Effects of Intestinal Microbial–Elaborated Butyrate on Oncogenic Signaling Pathways

Abstract

The intestinal microbiota is well known to have multiple benefits on human health, including cancer prevention and treatment. The effects are partially mediated by microbiota-produced short chain fatty acids (SCFAs) such as butyrate, propionate and acetate. The anti-cancer effect of butyrate has been demonstrated in cancer cell cultures and animal models of cancer. Butyrate, as a signaling molecule, has effects on multiple signaling pathways. The most studied effect is its inhibition on histone deacetylase (HDAC), which leads to alterations of several important oncogenic signaling pathways such as JAK2/STAT3, VEGF. Butyrate can interfere with both mitochondrial apoptotic and extrinsic apoptotic pathways. In addition, butyrate also reduces gut inflammation by promoting T-regulatory cell differentiation with decreased activities of the NF-κB and STAT3 pathways. Through PKC and Wnt pathways, butyrate increases cancer cell differentiation. Furthermore, butyrate regulates oncogenic signaling molecules through microRNAs and methylation. Therefore, butyrate has the potential to be incorporated into cancer prevention and treatment regimens. In this review we summarize recent progress in butyrate research and discuss the future development of butyrate as an anti-cancer agent with emphasis on its effects on oncogenic signaling pathways. The low bioavailability of butyrate is a problem, which precludes clinical application. The disadvantage of butyrate for medicinal applications may be overcome by several approaches including nano-delivery, analogue development and combination use with other anti-cancer agents or phytochemicals.