Estimation of phenolic conjugation by colonic mucosa.

Ramakrishna, B. S.; Gee, David; Weiss, A; Pannall, P R; Ic, Roberts-Thomson; Roediger, W. E. W.

doi:10.1136/jcp.42.6.620

Cited by 45 publications

(26 citation statements)

References 13 publications

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“…PAG and 4CS are formed from protein putrefaction of phenylalanine and tyrosine by the gut microbiota. Phenylalanine is converted to phenylacetate in the colon and subsequently conjugated with glutamine in the liver and the gut mucosa 53 , whereas 4CS is a product of microbial tyrosine breakdown via hydroxyphenylacetate to 4-cresyl , followed by conjugation with sulfate. 54 Age-related variations were also observed in the bacterial fermentation product, lactic acid, being negatively associated with aging in the American sample.…”

Section: Discussionmentioning

confidence: 99%

Microbial–Mammalian Cometabolites Dominate the Age-associated Urinary Metabolic Phenotype in Taiwanese and American Populations

et al. 2013

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Understanding the metabolic processes associated with aging is key to developing effective management and treatment strategies for age-related diseases. We investigated the metabolic profiles associated with age in a Taiwanese and an American population. 1H NMR spectral profiles were generated for urine specimens collected from the Taiwanese Social Environment and Biomarkers of Aging Study (SEBAS; n= 857; age 54-91 years) and the Mid-Life in the USA study (MIDUS II; n= 1148; age 35-86 years). Multivariate and univariate linear projection methods revealed some common age-related characteristics in urinary metabolite profiles in the American and Taiwanese populations, as well as some distinctive features. In both cases, two metabolites--4-cresyl sulfate (4CS) and phenylacetylglutamine (PAG)—were positively associated with age. In addition, creatine and β-hydroxy-β-methylbutyrate (HMB) were negatively correlated with age in both populations (p<4×10-6). These age-associated gradients in creatine and HMB reflect decreasing muscle mass with age. The systematic increase in PAG and 4CS was confirmed using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Both are products of concerted microbial-mammalian host co-metabolism and indicate an age-related association with the balance of host-microbiome metabolism.

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Section: Discussionmentioning

confidence: 99%

Microbial–Mammalian Cometabolites Dominate the Age-associated Urinary Metabolic Phenotype in Taiwanese and American Populations

et al. 2013

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“…A likely explanation for this is that the formula feeds currently available, including the products used in the present study, contain similar amounts of tyrosine (the substrate from which gut bacteria generate phenol and p-cresol) to levels found in breast milk. Phenols are usually detoxified by either sulfate or glucuronide conjugation in the colonic mucosa and then excreted in the urine or remain unabsorbed and excreted in the faeces (Ramakrishna et al 1989).…”

Section: Discussionmentioning

confidence: 99%

Protein-degradation products and bacterial enzyme activities in faeces of breast-fed and formula-fed infants

et al. 2003

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The aim of the present study was to determine the effects of age and diet (breast milk, formula milk and weaning diet) on metabolic activities in faecal samples from infants aged 1 week to 1 year, and to compare these findings with activities found in samples from adults. Such activities can provide valuable information on functional changes in the microbiota that may have significance for the health of the host. Fresh faecal samples were collected from forty-four breast-fed infants (twenty-four males, twenty females) and thirteen formula-fed infants (three males, ten females) throughout the first year of life. The samples were analysed for protein-breakdown products, including the faecal concentrations of NH 3 , phenol and p-cresol, and faecal bacterial enzyme activities. There was wide individual variation in all variables measured; however, the values in infants were substantially lower then those found in adults. In pre-weaned infants, faecal NH 3 concentration and b-glucuronidase activity were the only endpoints that were significantly different in breast-fed and formula-fed infants (P, 0·001 and P,0·05 respectively). This was not apparent after weaning. There was a significant difference between the breast-fed and formula-fed weaned groups and their pre-weaned counterparts only for NH 3 (P,0·05). b-Glucuronidase activity and phenol concentration were significantly (P,0·01) greater in weaned breast-fed infants compared with pre-weaned breast-fed infants. No differences were observed between pre-weaned and weaned formula-fed infants for any of the variables except for NH 3 concentration. It can be concluded from the present study that there are significant differences in two faecal characteristics between breast-and formula-fed infants and that changes occur as the infants grow older and are weaned onto solid foods.

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“…3). As regards the site of this competitive sulfonation, the colonic mucosa is known to have significant sulfonation capacity (25,31) and could potentially convert colonically produced p-cresol to PCS. However, with acetaminophen being rapidly absorbed from the small intestine and with the liver being regarded as the principal site of its metabolism (17), we envisage that some colonically produced p-cresol may escape further colonic modification and be sulfonated in the liver rather than in the gastrointestinal tract.…”

Section: Resultsmentioning

confidence: 99%

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Clayton

Baker

Lindon

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

693

573

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We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype, in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary metabolite profiles were determined by 1 H NMR spectroscopy. The predose spectra were statistically analyzed in relation to drug metabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. We conclude that, in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Given that acetaminophen is such a widely used and seemingly well-understood drug, this finding provides a clear demonstration of the immense potential and power of the pharmacometabonomic approach. However, we expect many other sulfonation reactions to be similarly affected by competition with p-cresol and our finding also has important implications for certain diseases as well as for the variable responses induced by many different drugs and xenobiotics. We propose that assessing the effects of microbiome activity should be an integral part of pharmaceutical development and of personalized health care. Furthermore, we envisage that gut bacterial populations might be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.T he effects of drug treatments can vary greatly between different individuals, and pharmacogenomics has been widely advocated as a potential means of personalizing human drug treatments to increase drug efficacy and to decrease adverse reactions (1-6). However, environmental factors (such as nutritional status, gut bacterial activities, age, disease, and other drug use) are also important determinants of individual metabolic phenotypes, which modulate drug metabolism, efficacy, and toxicity. Such environmental complications, which may also alter gene expression, will tend to limit the usefulness of predictions of drug-induced responses that are based only on genomic differences (7,8). For instance, for many classes of compound, enzyme induction state, which is environmentally determined, influences drug metabolism and toxicity and this is not captured in genomic data. Recognizing this important limitation of pharmacogenomics, a different approach to personalized drug treatment has recently been proposed wherein predose metabolite profiling would instead be used to predict a subject's responses to potential drug interventions (9). This ''pharmacometabonomic'' approach has a number of major advantages, which include the ready availability and relative ease of analysis of biofluids, such as urine and blood plasma, as well as the fact that ...

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Estimation of phenolic conjugation by colonic mucosa.

Cited by 45 publications

References 13 publications

Microbial–Mammalian Cometabolites Dominate the Age-associated Urinary Metabolic Phenotype in Taiwanese and American Populations

Microbial–Mammalian Cometabolites Dominate the Age-associated Urinary Metabolic Phenotype in Taiwanese and American Populations

Protein-degradation products and bacterial enzyme activities in faeces of breast-fed and formula-fed infants

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

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