The pleiotropic effects of vitamin D promoting bowel health

Lock, Daniel (2016) The pleiotropic effects of vitamin D promoting bowel health. Doctoral thesis, University of East Anglia.

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Abstract

Vitamin D insufficiency is seasonally endemic in populations north of the 40th parallel, and epidemiological data show an association with colorectal cancer risk and prognosis. Molecular mechanisms that underpin the relationship are not well established. Vitamin D status is shown to be associated with age-related silencing of tumour suppressors in colonic stem cells via aberrant DNA methylation, suggesting that insufficiency contributes to transformation. In this text, vitamin D’s ability to promote bowel health via modification of DNA methylation patterns has been investigated.
Chronic inflammation drives tumourigenesis, and vitamin D is recognised to promote proper immune function. Data presented here confirm that vitamin D differentiates monocytes to a tissue-resident macrophage phenotype. D-mediated differentiation is associated with hypomethylation of the TNFα promoter and response to LPS. Thus, we suggest that vitamin D attenuates aberrant DNA methylation in colonic stem cells by promoting resolution of systemic inflammation.
Mucosal inflammation mediated by PGE2 promotes aberrant DNA methylation. Pericryptal myofibroblasts interact with colonic stem cells via their secretomes, which are a source of PGE2. Supernatants from primary intestinal myofibroblasts were characterised by LC/MS mass spectroscopy in response to vitamin D. Vitamin D attenuated TNFα-induced transcription of COX2 and PGE2 secretion. PGE2 induced hypermethylation of SOX17 and DKK1 in colonic organoids, and myofibroblast supernatants regulated DNA methyltransferase activity in case-matched organoids. Furthermore, vitamin D ameliorated established aberrant DNA methylation in organoids propagated from inflamed mucosa. Thus, we suggest that vitamin D attenuates mucosal inflammation, and the effects of PGE2 driving aberrant DNA methylation in colonic stem cells.
Vitamin D status predicts colorectal cancer survival. The effects of vitamin D sufficiency on colorectal cancer cell lines was investigated. Vitamin D-treated cells exhibit a modified methylome, reduced transcription of MAP kinases, reduced phosphorylation of ERK1 and 2, and inhibition of proliferation. Thus we suggest that vitamin D sufficiency improves colorectal cancer prognosis via modification of established aberrant DNA methylation. Taken together, data support vitamin D sufficiency promoting bowel health via attenuation of aberrant age-related DNA methylation in colonic stem cells.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Biological Sciences
Depositing User:	Nicola Veasy
Date Deposited:	23 Mar 2018 15:10
Last Modified:	23 Mar 2018 15:10
URI:	https://ueaeprints.uea.ac.uk/id/eprint/66585
DOI:

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