Metabolic differences underlying two distinct rat urinary phenotypes, a suggested role for gut microbial metabolism of phenylalanine and a possible connection to autism

Abstract

a b s t r a c tA novel explanation is proposed for the metabolic differences underlying two distinct rat urinary compositional phenotypes i.e. that these may arise from differences in the gut microbially-mediated metabolism of phenylalanine. As part of this hypothesis, it is further suggested that elements of the mammalian gut microbiota may convert phenylalanine to cinnamic acid, either by means of an ammonia lyase-type reaction or by means of a three step route via phenylpyruvate and phenyllactate. The wider significance of such conversions is discussed with similar metabolism of tryptophan and subsequent glycine conjugation potentially explaining the origin of trans-indolylacryloylglycine, a postulated marker for autism. Ó 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Metabolite profilingMetabolite profiling ('metabonomics'/'metabolomics') is a rapidly growing area of analytical science that has immense biomedical potential, with urine samples being particularly informative, convenient to obtain and analyse [1]. A particular strength of this still-developing analytical approach is that metabolite profiles are sensitive to a whole range of factors, both genomic and environmental, and, thereby, provide a multifactorial overview of a subject's status. In one general application of this 'systems biology' approach, the changes that are induced in endogenous metabolite profiles by stressors, such as drugs and toxins, are monitored and evaluated [1]. However, 'baseline' metabolite profiles are also highly informative and may, for instance, be indicative of gender, other genetic factors, dietary status or disease [1,2]. A great deal remains to be understood regarding the significance of inter-subject variation in baseline metabolite profiles and, to do so, such variation has to be correlated with known factors. One new approach, called 'pharmaco-metabonomic phenotyping', or simply 'pharmacometabonomics', has considerable potential to reveal the hidden significance of baseline metabolite profiles [3,4]. Thus, in a first study in humans [4], the presence of high levels of p-cresol sulfate in the urine has been associated with a lower residual sulfonation capacity and an important and hitherto-unrecognised effect of the gut microbiota on paracetamol (acetaminophen) metabolism has been demonstrated. That study provides an important insight into the impact of the gut microbiota on drug metabolism [5] whilst also serving as a reminder of the major role gut microbes play in dictating urinary composition [6]. The present report further discusses the impact of the gut microbiota on baseline urinary metabolite profiles and addresses the origins of two different rat urinary phenotypes. The 'chlorogenic acid' phenotype and its originsRats are an important experimental model for many investigations and, in recent years, there have been repeated reports of two distinct rat urinary phenotypes, which are not attributable to dietary differences [7][8][9][10]. These phenotypes, whic...

Glyphosate’s Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern Diseases

“…A unique mouse phenotype has recently been identified that is defined by the behavior of its gut bacteria [60], and the authors suggest that this phenotype can be explained through increased metabolism of phenylalanine via the PAL pathway. Furthermore, this unique phenotype is also associated with excess synthesis of p-cresol, via a pathway involved in tyrosine breakdown.…”

Does the Human Gut Microbiota Contribute to the Etiology of Autism Spectrum Disorders?

“…Furthermore, several other microbial metabolites may interact with the nervous system of the host [3]. Differences in the microbiota may also result in altered microbial metabolism of aromatic amino acids, with consequent changes in systemic metabolites (as reflected in urinary metabolite profiles), which could lead to neurological symptoms [15]. For example, p-cresol may affect the metabolism of dopamine [15]; however, there is no consensus on fecal and urinary differences in p-cresol in ASD subjects to date [13].…”

“…Differences in the microbiota may also result in altered microbial metabolism of aromatic amino acids, with consequent changes in systemic metabolites (as reflected in urinary metabolite profiles), which could lead to neurological symptoms [15]. For example, p-cresol may affect the metabolism of dopamine [15]; however, there is no consensus on fecal and urinary differences in p-cresol in ASD subjects to date [13]. The microbiota could also be involved in disease etiology via interactions with the immune system [12].…”

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“…Glyphosate: In [133], it was proposed that impaired metabolism of aromatic amino acids might play a role in ASD. Glyphosate, the active ingredient in the popular herbicide, Roundup is known to disrupt aromatic amino acid metabolism in plants [134].…”

“…It has recently been shown that glyphosate exposure shifts the distribution of gut bacteria from beneficial towards pathogenic forms [136]. In [133], it was proposed that excess synthesis of p-cresol from the aromatic amino acid precursor, phenylalanine, by the pathogenic gut bacterium Clostridium difficile might explain impaired sulfation capacity in association with ASD. Sulfation of p-cresol to detoxify it would result in a depletion of available sulfation capacity.…”