Impact of fiber supplementation on the butyrate synthesis of the intestinal microbiota and how it affects the risk for colorectal cancer

Project Leader: Dr. Sören Ocvirk

Team: Sabine Schmidt

Fig. 1 A. Colonic tumors (indicated by white arrow) in mice treated with AOM/DSS (bright-field images using magnification in stereo-microscopy). B. Histopathological scoring of inflammation-related parameters in the colon of mice treated with AOM/DSS (n=8) or untreated control mice (n=8). (© DIfE)

Epidemiological studies suggest that the consumption of fiber is associated with a reduced risk of colorectal cancer (CRC), but the specific mechanisms underlying the protective effects of fiber and its links with the human gut microbiota remain unclear. In the gut, the intestinal microbiota converts dietary fiber to short-chain fatty acids such as butyrate, propionate and acetate. Butyrate plays a particular role as it serves as an energy source for colonic epithelial cells, affects gene transcription and cell cycle regulation and exerts significant anti-neoplastic and anti-inflammatory effects in vitro.

CRC patients often exhibit an altered composition of the intestinal microbiota characterized by a reduced diversity and an impaired metabolic capacity to synthesize butyrate. Recent studies in gnotobiotic mice indicate that members of the intestinal microbiota and their capacity to synthesize butyrate affect colonic tumorigenesis. However, evidence in support of this notion in a clinically relevant setting is lacking, in particular whether high-fiber consumption can shift a CRC-associated intestinal microbiota in such a way that higher amounts of butyrate are produced, and thereby the risk of CRC in humans is reduced. To target this question, an intervention trial is conducted targeting a population with one of the world’s highest prevalence rates for CRC: Alaska Native people have a high CRC risk and this is associated with a diet low in fiber and rich in fat, correlating with corresponding alterations in the gut microbiota (Ocvirk et al., 2019). A dietary intervention study (fiber supplementation vs. control) is being conducted to achieve proof-of-concept for high-fiber-mediated CRC risk reduction. For that purpose, we aim to identify the beneficial effects of fiber on intestinal inflammation, proliferation, the gut microbiota and its metabolome.

To answer the overall question, namely whether the microbiota-dependent effects of a high-fiber diet also prevent or attenuate colonic tumorigenesis, we will use a CRC mouse model (Fig. 1 A+B) and determine the impact of fiber/butyrate on colonic tumor formation as clinically relevant endpoint and identify related microbe-host interactions. Germfree wildtype mice will be colonized with the gut microbiota collected from individuals with a high CRC risk (“humanized mice”) and fed a high fiber diet or a control diet. Chemical induction of tumorigenesis will then reveal the impact of microbiota-dependent butyrate synthesis on colonic tumor formation including markers associated with CRC. Using this dual approach, correlations from the clinical trial will be investigated in the experimental model to identify mechanistic links and their functional consequences (colonic tumorigenesis).