Major phenylpropanoid‐derived metabolites in the human gut can arise from microbial fermentation of protein

Russell, Wendy; Duncan, Sylvia H.; Scobbie, Lorraine; Duncan, Gary; Cantlay, Louise; Calder, Andrew A.; Anderson, Susan E.; Flint, Harry J.

doi:10.1002/mnfr.201200594

Cited by 320 publications

(262 citation statements)

References 37 publications

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“…This supports the hypothesis that Bifidobacterium spp. regulate the growth of bacterial species with high enzymatic capacities to produce IS and PCS (27), such as bacteria from the Clostridales order and Ruminococcaceae family, which both decreased after synbiotics (28,29). The findings support those of a recent study that showed that consumption of Bifidobacterium-fermented milk and GOS reduced serum phenols in healthy adult women (30).…”

Section: Discussionsupporting

confidence: 85%

“…Lastly, the analysis of the stool microbiome may not have reflected alterations in the mucosalassociated microbiomes within the large and small bowel. Furthermore, despite recent studies inferring functional attributes of these microbial communities by comparison with reference microbial genomes (29), such an approach cannot readily account for variations in gene expression, which are influenced by the colonic environment (e.g., pH and carbohydrate availability) (28).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY)

Rossi

Johnson

Morrison

et al. 2016

Clinical Journal of the American Society of Nephrology

300

262

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Background and objectives The generation of key uremic nephrovascular toxins, indoxyl sulfate (IS), and p-cresyl sulfate (PCS), is attributed to the dysbiotic gut microbiota in CKD. The aim of our study was to evaluate whether synbiotic (pre-and probiotic) therapy alters the gut microbiota and reduces serum concentrations of microbiome-generated uremic toxins, IS and PCS, in patients with CKD.Design, setting, participants, & measurements Predialysis adult participants with CKD (eGFR=10-30 ml/min per 1.73 m 2 ) were recruited between January 5, 2013 and November 12, 2013 to a randomized, double-blind, placebo-controlled, crossover trial of synbiotic therapy over 6 weeks (4-week washout). The primary outcome was serum IS. Secondary outcomes included serum PCS, stool microbiota profile, eGFR, proteinuria-albuminuria, urinary kidney injury molecule-1, serum inflammatory biomarkers (IL-1b, IL-6, IL-10, and TNF-a), serum oxidative stress biomarkers (F 2 -isoprostanes and glutathione peroxidase), serum LPS, patient-reported health, Gastrointestinal Symptom Score, and dietary intake. A prespecified subgroup analysis explored the effect of antibiotic use on treatment effect.Results Of 37 individuals randomized (age =69610 years old; 57% men; eGFR=2468 ml/min per 1.73 m 2 ), 31 completed the study. Synbiotic therapy did not significantly reduce serum IS (22 mmol/L; 95% confidence interval [95% CI], 25 to 1 mmol/L) but did significantly reduce serum PCS (214 mmol/L; 95% CI, 227 to 22 mmol/L). Decreases in both PCS and IS concentrations were more pronounced in patients who did not receive antibiotics during the study (n=21; serum PCS, 225 mmol/L; 95% CI, 238 to 212 mmol/L; serum IS, 25 mmol/L; 95% CI, 28 to 21 mmol/L). Synbiotics also altered the stool microbiome, particularly with enrichment of Bifidobacterium and depletion of Ruminococcaceae. Except for an increase in albuminuria of 38 mg/24 h (P=0.03) in the synbiotic arm, no changes were observed in the other secondary outcomes. ConclusionIn patients with CKD, synbiotics did not significantly reduce serum IS but did decrease serum PCS and favorably modified the stool microbiome. Large-scale clinical trials are justified.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY)

Rossi

Johnson

Morrison

et al. 2016

Clinical Journal of the American Society of Nephrology

300

262

View full text Add to dashboard Cite

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“…However, we could not identify the p-aminobenzoic acid biosynthesis pathway in the genome (see Table S2 in the supplemental material), in line with previous results that F. prausnitzii M21/2 does not possess the complete folate biosynthesis pathway (40). Finally, F. prausnitzii secreted five previously unreported metabolites (see Table S2 in the supplemental material), namely, dihydroorotic acid, N-acetylglutamic acid, N-acetylaspartic acid, and 3-methy2-oxovaleric acid, as well as phenyllactic acid, which has already been shown to be produced by F. prausnitzii strains M21/2 and SL3/3 (41).…”

