Figure 4.

A model depicting the mechanism of the fiber-microbiota-butyrate axis in tumor suppression and evidence to support the relevance of this model to human cancer prevention. (A- D) Relevance of the model to human cancer. (A) Butyrate levels in macroscopically normal colonic tissue and colorectal adenocarcinomas from humans based on LC-MS measurements. Each histogram shows the mean ± SE from 11 biological replicates of each with significant differences indicated (*, p < 0.05). (B) A scatter plot of the samples from panel A. The samples were obtained from the University of North Carolina at Chapel Hill (white, left) and Colorado State University (black, right) tissue procurement facilities. (C) Western blot analysis of H3ac and total H3 levels in macroscopically normal colonic tissue and colorectal adenocarcinomas from 2 pairs of human samples. (D) Quantification of western blot data with H3ac levels normalized to total H3 in macroscopically normal colonic tissue and colorectal adenocarcinomas. Each histogram shows the mean ± SE from 5 biological replicates of each with significant differences indicated (*, p < 0.05). (E) Final working model.Dietary fiber is fermented by microbiota into butyrate, which is a short-chain fatty acid that is abundant (mM levels) in the lumen of the colon. In normal colonocytes, butyrate undergoes oxidative metabolism in the mitochondria to promote homeostasis. In the cancerous colonocyte, due to the Warburg effect, butyrate is metabolized to a lesser extent and accumulates in the nucleus where it functions as an HDAC inhibitor to induce apoptosis and inhibit cell proliferation. The importance of the Warburg effect in this model draws upon previous work (22). In addition to these cell-autonomous effects within the cancer cell, some of the tumor suppression could be mediated by butyrate promoting Treg cell differentiation and having anti-inflammatory effects in the presence of a complex gut microbiota.