Butyrate and the Intestinal Epithelium: Modulation of Proliferation and Inflammation in Homeostasis and Disease

Abstract

The microbial metabolite butyrate serves as a link between the intestinal microbiome and epithelium. The monocarboxylate transporters MCT1 and SMCT1 are the predominant means of butyrate transport from the intestinal lumen to epithelial cytoplasm, where the molecule undergoes rapid β-oxidation to generate cellular fuel. However, not all epithelial cells metabolize butyrate equally. Undifferentiated colonocytes, including neoplastic cells and intestinal stem cells at the epithelial crypt base preferentially utilize glucose over butyrate for cellular fuel. This divergent metabolic conditioning is central to the phenomenon known as "butyrate paradox", in which butyrate induces contradictory effects on epithelial proliferation in undifferentiated and differentiated colonocytes. There is evidence that accumulation of butyrate in epithelial cells results in histone modification and altered transcriptional activation that halts cell cycle progression. This manifests in the apparent protective effect of butyrate against colonic neoplasia. A corollary to this process is butyrate-induced inhibition of intestinal stem cells. Yet, emerging research has illustrated that the evolution of the crypt, along with butyrate-producing bacteria in the intestine, serve to protect crypt base stem cells from butyrate's anti-proliferative effects. Butyrate also regulates epithelial inflammation and tolerance to antigens, through production of anti-inflammatory cytokines and induction of tolerogenic dendritic cells. The role of butyrate in the pathogenesis and treatment of intestinal neoplasia, inflammatory bowel disease and malabsorptive states is evolving, and holds promise for the potential translation of butyrate's cellular function into clinical therapies.

Keywords: butyrate; intestinal epithelium; microbiome; short chain fatty acid.

Figure 1

Distinct metabolic pathways for cellular energy in differentiated and undifferentiated colonocytes are responsible for ‘the butyrate paradox’. Microbially-derived butyrate in the colonic lumen is transported intracellularly by SMCT1 and MCT1, among other membrane-bound transport proteins. The fate of cytoplasmic butyrate depends on the cell’s state of differentiation. (1) In differentiated colonocytes, butyrate is rapidly oxidized and utilized for cellular energy production. In undifferentiated colonocytes, such as neoplastic cells, cellular fuel is preferentially derived from glycolytic pathways, leading to intracellular butyrate accumulation. (2) Butyrate is an HDAC inhibitor, which results in hyperacetylation of histone H3 with consequent chromatin relaxation and expression of genes otherwise silenced by HDAC activity. (3) Specifically, butyrate-induced histone modification is associated with transcriptional activation of genes involved in cell cycle inhibition and apoptosis.

Figure 2

The epithelial crypt in mice facilitates production of a butyrate gradient which is necessary to maintain the proliferative potential of intestinal stem cells. Butyrate is an abundant energy source for surface level epithelial cells in the mammalian intestine. Rapid intracellular transport and oxidation by these cells produces a butyrate gradient, with significant depletion of butyrate levels at the crypt base. Disrupted crypt morphology, as in the case of mucosal injury, allows butyrate levels to rise at the crypt base, where it induces antiproliferative activity in intestinal stem cells, mediated by the transcription factor Foxo3.