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.
Highlights
Biological understanding of the complex and dynamic homeostatic mechanisms of the intestinal mucosa has recently become even more intricate, as investigators begin to consider the role of the microbiome in health and disease
We focus on the microbial metabolite butyrate, which represents one of the most extensively researched molecular mediators in the host–microbiome relationship
Since regulation of intestinal proliferation is relevant to the management of malabsorptive and inflammatory intestinal diseases, which have been associated with microbial dysbiosis, further investigation of butyrate’s role in the small intestinal epithelium is warranted [57]
Summary
Biological understanding of the complex and dynamic homeostatic mechanisms of the intestinal mucosa has recently become even more intricate, as investigators begin to consider the role of the microbiome in health and disease. We focus on the microbial metabolite butyrate, which represents one of the most extensively researched molecular mediators in the host–microbiome relationship. Studies to date suggest that butyrate is a chameleon in its ability to exert distinct, but sometimes contradictory effects on epithelial cells under different conditions. Evolving knowledge of the intestinal crypt at a molecular level has permitted a more detailed and discriminating appreciation for these incongruous experimental results. Understanding how butyrate interacts differently with differentiated enterocytes as opposed to undifferentiated cells in the epithelial crypt is of value for scientists and clinicians interested in intestinal neoplasms, inflammatory bowel disease, and malabsorptive states
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