Quantification of Enteric Dysfunction in Cystic Fibrosis: Inter- and Intraindividual Variability.

OBJECTIVES: To test the utility of various biomarkers as indicators of gut dysfunction in cystic fibrosis (CF) and determine whether intraindividual variations in these measures are repeatable over short intervals and whether interindividual variations correlate with clinical outcomes. STUDY DESIGN: We performed a cross-sectional, limited longitudinal study of children with CF aged 1-21 years who provided blood and stool samples at 2 or 3 visits, 2 weeks and 3 months apart, which were assayed for markers of intestinal inflammation (fecal calprotectin [fCal], lipocalin-2 [fLcn2], neopterin), and permeability (plasma lipopolysaccharide [LPS] antibodies, LPS-binding protein) by enzyme immunoassays. Control specimens were obtained from children without CF who had undergone esophagogastroduodenoscopy and had no evidence of gut inflammation. RESULTS: Twenty-six of 29 participants with CF completed the study. Sixty-nine stools (57 case/12 control) and 76 plasmas (60 case/16 control) were analyzed. LPS antibody had reliable intraindividual stability. fCal, fLcn2, and neopterin were significantly greater in CF than in control samples. fCal was negatively correlated with 3-month interval change (Δ) in weight-for-age z-score, body mass index/weight-for-length z-score, and forced expiratory volume in 1 second. fLcn2 was negatively correlated with FEV1 but not with anthropometrics. No marker correlated with Δbody mass index/weight-for-length z-score or ΔFEV1. CONCLUSIONS: fLcn2 is elevated in people with CF and might predict worse interval pulmonary function. Expanded studies are warranted to test if fLcn2 correlates with changes in additional outcomes.

Pathogen-Specific Effects of Probiotics in Children With Acute Gastroenteritis Seeking Emergency Care: A Randomized Trial.

BACKGROUND: It is unknown if probiotics exert pathogen-specific effects in children with diarrhea secondary to acute gastroenteritis. METHODS: Analysis of patient-level data from 2 multicenter randomized, placebo controlled trials conducted in pediatric emergency departments in Canada and the United States. Participants were 3-48 months with >3 diarrheal episodes in the preceding 24 hours and were symptomatic for <72 hours and <7 days in the Canadian and US studies, respectively. Participants received either placebo or a probiotic preparation (Canada-Lactobacillus rhamnosus R0011/Lactobacillus helveticus R0052; US-L. rhamnosus GG). The primary outcome was post-intervention moderate-to-severe disease (ie, ≥9 on the Modified Vesikari Scale [MVS] score). RESULTS: Pathogens were identified in specimens from 59.3% of children (928/1565). No pathogen groups were less likely to experience an MVS score ≥9 based on treatment allocation (test for interaction = 0.35). No differences between groups were identified for adenovirus (adjusted relative risk [aRR]: 1.42; 95% confidence interval [CI]: .62, 3.23), norovirus (aRR: 0.98; 95% CI: .56, 1.74), rotavirus (aRR: 0.86; 95% CI: .43, 1.71) or bacteria (aRR: 1.19; 95% CI: .41, 3.43). At pathogen-group and among individual pathogens there were no differences in diarrhea duration or the total number of diarrheal stools between treatment groups, regardless of intervention allocation or among probiotic sub-groups. Among adenovirus-infected children, those administered the L. rhamnosus R0011/L. helveticus R0052 product experienced fewer diarrheal episodes (aRR: 0.65; 95% CI: .47, .90). CONCLUSIONS: Neither probiotic product resulted in less severe disease compared to placebo across a range of the most common etiologic pathogens. The preponderance of evidence does not support the notion that there are pathogen specific benefits associated with probiotic use in children with acute gastroenteritis. CLINICAL TRIALS REGISTRATION: NCT01773967 and NCT01853124.

Maternal activation of the EGFR prevents translocation of gut-residing pathogenic Escherichia coli in a model of late-onset neonatal sepsis.

Late-onset sepsis (LOS) is a highly consequential complication of preterm birth and is defined by a positive blood culture obtained after 72 h of age. The causative bacteria can be found in patients' intestinal tracts days before dissemination, and cohort studies suggest reduced LOS risk in breastfed preterm infants through unknown mechanisms. Reduced concentrations of epidermal growth factor (EGF) of maternal origin within the intestinal tract of mice correlated to the translocation of a gut-resident human pathogen Escherichia coli, which spreads systemically and caused a rapid, fatal disease in pups. Translocation of Escherichia coli was associated with the formation of colonic goblet cell-associated antigen passages (GAPs), which translocate enteric bacteria across the intestinal epithelium. Thus, maternally derived EGF, and potentially other EGFR ligands, prevents dissemination of a gut-resident pathogen by inhibiting goblet cell-mediated bacterial translocation. Through manipulation of maternally derived EGF and alteration of the earliest gut defenses, we have developed an animal model of pathogen dissemination which recapitulates gut-origin neonatal LOS.