The influence of liver transplantation on the interplay between gut microbiome and bile acid homeostasis in children with biliary atresia.

BACKGROUND: Biliary atresia (BA) causes neonatal cholestasis and rapidly progresses into cirrhosis if left untreated. Kasai portoenterostomy may delay cirrhosis. BA remains among the most common indications for liver transplantation (LT) during childhood. Liver function and gut microbiome are interconnected. Disturbed liver function and enterohepatic signaling influence microbial diversity. We, herein, investigate the impact of LT and reestablishment of bile flow on gut microbiome-bile acid homeostasis in children with BA before (pre, n = 10), 3 months (post3m, n = 12), 12 months (post12m, n = 9), and more than 24 months (post24 + m, n = 12) after LT. METHODS: We analyzed the intestinal microbiome of BA patients before and after LT by 16S-rRNA-sequencing and bioinformatics analyses, and serum primary and secondary bile acid levels. RESULTS: The gut microbiome in BA patients exhibits a markedly reduced alpha diversity in pre (p = 0.015) and post3m group (p = 0.044), and approximated healthy control groups at later timepoints post12m (p = 1.0) and post24 + m (p = 0.74). Beta diversity analysis showed overall community structure similarities of pre and post3m (p = 0.675), but both differed from the post24 + m (p < 0.001). Longitudinal analysis of the composition of the gut microbiome revealed the Klebsiella genus to show increased abundance in the post24 + m group compared with an age-matched control (p = 0.029). Secondary bile acid production increased 2+ years after LT (p = 0.03). Multivariable associations of microbial communities and clinical metadata reveal several significant associations of microbial genera with tacrolimus and mycophenolate mofetil-based immunosuppressive regimens. CONCLUSIONS: In children with BA, the gut microbiome shows strongly reduced diversity before and shortly after LT, and approximates healthy controls at later timepoints. Changes in diversity correlate with altered secondary bile acid synthesis at 2+ years and with the selection of different immunosuppressants.

[Fecal Microbiota Transfer (FMT) in Children and Adolescents - Review and statement by the GPGE microbiome working group]. / Fäkaler Mikrobiota Transfer (FMT) bei Kindern und Jugendlichen ­ Review und Stellungnahme der GPGE AG Mikrobiom.

The human microbiome and especially the gastrointestinal microbiota are associated with health and disease. Disturbance in the composition or function of fecal microbiota (dysbiosis) plays a role in the development of pediatric gastrointestinal diseases. Fecal microbiota transfer (FMT) is a special intervention, where microbiota are transferred from a healthy donor.In this review we describe the current state of knowledge for FMT in pediatric patients. There is satisfactory evidence concerning FMT in patients with recurrent C. difficile infection. For inflammatory bowel disease, few studies show a potential benefit.Adverse events occurred frequently in clinical studies, but were mostly mild and transient. There are hardly any data on long-term side effects of FMT, which are particularly significant for pediatrics. In practice, there is uncertainty as to which application route, dosage or frequency should be used. Legally, donor stool is considered a drug in German-speaking countries, for which no marketing authorization exists.In conclusion, knowledge about physiology, efficacy and side effects of FMT is insufficient and legal concerns complicate its implementation. More studies on this topic are needed urgently.

Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations.

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling.

Recombinant human parathyroid hormone (1-84) replacement therapy in a child with hypoparathyroidism.

First line conventional therapy of hypoparathyroidism comprises oral calcium and active vitamin D analogues. This approach may fail to correct hypocalcemia and hyperphosphatemia caused by the absence of parathyroid hormone and carries the risk of long-term complications including ectopic calcifications and renal damage. Full-length recombinant human parathyroid hormone (rhPTH[1-84]) is approved for the treatment of hypoparathyroidism in adults refractory to conventional therapy. To date, there is no data in children. Here, we report the successful use of rhPTH(1-84) in a 5-year old girl with hypoparathyroidism and concomitant chronic diarrhea manifesting as part of the autoimmune polyglandular syndrome type 1. Prior to starting rhPTH(1-84), the patient had been on conventional and later on rhPTH(1-34) continuous pump therapy. Conventional therapy failed to meet serum and urinary calcium target levels, whilst the pump therapy wasn't well tolerated and posed handling difficulties. Dose optimization for rhPTH(1-84) was informed by serum ionized calcium, spot urinary calcium-to-creatinine ratio and 24-hour urinary calcium excretion. Twice-daily subcutaneous injections of rhPTH(1-84) with a total dose of 3.35 µg/kg/d was well-tolerated, raised serum ionized calcium to target range (1.05-1.15 mmol/L) and normalized serum phosphate levels. Urinary calcium excretion was slightly above the recommended limit of 4 mg/kg/24 h, but improved compared to conventional therapy, with no evidence of nephrocalcinosis. Twice-daily administration stabilized serum calcium and phosphate levels compared to once-daily injections. rhPTH(1-84) treatment was well tolerated and the girl did not manifest any acute clinical complications of hypoparathyroidism throughout the entire observation period. Our experience with this case indicates that rhPTH(1-84) may be a physiological hormone replacement for managing hypoparathyroidism in children.

Education, school type and screen time were associated with overweight and obesity in 2930 adolescents.

AIM: This cross-sectional study analysed the influence of socio-economic factors on screen time, overweight and obesity. METHODS: We asked adolescents aged 10, 14 and 17 from 10 school types in urban and rural regions in Upper Austria to complete questionnaires from December 2012 to February 2013. Their parents were also asked to complete questionnaires. RESULTS: The questionnaires were completed by 2930 adolescents and 2209 parents. Total weekend screen time was significantly associated with a higher body mass index (BMI) in 10-year-old boys (p < 0.005) and 10-year-old girls (p = 0.002), and there were significant associations between higher BMI and television time and longer weekend video game use in subjects aged 10 and 14. Higher education levels were associated with shorter daily video game use and longer computer use. Males (p < 0.0001) and adolescents from immigrant families (p < 0.0001) reported longer screen times at all ages. Lower parental education and higher parental BMI correlated significantly with longer screen time and BMI in the youngest age group. CONCLUSION: The greatest weight problems were in younger adolescents, despite shorter screen times, and boys and adolescents from immigrant families reported the longest screen times. Prevention strategies need to start early.

Gender differences and the role of parental education, school types and migration on the body mass index of 2930 Austrian school children : A cross-sectional study.

BACKGROUND: Austria faces increasing numbers of childhood overweight and obesity. Despite increasing numbers of studies, associations between parental body mass index (BMI) and education and the school type on overweight/obesity in students have not been reported. The objective of this study was to evaluate the influence of these parameters on the genesis of overweight/obesity in a large cohort representative of youth in Upper Austrian. METHODS: A cross-sectional analysis of data from 2930 children and adolescents aged 10, 14 or 17 years from 11 different state school types was conducted. Students and their parents completed a questionnaire and heights and weights were measured. RESULTS: Of the students 16.9% fulfilled the criteria for overweight and 5.6% for obesity, with the highest rates in the 10-year-olds (19.6% and 5.8%, respectively). While no gender differences were present in the youngest age group, the body mass index (BMI) during adolescence remained higher in boys but decreased significantly in girls. Male gender remained a risk factor through all calculations. Boys were overrepresented in schools with lower education levels and more often had BMIs ≥ 85th and ≥95th percentile. Higher parental education levels and lower parental BMIs were associated with lower BMIs of their offspring. Migration was an additional association factor for BMIs ≥ 85th percentile. CONCLUSION: Low parental education levels, higher parental BMIs and migration background were associated with overweight and obesity in 10-year-olds. In adolescence, male gender and higher parental BMIs remained risk factors.