Dataset Information

Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival.

ABSTRACT:

Purpose

Metabolomics is a discovery tool for novel associations of metabolites with disease. Here, we interrogated the metabolome of human breast tumors to describe metabolites whose accumulation affects tumor biology.

Experimental design

We applied large-scale metabolomics followed by absolute quantification and machine learning-based feature selection using LASSO to identify metabolites that show a robust association with tumor biology and disease outcome. Key observations were validated with the analysis of an independent dataset and cell culture experiments.

Results

LASSO-based feature selection revealed an association of tumor glycochenodeoxycholate levels with improved breast cancer survival, which was confirmed using a Cox proportional hazards model. Absolute quantification of four bile acids, including glycochenodeoxycholate and microbiome-derived deoxycholate, corroborated the accumulation of bile acids in breast tumors. Levels of glycochenodeoxycholate and other bile acids showed an inverse association with the proliferation score in tumors and the expression of cell-cycle and G₂-M checkpoint genes, which was corroborated with cell culture experiments. Moreover, tumor levels of these bile acids markedly correlated with metabolites in the steroid metabolism pathway and increased expression of key genes in this pathway, suggesting that bile acids may interfere with hormonal pathways in the breast. Finally, a proteome analysis identified the complement and coagulation cascade as being upregulated in glycochenodeoxycholate-high tumors.

Conclusions

We describe the unexpected accumulation of liver- and microbiome-derived bile acids in breast tumors. Tumors with increased bile acids show decreased proliferation, thus fall into a good prognosis category, and exhibit significant changes in steroid metabolism.

SUBMITTER: Tang W

PROVIDER: S-EPMC6774910 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival.

Tang Wei W Putluri Vasanta V Ambati Chandrashekar R CR Dorsey Tiffany H TH Putluri Nagireddy N Ambs Stefan S

Clinical cancer research : an official journal of the American Association for Cancer Research 20190711 19

<h4>Purpose</h4>Metabolomics is a discovery tool for novel associations of metabolites with disease. Here, we interrogated the metabolome of human breast tumors to describe metabolites whose accumulation affects tumor biology.<h4>Experimental design</h4>We applied large-scale metabolomics followed by absolute quantification and machine learning-based feature selection using LASSO to identify metabolites that show a robust association with tumor biology and disease outcome. Key observations were ...[more]

PMID: 31296531

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Project description:Diarrhea is one of the most common infirmities affecting international travelers, occurring in 20 to 50% of persons from industrialized countries visiting developing regions. Enterotoxigenic Escherichia coli (ETEC) is the most common causative agent and is isolated from approximately half of the cases of traveler's diarrhea. Rifaximin, a largely water-insoluble, nonabsorbable (<0.4%) antibiotic that inhibits bacterial RNA synthesis, is approved for use for the treatment of traveler's diarrhea caused by diarrheagenic E. coli. However, the drug has minimal effect on the bacterial flora or the infecting E. coli strain in the aqueous environment of the colon. The purpose of the present study was to evaluate the antimicrobial effect and bioavailability of rifaximin in aqueous solution in the presence and absence of physiologic concentrations of bile acids. The methods used included growth measurement of ETEC (strain H10407), rifaximin solubility measurements, total bacterial protein determination, and assessment of the functional activity of rifaximin by monitoring inhibition of bacterial beta-galactosidase expression. Solubility studies showed rifaximin to be 70- to 120-fold more soluble in bile acids (approximately 30% in 4 mM bile acids) than in aqueous solution. Addition of both purified bile acids and human bile to rifaximin at subinhibitory and inhibitory concentrations significantly improved the drug's anti-ETEC effect by 71% and 73%, respectively, after 4 h. This observation was confirmed by showing a decrease in the overall amount of total bacterial protein expressed during incubation of rifaximin plus bile acids. Rifaximin-treated samples containing bile acids inhibited the expression of ETEC beta-galactosidase at a higher magnitude than samples that did not contain bile acids. The study provides data showing that bile acids solubilize rifaximin on a dose-response basis, increasing the drug's bioavailability and antimicrobial effect. These observations suggest that rifaximin may be more effective in the treatment of infections in the small intestine, due to the higher concentration of bile in this region of the gastrointestinal tract than in the colon. The water insolubility of rifaximin is the likely explanation for the drug's minimal effects on colonic flora and fecal pathogens, despite in vitro susceptibility.

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Dataset Information

Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival.

Purpose

Experimental design

Results

Conclusions

Publications

Liver- and Microbiome-derived Bile Acids Accumulate in Human Breast Tumors and Inhibit Growth and Improve Patient Survival.

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