Gut microbiota-associated compounds increase lethal prostate cancer risk.

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147 Background: Gut-microbiota-mediated metabolism of trimethylamine-associated nutrients and amino acids has been linked to altered cholesterol metabolism and endothelial inflammation. However, the association between these compounds and lethal prostate cancer (PCa) remains unknown. Methods: A nested case-control study was performed using samples from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial to evaluate the association between baseline serum levels of target metabolites (choline, carnitine, betaine, γ-butyrobetaine, crotonobetaine, trimethylamine N-oxide, phenylacetylglutamine, hippuric acid, and p-cresol sulfate) and lethal PCa risk. Lethal cases were randomly matched to controls at a 1:3 ratio on the basis of age, race, and enrollment date. Multivariable logistic regression, conditioned on case status and adjusted for PSA and BMI, was performed to assess the association between analyte quartile (Q) with lethal PCa. Trend of increasing odd ratios (OR) was evaluated using the Cochran-Armitage test. Results: 173 lethal PCa cases and 519 controls were analyzed. Relative to those in Q1, cases with baseline levels of choline and betaine above the median exhibited increased odds of developing lethal PCa after adjusting for BMI and PSA (Table). Lethal PCa risk increased across quartiles of choline in a dose-dependent fashion ( P-trend: 0.005), but not for betaine (P-trend: 0.08). Higher serum levels of other trimethylamine-associated compounds including γ-butyrobetaine, crotonobetaine, trimethylamine N-oxide were not consistently associated with PCa mortality. Baseline serum levels of phenylacetylglutamine, a gut-microbiota metabolite of phenylalanine, were associated with incident lethal PCa, with risk increasing across quantiles (P-trend: 0.003). Elevations in hippuric acid and p-cresol sulfate levels were not consistently associated with greater lethal PCa risk. Conclusions: Serum levels choline, betaine, and phenylacetylglutamine are associated with PCa mortality, underscoring the potential role of gut-microbiota-mediated metabolism in the biology of lethal PCa. Clinical trial information: NCT00002540. [Table: see text]