Molecular roles of short chain fatty acids in colorectal cancer

Colorectal cancer is the third most common malignancy in the western world in respect to incidence and mortality rates. In Australia, colorectal cancer was the second most common registrable cancer in 2001 with 12,844 new cases reported and since 1991 both male and female incidence rates have increased each year by an average of 0.3% and 0.1% respectively. Despite advances in both surgical resection technique, and adjuvant and neo-adjuvant chemo-radiotherapy, unless the cancer is detected at a very early stage, long term and disease-free survival rates are less than 100%. Prevention is the key to achieving long term survival.\ud \ud Low fibre diet is considered to be one of many possible causes of colorectal cancer. It has been suggested that high dietary fibre intake reduces the risk of colorectal cancer by increasing stool bulk and reducing transit time, thus minimising exposure of colorectal mucosa to potential carcinogens, while also altering microbial composition and reducing intraluminal pressure. With advances in molecular biology, the focus of research has shifted from the protective effects of a high fibre diet to the study of short chain fatty acids.\ud \ud Butyrate acid has been implicated as potentially the most significant short chain fatty acid in protecting the colorectal mucosa against colorectal cancer. Butyrate is a product of the bacterial fermentation of undigested dietary fibre in the lumen of the colon and rectum. It is the ligand to the short chain fatty acid receptors GPR43 and GPR41. At the cellular level, butyrate induces apoptosis by inhibition of histone deacetylase activity and induction of p21ᵂᵃᶠ¹/ᶜⁱᵖ¹ expression.\ud \ud The study aims to assess by immunohistochemistry and real-time RT-PCR, the expression of GPR43 and GPR41 in human colorectal mucosa and tumours, and the effects of butyrate on GPR43 and GPR41 in colorectal cancer cell lines. Immunohistochemical staining of paired, same subject normal colorectal mucosa and tumours suggested a significant down regulation of GPR43 and GPR41 in tumours. Butyrate reduced the GPR43 expression across three concentrations in HT-29. In summary, while more research is needed, GPR43 and GPR41 may play a role in mediating the apoptotic effects of butyrate