Differences in faecal microbiome composition between adult patients with UCD and PKU and healthy control subjects

Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases causing hyperammonemic encephalopathy. Despite intensive dietary and pharmacological therapy, outcome is poor in a subset of UCD patients. Reducing ammonia production by changing faecal microbiome in UCD is an attractive tr...

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Published in:	Molecular genetics and metabolism reports Vol. 29; p. 100794
Main Authors:	Timmer, C., Davids, M., Nieuwdorp, M., Levels, J.H.M., Langendonk, J.G., Breederveld, M., Ahmadi Mozafari, N., Langeveld, M.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-12-2021 Elsevier
Subjects:	Faecal Gut Hyperammonemia Microbiome Phenylketonuria Research Paper Urea cycle defect DESeq PCoA OTCd ADI Ammonium scavengers Alpha Diversity DEGs ASLd Genus EAA supplement Proteolytic capacity Faecal RT-qPCR 16S rRNA Phenylketonuria ASV Gut Hyperammonemia ARG1d PFAA UCD Sodium BPA Urea cycle defect FPD PKU ASSd Metagenome BCAA Microbiome PFAA, precursor free amino acid supplement, in this case phenylalanine free DEGs, differentially expressed genes FPD, Faiths Phylogenetic Diversity, alpha diversity metric accounting for genetic diversity Alpha Diversity, the species diversity in a microbial sample. Used to represent the taxonomic diversities of individual samples Metagenome, microbiome collective genome 16S rRNA, taxonomic marker genes, common to all bacteria ARG1d, arginase 1 (ARG1) deficiency RT-qPCR, real-time quantitative polymerase chain reaction ASV, Amplified Sequence Variant. A specific nucleotide sequence representing a bacterial lineage EAA supplement, essential amino acids supplement containing L-histidine, L-isoleucine, L-leucine, l-lysine, L-methionine, L-phenylalanine, L-threonine, L-tryptofaan and L-valine with optional L-cystine and L-tyrosine added (depending on what product is used) UCD, urea cycle defect ADI, Arginine Deimination. Bacteria derive energy from the deamination of arginine to citrulline and citrulline cleavage to ornithine plus carbamoyl phosphate. The latter is then converted into ATP and carbon dioxide, or used for pyrimidine biosynthesis. This route also generates two moles of ammonia (one from the arginine-citrulline conversion, the second from carbamoyl phosphate hydrolysis) Proteolytic capacity, the capacity to break proteins down into smaller polypeptides or amino acids. In this study: enzymes involved in protein degradation ASLd, argininosuccinate lyase (ASL) deficiency ASSd, argininosuccinate synthetase (ASS) deficiency Genus, a taxonomic rank BCAA, branched chain amino acids: isoleucine, leucine and valine PCoA, Principal Coordinate Analysis. PCoA is aimed at graphically representing a resemblance matrix between p elements (individuals, variables, objects, among others). By using PCoA we can visualize individual and/or group differences. Individual differences can be used to show outliers Ammonium scavengers, agents developed for the reduction of blood ammonia concentration used for the treatment of patients with urea cycle disorders. Sodiumbenzoate and phenylbutyrate are ammonium scavengers Sodium BPA, sodium phenylbutyrate OTCd, ornithine transcarbamylase deficiency DESeq, an R package to analyse count data from high-throughput sequencing assays such as RNA-Seq and test for differential expression PKU, Phenylketonuria
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Summary:	Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases causing hyperammonemic encephalopathy. Despite intensive dietary and pharmacological therapy, outcome is poor in a subset of UCD patients. Reducing ammonia production by changing faecal microbiome in UCD is an attractive treatment approach. We compared faecal microbiome composition of 10 UCD patients, 10 healthy control subjects and 10 phenylketonuria (PKU) patients. PKU patients on a low protein diet were included to differentiate between the effect of a low protein diet and the UCD itself on microbial composition. Participants were asked to collect a faecal sample and to fill out a 24 h dietary journal. DNA was extracted from faecal material, taxonomy was assigned and microbiome data was analyzed, with a focus on microbiota involved in ammonia metabolism. In this study we show an altered faecal microbiome in UCD patients, different from both PKU and healthy controls. UCD patients on dietary and pharmacological treatment had a less diverse faecal microbiome, and the faecal microbiome of PKU patients on a protein restricted diet with amino acid supplementation showed reduced richness compared to healthy adults without a specific diet. The differences in the microbiome composition of UCD patients compared to healthy controls were in part related to lactulose use. Other genomic process encodings involved in ammonia metabolism, did not seem to differ. Since manipulation of the microbiome is possible, this could be a potential treatment modality. We propose as a first next step, to study the impact of these faecal microbiome alterations on metabolic stability. The faecal microbiome of UCD patients was less diverse compared to PKU patients and even more compared to healthy controls.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2214-4269 2214-4269
DOI:	10.1016/j.ymgmr.2021.100794