Microbial Oncotarget: Bacterial-Produced Butyrate, Chemoprevention and Warburg Effect

The Human Microbiome Project is using next-generation sequencing and metagenomics to characterize microbial communities that inhabit our gastrointestinal tract and other body sites [1, 2]. Based on these efforts, it is becoming increasingly clear that commensal microbiota play a significant role in shaping human health and disease. Yet it will be necessary to identify important microbial metabolites and to understand how they regulate host biology. Butyrate is a short-chain fatty acid produced by bacterial fermentation of dietary fiber in the colon. Previous studies have demonstrated that colonocytes from germfree mice, which lack microbiota and butyrate, proliferate less and are in an energy-deprived state compared to colonocytes from conventionally-raised control mice [3, 4]. Cell proliferation and energy metabolism were restored when germfree mice were colonized with a butyrate-producing bacterium or when butyrate was provided directly through the diet. These results indicate that the microbial metabolite butyrate maintains colonocyte homeostasis. Intriguingly, although butyrate promotes proliferation of normal colonocytes, it has the opposite effect on cancerous cells where it inhibits cell proliferation and also induces apoptosis [5]. However, the mechanistic basis for butyrate having opposite effects on normal and cancerous cells is so poorly understood that it has been referred to the butyrate paradox. A recent study by Donohoe et al. now provides considerable mechanistic insight by demonstrating that a fundamental difference in energy metabolism between normal and cancerous colonocytes can explain the butyrate paradox [6]. Normal colonocytes utilize butyrate as their preferred energy source , which as a fatty acid undergoes oxidative metabolism in the mitochondria. This was shown to underlie the ability of butyrate to stimulate normal colonocyte proliferation (Fig. 1A). In contrast, due to the Warburg effect, cancerous colonocytes become addicted to glucose and undergo high levels of glycolysis with relatively little mitochondrial oxidative metabolism. As a result, butyrate was not metabolized to the same extent in cancerous colonocytes, accumulated in the nucleus, and functioned as a histone deacetylase (HDAC) inhibitor to regulate genes that inhibited cell proliferation and promoted apoptosis (Fig. 1B). An important aspect of this study was the ability to prevent the Warburg effect from occurring in cancerous colonocytes by performing RNAi to deplete an important mediator of the Warburg effect (LDHA) or by growing the cancer cells in low-glucose conditions (which forced them to use glutamine