Folate, methylation and cancer: more than just a gut feeling

Samenvatting

Folate and other B-vitamins are essential for human life. Human cells are not able to produce folate and are therefore depending on other sources such as diet. Notably, several bacteria in the human large intestine also synthesize folate. The large intestine therefore represents a substantial local folate depot.

A folate deficiency has been associated with an increased risk of cancer of the large intestine (colorectal cancer). An excessive intake of synthetic folate (folic acid), however, may also increase colorectal cancer risk. In the light of cancer prevention, further insights into causal mechanisms that link folate to cancer risk are urgently needed. Folate mediates a biochemical process called one-carbon metabolism and provides methyl groups for DNA methylation. DNA methylation determines gene activity. Several studies, including my own research, showed that intake of folate is associated with DNA methylation of cancer-related genes.

So far, little attention has been paid to intestinal folate depots in relation to disease mechanisms. This raises the question whether bacterial biosynthesis of folate is involved in regulation of DNA methylation. I aim to better understand the relation between folate-producing bacteria, folate levels and DNA methylation in the large intestine.

I will combine experimental animal and observational human studies to fully characterize the role of intestinal folate depots in relation to DNA methylation. I will use pioneering strategies, such as rectal infusion of folate and colonization with folate-producing bacteria, to study effects on intestinal DNA methylation in well-controlled mice experiments. Subsequently, I will quantify intestinal folate depots and study the relation with DNA methylation and folate-biosynthesis capacity in the human large intestine. The proposed research sheds further light on the hypothesis that intestinal folate depots are important for regulation of DNA methylation. This information enhances a better understanding of potential disease mechanisms in the large intestine.

Kenmerken

Projectnummer

016.Veni.188.082

Hoofdaanvrager

Dr. ing. D.E.G. Kok

Verbonden aan

Wageningen University & Research, Division of Human Nutrition

Looptijd

01/12/2017 tot 01/09/2021