Antibiotics in early life associate with specific gut microbiota signatures in a prospective longitudinal infant cohort.

BACKGROUND: The effects of antibiotics on infant gut microbiota are unclear. We hypothesized that the use of common antibiotics results in long-term aberration in gut microbiota. METHODS: Antibiotic-naive infants were prospectively recruited when hospitalized because of a respiratory syncytial virus infection. Composition of fecal microbiota was compared between those receiving antibiotics during follow-up (prescribed at clinicians' discretion because of complications such as otitis media) and those with no antibiotic exposure. Fecal sampling started on day 1, then continued at 2-day intervals during the hospital stay, and at 1, 3 and 6 months at home. RESULTS: One hundred and sixty-three fecal samples from 40 patients (median age 2.3 months at baseline; 22 exposed to antibiotics) were available for microbiota analyses. A single course of amoxicillin or macrolide resulted in aberration of infant microbiota characterized by variation in the abundance of bifidobacteria, enterobacteria and clostridia, lasting for several months. Recovery from the antibiotics was associated with an increase in clostridia. Occasionally, antibiotic use resulted in microbiota profiles associated with inflammatory conditions. CONCLUSIONS: Antibiotic use in infants modifies especially bifidobacterial levels. Further studies are warranted whether administration of bifidobacteria will provide health benefits by normalizing the microbiota in infants receiving antibiotics.

Impact of paediatric onset primary sclerosing cholangitis on clinical course and outcome of inflammatory bowel disease: a case-control population-based study in Finland.

Introduction and aim: The aim of this study was to investigate the outcome of a paediatric onset of inflammatory bowel disease (IBD) in a cohort of subjects with primary sclerosing cholangitis (PSC) and in a matched-age population-based control group without PSC. Methods: We identified 28 IBD-PSC cases (median age at IBD diagnosis 12.5 years, 25-75th: 10-16 years) and selected three IBD controls for each case matched for age and year of IBD diagnosis. All data regarding the gastrointestinal tract and liver were collected at diagnosis and at last follow-up (median 15 years). Results: At diagnosis the prevalence of pancolitis was similar between the groups (78% and 79%, respectively p = -.30), but histologic inflammation was milder in IBD-PSC (61% vs 30%, p = .06). At last follow-up (median age 29 years) pancolitis was less frequent (6% and 33%, respectively p = .04) and the remission higher (76% and 47%, respectively p = .08) in IBD-PSC patients than in IBD patients. Panproctolectomy (32% in IBD-PSC and 34% in IBD, p = 1.0) and the rate of pouchitis (62% and 70%, respectively p = .8) were similar. Conclusions: The outcome of paediatric onset IBD in patients with PSC in adulthood seems to be comparable to those with IBD only.

Fecal Calprotectin Test Performed at Home: A Prospective Study of Pediatric Patients With Inflammatory Bowel Disease.

OBJECTIVES: Measuring fecal calprotectin (FC) in a laboratory is time-consuming and that is why home tests have been developed. We studied the use of an FC home test in pediatric patients with inflammatory bowel disease (PIBD) in real-life settings. METHODS: The patients were asked to perform the IBDoc FC home test monthly for 6 months and to report their clinical disease activity at testing. Clinical decision-making, however, was guided by routine FC enzyme-linked immunosorbent assay (ELISA) for patients with raised IBDoc values. Spare frozen samples were analyzed using ELISA and IBDoc in the laboratory. The participants completed a questionnaire about FC testing at the start and end of the study. RESULTS: Of the 52 patients, 35 (67%) ages 5 to 18 years completed the study, and 197 home tests were performed. Of these, 15% failed, mainly because of technical reasons. Just under half of the patients (47%) considered home testing comparable or superior to routine testing. In contrast, the parents were unsatisfied (61%), mostly because the IBDoc results were significantly different from ELISA and they found the phone application difficult to handle but whenever the IBDoc was performed by a laboratory professional it was comparable with ELISA, suggesting that practical issues hampered home testing. Despite their reservations, more than 80% of parents felt that home testing would improve disease management. CONCLUSIONS: PIBD patients and their families were interested in FC home monitoring and willing to adopt testing as a part of their disease management, but this approach requires thorough guidance.

Environmental Risk Factors of Pediatric-Onset Primary Sclerosing Cholangitis and Autoimmune Hepatitis.

OBJECTIVES: The aim of this population-based observational case-control questionnaire study was to investigate the possible role of environmental risk factors associated with pediatric-onset autoimmune liver diseases. METHODS: Seventy-one patients with autoimmune liver diseases (<16 years) received a questionnaire with 22 items, evaluating contact with environmental factors (eg, family manners, type of housing, pets) before the diagnosis. Two age- and sex-matched control groups were used: inflammatory bowel disease (IBD; n = 91) and healthy subjects (n = 716; matched also for place of residence at birth). Univariate analysis (odds ratio [OR] and 95% confidence interval) for all variables was calculated. Fisher exact test was performed to depict associations between variables and the multivariate logistic regression to test their interactions. RESULTS: In the final analyses, the responses of 51 autoimmune liver diseases cases (n = 51/71, 72%), 59 IBD controls (n = 59/91, 65%), and 292 healthy controls (n = 292/716, 41%) were investigated. In univariate analysis only having a cat, a dog, and a cat or a dog were risk factors of autoimmune liver diseases (OR varying between 2.6-3.4); no other significant associations (eg, place of residence, number of siblings, family manners) were found. Multivariate logistic regression analyses showed that especially living with a cat in block of flats was a risk factor (OR 3.6, 1.2-10.8). CONCLUSIONS: Living in a close contact with a pet (especially a cat) was a risk factor of autoimmune liver diseases. This finding may suggest an involvement of an unidentified agent (ie, toxin/microbe) among the triggers of these diseases.

