Barrett's metaplasia: molecular mechanisms and nutritional influences

Barrett's metaplasia is discussed in the context of a general theory for the formation of metaplasias based on developmental biology. The phenotype of a particular tissue type becomes established during embryonic development by the expression of a specific set of transcription factors. If this combination becomes altered, then the tissue type can be altered. Such events may occur by mutation or by environmental effects on gene expression, normally within the stem cell population of the tissue. A macroscopic patch of metaplastic tissue will arise only if the new gene activity state is self-sustaining in the absence of its original causes, and if the new tissue type can outgrow the parent tissue type. An important candidate gene for the causation of Barrett's metaplasia is Cdx2 (Caudal-type homeobox 2). In normal development, this is expressed in the future intestine, but not the future foregut. Mouse knockout studies have shown that it is needed for intestinal development, and that its loss from adult intestine can lead to squamous transformations. It is also expressed in Barrett's metaplasia and can be activated in oesophageal cell cultures by treatment with bile acids. We have investigated the ability of Cdx2 to bring about intestinal transformations in oesophageal epithelium. Our results show that Cdx2 can activate a programme of intestinal gene expression when overexpressed in HET-1A cells, or in fetal epithelium, but not in the adult epithelium. This suggests that Cdx2, although necessary for formation of intestinal tissue, is not sufficient to provoke Barrett's metaplasia in adult life and that overexpression of additional transcription factors is necessary. In terms of diet and nutrition, there is a known association of Barrett's metaplasia with obesity. This may work through an increased risk of gastro-oesophageal reflux. Acid and bile are known to activate Cdx2 expression in oesophageal cells. It may also increase circulating levels of TNFalpha (tumour necrosis factor alpha), which activates Cdx2. In addition, there may be effects of diet on the composition of the bile.