Formation of Phenolic and Indolic Compounds by Anaerobic Bacteria in the Human Large Intestine

Smith, E. A.; Macfarlane, G.T.

doi:10.1007/s002489900020

Cited by 206 publications

(167 citation statements)

References 31 publications

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“…Thus, we might reasonably expect that, by competing for PAPS or for one or more sulfotransferases, the flux of p-cresol through the system will affect the sulfonation of a wide range of drugs and endogenous compounds, thereby influencing normal bodily processes as well as drug metabolic fate, efficacy, and toxicity. However, given what is known about gut bacterial production of p-cresol from protein residues (23,43,(52)(53)(54) (Fig. 3), with Clostridium difficile being one of a number of p-cresol producers (53,54), our present results show that environmental factors can exert a dominant influence on the extent to which a compound becomes sulfonated in the human body.…”

Section: Resultsmentioning

confidence: 82%

“…S1), and no other components of the predose spectra were found to have such clear discriminatory potential in regard to the S/G ratios observed. On closer inspection, the predose urinary levels of PCS and PAG were found to be broadly correlated (r ϭ 0.75), which, in retrospect, was unsurprising because there is a significant degree of commonality in their origins before the final sulfate and glutamine conjugations; thus, p-cresol and phenylacetic acid are known to be produced from tyrosine and phenylalanine, respectively, with these conversions being largely analogous and dependent on the action of colonic bacteria (23) (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

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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.

697

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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Section: Resultsmentioning

confidence: 82%

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.

697

573

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“…Because tryptophanase activity derives from only a subset of enteric bacteria, non-indole-producing bacteria, such as various Bifidobacterium species, have been administered as a test probiotic to dialysis patients to decrease their plasma levels of indoxyl sulfate (26). Conversely, a different set of enteric bacteria has been implicated in the metabolic transformation of indole to indole-3-propionic acid (IPA) (27). IPA, also identified only in the plasma of conv mice, has been shown to be a powerful antioxidant (28), and is currently being investigated as a possible treatment for Alzheimer's disease (29,30).…”

Section: Resultsmentioning

confidence: 99%

Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites

Wikoff

Anfora²,

Li³

et al. 2009

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

2,327

1,878

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Although it has long been recognized that the enteric community of bacteria that inhabit the human distal intestinal track broadly impacts human health, the biochemical details that underlie these effects remain largely undefined. Here, we report a broad MS-based metabolomics study that demonstrates a surprisingly large effect of the gut ''microbiome'' on mammalian blood metabolites. Plasma extracts from germ-free mice were compared with samples from conventional (conv) animals by using various MS-based methods. Hundreds of features were detected in only 1 sample set, with the majority of these being unique to the conv animals, whereas Ϸ10% of all features observed in both sample sets showed significant changes in their relative signal intensity. Amino acid metabolites were particularly affected. For example, the bacterial-mediated production of bioactive indole-containing metabolites derived from tryptophan such as indoxyl sulfate and the antioxidant indole-3-propionic acid (IPA) was impacted. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes. Multiple organic acids containing phenyl groups were also greatly increased in the presence of gut microbes. A broad, drug-like phase II metabolic response of the host to metabolites generated by the microbiome was observed, suggesting that the gut microflora has a direct impact on the drug metabolism capacity of the host. Together, these results suggest a significant interplay between bacterial and mammalian metabolism.

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“…A smaller percentage of Trp is converted by bacteria into indole-3-acetic acid (IAA), indole-3-propionic acid (IPA), and indole-3-lactic acid (ILA). Intestinal microorganisms also metabolize Trp to tryptamine, which is then converted into IAA [3]. The latter can be conjugated with glycine to yield indole-3-acetylglycine (IAA-Gly) [4].…”

Section: Introductionmentioning

confidence: 99%

Quantitative profiling of tryptophan metabolites in serum, urine, and cell culture supernatants by liquid chromatography–tandem mass spectrometry

et al. 2011

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A sensitive, selective, and comprehensive method for the quantitative determination of tryptophan and 18 of its key metabolites in serum, urine, and cell culture supernatants was developed. The analytes were separated on a C18 silica column by reversed-phase liquid chromatography and detected by electrospray ionization tandem mass spectrometry in positive ion multiple reaction monitoring (MRM) mode, except for indoxyl sulfate which was measured in negative ion MRM mode in a separate run. The limits of detection and lower limits of quantification were in the range of 0.1-50 and 0.5-100 nM, respectively. Fully 13 C isotope-labeled and deuterated internal standards were used to achieve accurate quantification. The applicability of the method to analyze serum, urine, and cell culture supernatants was demonstrated by recovery experiments and the evaluation of matrix effects. Precision for the analysis of serum, urine, and cell culture supernatants ranged between 1.3% and 16.0%, 1.5% and 13.5%, and 1.0% and 17.4%, respectively. The method was applied to analyze changes in tryptophan metabolism in cell culture supernatants from IFN-γ-treated monocytes and immature or mature dendritic cells.

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Formation of Phenolic and Indolic Compounds by Anaerobic Bacteria in the Human Large Intestine

Cited by 206 publications

References 31 publications

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

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

Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites

Quantitative profiling of tryptophan metabolites in serum, urine, and cell culture supernatants by liquid chromatography–tandem mass spectrometry

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