Fecal Microbiota in Pediatric Inflammatory Bowel Disease and Its Relation to Inflammation.

OBJECTIVES: Inflammatory bowel disease (IBD) is considered to result from interplay between host and intestinal microbiota. While IBD in adults has shown to be associated with marked changes in the intestinal microbiota, there are only a few studies in children, and particularly studies focusing on therapeutic responses are lacking. Hence, this prospective study addressed the intestinal microbiota in pediatric IBD especially related to the level of inflammation. METHODS: In total, 68 pediatric patients with IBD and 26 controls provided stool and blood samples in a tertiary care hospital and 32 received anti-tumor necrosis factor-α (anti-TNF-α). Blood inflammatory markers and fecal calprotectin levels were determined. The intestinal microbiota was characterized by phylogenetic microarray and qPCR analysis. RESULTS: The microbiota varied along a gradient of increasing intestinal inflammation (indicated by calprotectin levels), which was associated with reduced microbial richness, abundance of butyrate producers, and relative abundance of Gram-positive bacteria (especially Clostridium clusters IV and XIVa). A significant association between microbiota composition and inflammation was indicated by a set of bacterial groups predicting the calprotectin levels (area under curve (AUC) of 0.85). During the induction of anti-TNF-α, the microbial diversity and similarity to the microbiota of controls increased in the responder group by week 6, but not in the non-responders (P<0.01; response related to calprotectin levels). The abundance of six groups of bacteria including those related to Eubacterium rectale and Bifidobacterium spp. predicted the response to anti-TNF-α medication. CONCLUSIONS: Intestinal microbiota represents a potential biomarker for correlating the level of inflammation and therapeutic responses to be further validated.

Faecal and Serum Metabolomics in Paediatric Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease [IBD] is considered to result from the interplay between host and intestinal microbiota but its pathogenesis is incompletely understood. While IBD in adults has shown to be associated with marked changes in body fluid metabolomics, there are only few studies in children. Hence, this prospective study addressed the faecal and serum metabolomics in newly diagnosed paediatric IBD. METHODS: Paediatric patients with IBD undergoing diagnostic endoscopies and controls also with endoscopy but no signs of inflammation provided blood and stool samples in a tertiary care hospital. Blood inflammatory markers and faecal calprotectin levels were determined. The serum and faecal metabolomics were determined using ultra-high pressure liquid chromatography coupled to a mass spectrometer. RESULTS: Serum and faecal metabolite profiles in newly diagnosed paediatric IBD patients were different from healthy controls and categorized Crohn's disease and ulcerative colitis [UC] patients into separate groups. In serum, amino acid metabolism, folate biosynthesis and signalling pathways were perturbed in Crohn's disease; in UC also sphingolipid metabolic pathways were perturbed when compared to controls. In faecal samples, there was an increased level of several metabolites in UC in contrast to low or intermediate levels in Crohn's disease. There was a clear correlation with the level of inflammation, i.e. faecal calprotectin levels and the profile of various biologically important metabolites [carnosine, ribose and, most significantly, choline]. CONCLUSION: Characterization of inflammatory pattern using metabolomics analysis is a promising tool for better understanding disease pathogenesis of paediatric IBD.

Clinical course and prognosis of pediatric-onset primary sclerosing cholangitis.

BACKGROUND: The natural history of pediatric-onset primary sclerosing cholangitis (PSC) and overlap with autoimmune hepatitis (PSC/AIH) is poorly known. OBJECTIVE: The aim of this study was to evaluate the clinical outcome of patients with pediatric-onset disease in a tertiary referral center. METHODS: We traced 33 patients (median age at diagnosis 16 years), with PSC or PSC/AIH in cholangiography and liver histology diagnosed between December 1993 and 2011, at Helsinki University Hospital. Diagnostic procedures and long-term follow-up were reassessed until the end of December 2013. RESULTS: PSC was confirmed in all 33 patients; 19 of them had an overlap with AIH. At diagnosis, three of 33 had cirrhosis. Inflammatory bowel disease (IBD) was associated in 76% of the patients, mostly ulcerative colitis (70%); treatment of IBD being a minor determinant of the clinical outcome of liver disease. In the last follow-up (median nine years), all patients were alive, and no malignancy occurred. Most patients (91%) were on ursodeoxycholic acid and 12 PSC/AIH patients on immunosuppression. Endoscopic retrograde cholangiography during follow-up showed a progression of intra-hepatic disease in 12 patients (36%). Four patients (12%) had undergone liver transplantation, and one was listed; no recurrence of the disease in the graft was seen. CONCLUSION: The clinical course and outcome of pediatric-onset PSC and PSC/AIH seem to be favourable in the majority of patients until early adulthood. In about one-third of patients, however, PSC is progressive, challenging the current treatment guidelines and warranting further studies on disease pathogenesis.