The deleterious metabolic and genotoxic effects of the bacterial metabolite p-cresol on colonic epithelial cells

Andriamihaja, Mireille; Lan, Annaïg; Beaumont, Martín; Audebert, Marc; Wong, Ximena; Yamada, Kana; Yin, Yulong; Tomé, Daniel; Carrasco‐Pozo, Catalina; Gotteland, Martín; Kong, Xiangfeng; Blachier, François

doi:10.1016/j.freeradbiomed.2015.04.004

Cited by 125 publications

(110 citation statements)

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“…In contrast, p -cresol and indole did not significantly decrease Tnf mRNA levels. Because p -cresol has been previously shown to be toxic for intestinal epithelial cells (24) while indole has beneficial effects on gut barrier function (25, 26), we decided to further explore the hepatic effects of this potentially protective bacterial metabolite derived from tryptophan. In order to evaluate whether the effects of indole were dose dependent, PCLS exposed or not to LPS were treated with 10 to 1000 µM indole.…”

Section: Resultsmentioning

confidence: 99%

The gut microbiota metabolite indole alleviates liver inflammation in mice

et al. 2018

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The gut microbiota regulates key hepatic functions, notably through the production of bacterial metabolites that are transported via the portal circulation. We evaluated the effects of metabolites produced by the gut microbiota from aromatic amino acids (phenylacetate, benzoate, p-cresol, and indole) on liver inflammation induced by bacterial endotoxin. Precision-cut liver slices prepared from control mice, Kupffer cell (KC)-depleted mice, and obese mice (ob/ob) were treated with or without LPS and bacterial metabolites. We observed beneficial effects of indole that dose-dependently reduced the LPS-induced up-regulation of proinflammatory mediators at both mRNA and protein levels in precision-cut liver slices prepared from control or ob/ob mice. KC depletion partly prevented the antiinflammatory effects of indole, notably through a reduction of nucleotide-binding domain and leucine-rich repeat containing (NLR) family pyrin domain-containing 3 (NLRP3) pathway activation. In vivo, the oral administration of indole before an LPS injection reduced the expression of key proteins of the NF-κB pathway and downstream proinflammatory gene up-regulation. Indole also prevented LPS-induced alterations of cholesterol metabolism through a transcriptional regulation associated with increased 4β-hydroxycholesterol hepatic levels. In summary, indole appears as a bacterial metabolite produced from tryptophan that is able to counteract the detrimental effects of LPS in the liver. Indole could be a new target to develop innovative strategies to decrease hepatic inflammation.—Beaumont, M., Neyrinck, A. M., Olivares, M., Rodriguez, J., de Rocca Serra, A., Roumain, M., Bindels, L. B., Cani, P. D., Evenepoel, P., Muccioli, G. G., Demoulin, J.-B., Delzenne, N. M. The gut microbiota metabolite indole alleviates liver inflammation in mice.

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Section: Resultsmentioning

confidence: 99%

The gut microbiota metabolite indole alleviates liver inflammation in mice

et al. 2018

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“…Indole is the precursor of indoxyl sulfate, which has been linked with hypertension and cardiovascular disease in people with chronic kidney disease 47. Likewise, p-cresol, the precursor of p-cresol sulfate, has been shown to act as an inhibitor of colonocyte oxygen consumption and as a genotoxic agent in vitro 48. Production rates of these potentially toxic compounds are found to be markedly lower in vegetarians than in people consuming an unrestricted diet 49.…”

Section: Discussionmentioning

confidence: 99%

Effects of dietary fat on gut microbiota and faecal metabolites, and their relationship with cardiometabolic risk factors: a 6-month randomised controlled-feeding trial

