin clearance, pancreatic insufficiency, intestinal inflammation, small bowel bacterial overgrowth, and specifics of individual host genetics. 6,33 Evidence of chronic gut inflammation is seen in CF even in the absence of overt GI symptoms and is thought to be a driver of systemic inflammation in the disease. 34 Recent work in a murine model has clarified that CFTR knockout mice acquire an aberrant GI microbiota in the absence of antibiotic exposure.…”