Effects of a Synthetic Amino Acid Diet: Insights from the Guy Microbiome, Inflammation, and Behavior

Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism primarily treated through a phenylalanine-restrictive diet and frequently supplemented with an amino acid formula to maintain proper nutrition. PKU patients often report high levels of anxiety along with symptoms of gastrointestinal distress (i.e., chronic diarrhea, constipation, cramps); symptoms previously associated with gut microbiome dysbiosis. Little is known of the effects of these dietary interventions on the gut microbiome of PKU patients, particularly in adults. The gut microbiome is a collection of microbes residing primarily in the large intestine. The colon is a major production site for short chain fatty acids (SCFAs) through anaerobic fermentation by commensal bacteria. SCFAs provide a source of energy for the colonocytes, as well as provide anti-inflammatory benefits. The production of SCFA appears to be dependent on the availability of soluble fibers and members of the gut microbiota capable of fermentation. We characterized the gut microbiome of adults with PKU for the first time and identified signs of dysbiosis. We then focused on the synthetic, low fiber, nature of the amino acid diet in a murine model. In this interdisciplinary study, we monitored the effect of a consuming synthetic diet on the composition of the murine gut microbiome over the course of 13 weeks, beginning at weaning. At the conclusion of the feeding period, mice we observed for anxiolytic behavior, locomotion, and cognition. We also searched for markers of inflammation through colon shrinkage, changes in cytokine levels within several tissues, and determined the concentration of SCFAs in the colon at the conclusion of the feeding period. The gut microbiome of mice fed the synthetic diet experienced significant deviation from the control group which affected relative abundance of beneficial bacteria. Mice on the synthetic diet were found to have shorter colons, lower concentration of SCFAs in the colon, and demonstrated elevated exploratory behavior.