Wan

Wang²,

Yuan

et al. 2019

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ObjectiveTo investigate whether diets differing in fat content alter the gut microbiota and faecal metabolomic profiles, and to determine their relationship with cardiometabolic risk factors in healthy adults whose diet is in a transition from a traditional low-fat diet to a diet high in fat and reduced in carbohydrate.MethodsIn a 6-month randomised controlled-feeding trial, 217 healthy young adults (aged 18–35 years; body mass index <28 kg/m2; 52% women) who completed the whole trial were included. All the foods were provided during the intervention period. The three isocaloric diets were: a lower-fat diet (fat 20% energy), a moderate-fat diet (fat 30% energy) and a higher-fat diet (fat 40% energy). The effects of the dietary interventions on the gut microbiota, faecal metabolomics and plasma inflammatory factors were investigated.ResultsThe lower-fat diet was associated with increased α-diversity assessed by the Shannon index (p=0.03), increased abundance of Blautia (p=0.007) and Faecalibacterium (p=0.04), whereas the higher-fat diet was associated with increased Alistipes (p=0.04), Bacteroides (p<0.001) and decreased Faecalibacterium (p=0.04). The concentration of total short-chain fatty acids was significantly decreased in the higher-fat diet group in comparison with the other groups (p<0.001). The cometabolites p-cresol and indole, known to be associated with host metabolic disorders, were decreased in the lower-fat diet group. In addition, the higher-fat diet was associated with faecal enrichment in arachidonic acid and the lipopolysaccharide biosynthesis pathway as well as elevated plasma proinflammatory factors after the intervention.ConclusionHigher-fat consumption by healthy young adults whose diet is in a state of nutrition transition appeared to be associated with unfavourable changes in gut microbiota, faecal metabolomic profiles and plasma proinﬂammatory factors, which might confer adverse consequences for long-term health outcomes.Trial registration number NCT02355795; Results.

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“…Moreover, this metabolite was capable of supporting colonic tumor growth through stimulation of cell bioenergetics and cell proliferation [36]. Another bacterial metabolite, p-cresol, which is produced from L-tyrosine by the intestinal microbiota and which is present in the feces at low millimolar concentration, partially inhibits oxygen consumption in colonocytes [9]. Ammonia (considered as the sum of NH 4 + and NH 3 ), which is produced by the bacterial microbiota from amino acid deamination and hydrolysis of urea by the bacterial ureases, is present at millimolar concentrations in the colonic luminal content [20].…”

Section: Bacterial Metabolites and Colonic Epithelium Energy Metabolismmentioning

confidence: 99%

“…By using the sensitive H2AX genotoxicity test, p-cresol has been found to alter dose-dependently the DNA integrity in colonocytes without cytotoxic effects [9]. Phenol, which is produced by the intestinal microbiota from L-tyrosine, can react with nitrite, leading to the formation of the mutagenic compound p-diazoquinone [60].…”

Section: Bacterial Metabolites and Colonic Epithelial Cell Dna Integritymentioning

confidence: 99%

“…These gases, especially, can be beneficial or deleterious for the intestinal epithelium in a concentrationdependent way [8,9]. High-protein diets increase the fecal concentrations of amino acid-derived bacterial metabolites, such as branched-chain fatty acids, phenolic and indolic compounds, hydrogen sulfide (H 2 S), and ammonia, among others [10].…”

Section: Introductionmentioning

confidence: 99%

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Colon epithelial cells luminal environment and physiopathological consequences: impact of nutrition and exercise

Blachier

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et al. 2018

Nutrire

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The colonic epithelial cells represent a border between the colon luminal content, containing notably bacteria and a complex mixture of compounds, and the "milieu interieur" as defined by the French physiologist Claude Bernard. The physical-chemical composition of the luminal content, including luminal pH and bacterial metabolite, that obviously is not constant, is modified for instance according to the diet. Data obtained recently indicate that physical exercise may also modify the colonic luminal content. Evidence has indicated that modification of the luminal content characteristics has, indeed, consequences for the colonic epithelial cells, notably in terms of energy metabolism and DNA integrity. Although such alterations impact presumably the homeostatic process of the colonic epithelium renewal and the epithelial barrier function, their contribution to pathological processes like mucosal inflammation, pre-neoplasia, and neoplasia remains partly elusive. Open questions remain regarding the individual and collective roles of luminal changes, particularly in a long-term perspective. These questions are related particularly to the capacity of the bacterial metabolites to cross the mucus layer before entering the colonocytes, to the concentrations of metabolites in proximity of the colonic crypt stem cells, and to the capacity of colonocytes to detoxicate deleterious compounds, to take up and utilize beneficial compounds.

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The deleterious metabolic and genotoxic effects of the bacterial metabolite p-cresol on colonic epithelial cells

Cited by 125 publications

References 51 publications

The gut microbiota metabolite indole alleviates liver inflammation in mice

The gut microbiota metabolite indole alleviates liver inflammation in mice

Effects of dietary fat on gut microbiota and faecal metabolites, and their relationship with cardiometabolic risk factors: a 6-month randomised controlled-feeding trial

Colon epithelial cells luminal environment and physiopathological consequences: impact of nutrition and exercise

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