Towards understanding the role of the microbiome in cancer

Globally, colorectal cancer (CRC) is the third leading cause of cancer-related death. It has been suggested that the gut microbiome may play an important role in CRC initiation and progression, as there is evidence of a pathological imbalance in the gut microbiome in CRC patients. In addition to this, several studies have identified specific bacterial species, which are highly enriched in stool and tissue samples from CRC patients. As diet can influence microbiome composition, diet-microbiome interaction might play an important role in the development of CRC.

Here, we study tumor initiation and progression, host-microbiome interaction and the influence of diet on these processes, more specifically the impact of high-fat low carb diet (ketogenic diet).

Using a low-carb high-fat diet, we evaluate the influence of diet on the complex interplay between microbiome, metabolome and host in CRC initiation and progression in a humanized in vivo mouse model of CRC. Mice undergo fecal microbial transplant of a mix of fecal samples from healthy human donors. Colorectal cancer is chemically induced using azoxymethane and dextran sodium sulfate and mice are fed standard rodent chow or a high-fat low-carb diet. Tumor incidence and tumor size, the evolution of the fecal microbiome over time, the plasma metabolome and the host immune cell responses are characterized. Further in vitro experiments allow for the study of host cell stemness under ketogenic diet (organoid formation assays).

We have observed a lower tumor incidence in mice fed a high-fat low-carb diet, accompanied by specific changes in the gut microbiome and in the metabolome profile of these mice. Immune responses are also altered, showing lower overall inflammation. Increased stemness of colon crypts is observed from mice fed high-fat low-carb diet, possibly reflecting a better potential for repair of damages to the colon epithelium. The results of this study may lead to a better understanding of how different bacteria and the products we consume affect CRC development and help in developing strategies to circumvent the harmful effects of CRC-associated bacteria.

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