Section: Figmentioning

confidence: 65%

Functional Metabolic Map of Faecalibacterium prausnitzii, a Beneficial Human Gut Microbe

et al. 2014

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eThe human gut microbiota plays a central role in human well-being and disease. In this study, we present an integrated, iterative approach of computational modeling, in vitro experiments, metabolomics, and genomic analysis to accelerate the identification of metabolic capabilities for poorly characterized (anaerobic) microorganisms. We demonstrate this approach for the beneficial human gut microbe Faecalibacterium prausnitzii strain A2-165. We generated an automated draft reconstruction, which we curated against the limited biochemical data. This reconstruction modeling was used to develop in silico and in vitro a chemically defined medium (CDM), which was validated experimentally. Subsequent metabolomic analysis of the spent medium for growth on CDM was performed. We refined our metabolic reconstruction according to in vitro observed metabolite consumption and secretion and propose improvements to the current genome annotation of F. prausnitzii A2-165. We then used the reconstruction to systematically characterize its metabolic properties. Novel carbon source utilization capabilities and inabilities were predicted based on metabolic modeling and validated experimentally. This study resulted in a functional metabolic map of F. prausnitzii, which is available for further applications. The presented workflow can be readily extended to other poorly characterized and uncharacterized organisms to yield novel biochemical insights about the target organism.

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“…32 We predicted the production of aromatic amino acid-derived phenolic metabolites by gut microbes (Table S4), which is supported by experimental data and may have implications for vascular health. 23 In our model, cadaverine was only produced by the 5 Gammaproteobacteria (Table S4). This compound is elevated in the fecal extracts of ulcerative colitis (UC) patients.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the well-described microbial production of a variety of phenolic compounds from aromatic amino acids 23 was predicted (Table S4). Other modeled products derived from amino acids included sulfide and ammonia, which are toxic and disturb colonocyte energy metabolism.…”

Section: Luminal Secretionmentioning

confidence: 99%

Systematic prediction of health-relevant human-microbial co-metabolism through a computational framework

2015

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Keywords: human gut microbiome, in silico, metabolome, metabolic modelingThe gut microbiota is well known to affect host metabolic phenotypes. The systemic effects of the gut microbiota on host metabolism are generally evaluated via the comparison of germfree and conventional mice, which is impossible to perform for humans. Hence, it remains difficult to determine the impact of the gut microbiota on human metabolic phenotypes. We demonstrate that a constraint-based modeling framework that simulates "germfree" and "exgermfree" human individuals can partially fill this gap and allow for in silico predictions of systemic human-microbial cometabolism. To this end, we constructed the first constraint-based host-microbial community model, comprising the most comprehensive model of human metabolism and 11 manually curated, validated metabolic models of commensals, probiotics, pathogens, and opportunistic pathogens. We used this host-microbiota model to predict potential metabolic host-microbe interactions under 4 in silico dietary regimes. Our model predicts that gut microbes secrete numerous health-relevant metabolites into the lumen, thereby modulating the molecular composition of the body fluid metabolome. Our key results include the following: 1. Replacing a commensal community with pathogens caused a loss of important host metabolic functions. 2. The gut microbiota can produce important precursors of host hormone synthesis and thus serves as an endocrine organ. 3. The synthesis of important neurotransmitters is elevated in the presence of the gut microbiota. 4. Gut microbes contribute essential precursors for glutathione, taurine, and leukotrienes. This computational modeling framework provides novel insight into complex metabolic host-microbiota interactions and can serve as a powerful tool with which to generate novel, non-obvious hypotheses regarding host-microbe co-metabolism.

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Major phenylpropanoid‐derived metabolites in the human gut can arise from microbial fermentation of protein

Abstract: This study demonstrates that certain microbial species have the ability to ferment all three AAAs and that protein fermentation is the likely source of major phenylpropanoid-derived metabolites in the colon.

Cited by 320 publications

References 37 publications

Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY)

Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY)

Functional Metabolic Map of Faecalibacterium prausnitzii, a Beneficial Human Gut Microbe

Systematic prediction of health-relevant human-microbial co-metabolism through a computational framework

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