Phenylketonuria and Gut Microbiota: A Controlled Study Based on Next-Generation Sequencing

Abstract

Phenylketonuria (PKU) is an inborn error of metabolism associated with high blood levels of phenylalanine (Phe). A Phe-restricted diet supplemented with L-amino acids is the main treatment strategy for this disease; if started early, most neurological abnormalities can be prevented. The healthy human gut contains trillions of commensal bacteria, often referred to as the gut microbiota. The composition of the gut microbiota is known to be modulated by environmental factors, including diet. In this study, we compared the gut microbiota of 8 PKU patients on Phe-restricted dietary treatment with that of 10 healthy individuals. The microbiota were characterized by 16S rRNA sequencing using the Ion Torrent™ platform. The most dominant phyla detected in both groups were Bacteroidetes and Firmicutes. PKU patients showed reduced abundance of the Clostridiaceae, Erysipelotrichaceae, and Lachnospiraceae families, Clostridiales class, Coprococcus, Dorea, Lachnospira, Odoribacter, Ruminococcus and Veillonella genera, and enrichment of Prevotella, Akkermansia, and Peptostreptococcaceae. Microbial function prediction suggested significant differences in starch/glucose and amino acid metabolism between PKU patients and controls. Together, our results suggest the presence of distinct taxonomic groups within the gut microbiome of PKU patients, which may be modulated by their plasma Phe concentration. Whether our findings represent an effect of the disease itself, or a consequence of the modified diet is unclear.

Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria

“…Emerging evidence suggests that another contributing factor includes changes in the intestinal microbiota with the synthetic PKU diet (4, 13), which may result in degradation of Tyr and Trp, thus reducing their bioavailability for synthesis of neurotransmitters. We demonstrate that larger quantities of Tyr consumed at fewer daily meals with AA-MF compared with GMP-MF, result in greater degradation of Tyr to potentially harmful compounds synthesized by intestinal bacteria.…”

“…Thus, the concentration of Tyr and Trp in medical foods for the management of PKU may impact neurotransmitter synthesis; however, the bioavailability of these amino acids for absorption from the gastrointestinal tract has not been studied. This is an important consideration, given evidence that the intestinal microbiome is altered in human PKU with ingestion of AA-MF (13) and improved with ingestion of a diet containing GMP. GMP alters microbial phyla and increases production of short chain fatty acids compared with a diet containing amino acids (4, 5).…”

Intestinal microbiota in rainbow trout,Oncorhynchus mykiss, fed diets with different levels of fish-based and plant ingredients: A correlative approach with some plasma metabolites

“…Phenylketonuric patients, whose diet was restricted in phenylalanine supply, showed reduced prevalence of several bacterial groups, inclusive of Clostridiaceae, compared to healthy controls (de Oliveira et al, 2016). Whether this effect was due to the disease or to the diet was not elucidated, but that suggested some relationship between plasma phenylalanine and gut microbiota, possibly including Clostridium sp.…”

Predicting and preventing intestinal dysbiosis on the basis of pharmacological gut microbiota metabolism

“…This interesting prospect, i.e., fecal gut microbiota transplantation to combat intestine‐related diseases, has led to the development of methods by different research groups to evaluate the gut microbiota status in human subjects . These approaches can be classified as: Untargeted approaches that search for bacteria responsible for dysbiosis without any prior knowledge of which types of bacterium might be involved Targeted approaches that search for specific pathogens and the correlation of these to gut microbiota‐related dysbiosis …”

“…One example of an untargeted approach is that of Pinheiro de Oliveira and co‐workers who developed a method that detects thousands of different species using DNA gene amplification . For the aforementioned DNA approaches, it is difficult to determine a correlation between the presence of a bacterial species and its involvement in intestinal dysbiosis without knowledge of how its metabolism affects the intestinal environment …”