DNA Methylation in the Rectal Mucosa Is Associated with Crypt Proliferation and Fecal Short-Chain Fatty Acids

Daniel Worthley, Vicki Whitehall, Richard Le Leu, Natsumi Irahara, R Buttenshaw, Kylie-Ann Mallitt, S Greco, I Ramsnes, Jean Winter, Ying Hu, Shuji Ogino, Graeme Young, Barbara Leggett

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    Abstract

    Background: DNA methylation varies throughout the normal colorectal mucosa and DNA methylation in normal appearing mucosa is associated with serrated and adenomatous neoplasia elsewhere within the colorectum. Aims: The purpose of this study was to measure luminal chemistry, rectal proliferation and mucosal DNA methylation and thus determine whether regional and pathological patterns of DNA methylation could be explained by luminal and epithelial factors. Methods: Twenty healthy subjects had normal rectal mucosal biopsies and a 24-h fecal collection. Rectal biopsies were analyzed for epithelial proliferation (Ki67 immunohistochemistry) and DNA methylation at 17 different markers, including "type A" markers (ESR1, GATA5, HIC1, HPP1, SFRP1), "type C" markers (MGMT, MLH1, CDKN2A, MINT1, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. Fecal analysis included short-chain fatty acids (SCFA), pH and ammonia. Mean "type A" and CIMP panel methylation Z-scores were calculated. Results: Rectal proliferation was significantly correlated with methylation at ESR1 (ρ = 0.81, P = 0.003) and GATA5 (ρ = 0.78, P = 0.012). LINE-1 methylation was 71.7 vs. 74.1%, in patients with "low" and "high" fecal total SCFA concentration (defined by the median value), respectively (P = 0.0019). On multivariate linear regression "type A" methylation was independently associated with rectal proliferation (P = 0.001). LINE-1 methylation was directly associated with rectal proliferation (P = 0.038) and total fecal SCFA concentration (P = 0.002), and inversely associated with fecal NH3 concentrations (P = 0.003). Conclusions: DNA methylation in normal rectal mucosa is associated with crypt proliferation and fecal SCFA concentration. These associations may help to explain regional differences in DNA methylation as well as providing a possible link between the colorectal lumen and carcinogenesis.

    Original languageEnglish
    Pages (from-to)387-396
    Number of pages10
    JournalDigestive Diseases and Sciences
    Volume56
    Issue number(2)
    DOIs
    Publication statusPublished - Feb 2011

    Keywords

    • Carcinogenesis
    • Colorectal cancer
    • DNA methylation
    • Epigenetics

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  • Cite this

    Worthley, D., Whitehall, V., Le Leu, R., Irahara, N., Buttenshaw, R., Mallitt, K-A., Greco, S., Ramsnes, I., Winter, J., Hu, Y., Ogino, S., Young, G., & Leggett, B. (2011). DNA Methylation in the Rectal Mucosa Is Associated with Crypt Proliferation and Fecal Short-Chain Fatty Acids. Digestive Diseases and Sciences, 56((2)), 387-396. https://doi.org/10.1007/s10620-010-1312-4