Protective Effects of Butyric Acid in Colon Cancer

Abstract

A great deal of evidence indicates that cancer is the result of a reciprocal interaction between genetic susceptibility and environmental factors. Apparently, only 5% of all cancers is linked to genetic, inheritable alterations, while the remainder is associated with environmental conditions that act in concert with individual susceptibility.¹ In this context, dietary habit covers a fundamental role. Following the recent publication from the American Institute for Cancer Research² (AICR), a “correct” diet could decrease the cancer rate by as much as 20%. For some specific cancers, the effect is even more dramatic: from 33 to 50% of breast cancer can be prevented through diet, and as much as 33% of lung cancer and 75% of colorectal cancers are prevented by correct diet choices. Colorectal cancer represents one of the well studied cancers at the molecular level: here, the steps of tumor progression show in vivo an accumulation of morphological changes that result in vivo in mutations in specific genes. Loss of function of the APC tumor suppressor gene causes hyperproliferation of normal epithelium and early adenoma; the subsequent activation of k-ras oncogene and inactivation of DCC and p53 tumor suppressor genes are associated with late adenoma and carcinoma.^3,4 Colorectal cancers are very common causing over 50,000 deaths per year in the United States, 11% of total deaths from cancer. They result from the combined effect of inherited factors and stochastic genetic mutations, partially related to environmental conditions such as diet composition.⁵ Considerable epidemiological data support the hypothesis that a diet rich in fiber is associated with a decreased risk of intestinal cancers.^6,7 Although this views appears simplistic and remains controversial for many aspects, it is currently generally accepted. In fact, one of the fifteen recommendations of the AICR advises to “eat a variety of vegetables and fruits all year round”.² Several mechanisms have been considered in order to explain the protective effect of dietary fiber (DF). They include dilution of luminal carcinogen concentration, fiber-associated changes in colonic transit that decrease colonic enterocyte exposure to luminal carcinogens, interactions with intestinal contents, production of tissue factors by stimulation of colonic mucosa, role of bile acids and direct antineoplastic activity by DF components.^8–13 A different mechanism by which fiber may modulate carcinogenesis is related to the production of butyric acid (BA), a component of the short-chain fatty acids (SFCA) obtained by degradation of poorly fermented fiber by colonic microflora. This review will focus on the molecular aspects that affect the activity of BA on in vivo and in vivo models.