Molecular analysis of the effect of short-chain fatty acids on intestinal cell proliferation

Short-chain fatty acids (SCFA), particularly butyrate, were shown to regulate cell proliferation in vitro and in vivo. Indeed, butyrate is the major fuel for colonic epithelial cells, and it can influence cell proliferation through the release of growth factors or gastrointestinal peptides such as gastrin, or through modulation of mucosal blood flow. Lastly, SCFA can act directly on genes regulating cell proliferation, and butyrate is the main SCFA to display such an effect. Butyrate inhibits histone deacetylase, which will allow histone hyperacetylation. Such hyperacetylation leads to transcription of several genes, including p21/Cip1. Moreover, it will allow cyclin D3 hyper-expression by inhibiting its degradation. The induction of the cyclin-dependent kinase inhibitory protein p21/Cip1 accounts for cell arrest in the G1 phase of the cell cycle. However, in the absence of p21 other mechanisms are initiated, leading to inhibition of cell proliferation.