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Gut microbiota carcinogen metabolism causes distal tissue tumours

ABSTRACT:

Exposure to environmental pollutants and human microbiome composition are important predisposition factors for tumour development. Similar to drug molecules, pollutants are typically metabolised in the body, which can change their carcinogenic potential and impact tissue distribution through altered toxicokinetics. Although recent studies demonstrated that human-associated microbes can chemically convert a wide range of xenobiotics and influence the profile and tissue exposure of resulting metabolites, the effect of microbial biotransformation on chemical-induced tumour development remains unclear. Here we show that the depletion of the gut microbiota dramatically reduces the development and severity of nitrosamine-induced urinary bladder cancer in mice, which affects the toxicokinetics of nitrosamines. We causally linked this carcinogen biotransformation to specific gut bacterial isolates in vitro and in vivo using individualized bacterial culture collections and gnotobiotic mouse models, respectively. We tested gut communities from different human donors to demonstrate that microbial carcinogen metabolism varies between individuals and we showed that this metabolic activity applies to structurally related nitrosamine-carcinogens. Altogether, these results suggest gut microbiota carcinogen metabolism as a contributing factor for chemical-induced carcinogenesis, which could open avenues to target the microbiome for improved predisposition risk assessment and prevention of cancer.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

SUBMITTER: Boyao Zhang

PROVIDER: MTBLS3581 | MetaboLights | 2024-06-05

REPOSITORIES: MetaboLights

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Project description:On going efforts are directed at understanding the mutualism between the gut microbiota and the host in breast-fed versus formula-fed infants. Due to the lack of tissue biopsies, no investigators have performed a global transcriptional (gene expression) analysis of the developing human intestine in healthy infants. As a result, the crosstalk between the microbiome and the host transcriptome in the developing mucosal-commensal environment has not been determined. In this study, we examined the host intestinal mRNA gene expression and microbial DNA profiles in full term 3 month-old infants exclusively formula fed (FF) (n=6) or breast fed (BF) (n=6) from birth to 3 months. Host mRNA microarray measurements were performed using isolated intact sloughed epithelial cells in stool samples collected at 3 months. Microbial composition from the same stool samples was assessed by metagenomic pyrosequencing. Both the host mRNA expression and bacterial microbiome phylogenetic profiles provided strong feature sets that clearly classified the two groups of babies (FF and BF). To determine the relationship between host epithelial cell gene expression and the bacterial colony profiles, the host transcriptome and functionally profiled microbiome data were analyzed in a multivariate manner. From a functional perspective, analysis of the gut microbiota's metagenome revealed that characteristics associated with virulence differed between the FF and BF babies. Using canonical correlation analysis, evidence of multivariate structure relating eleven host immunity / mucosal defense-related genes and microbiome virulence characteristics was observed. These results, for the first time, provide insight into the integrated responses of the host and microbiome to dietary substrates in the early neonatal period. Our data suggest that systems biology and computational modeling approaches that integrate “-omic” information from the host and the microbiome can identify important mechanistic pathways of intestinal development affecting the gut microbiome in the first few months of life. KEYWORDS: infant, breast-feeding, infant formula, exfoliated cells, transcriptome, metagenome, multivariate analysis, canonical correlation analysis 12 samples, 2 groups

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Gut microbiota carcinogen metabolism causes distal tissue tumours

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