Ketogenic Diet as a Chemopreventative and Therapeutic Strategy for Colon Cancer

Dmitrieva-Posocco O, Wong AC, Lundgren P, et al. β-Hydroxybutyrate suppresses colorectal cancer. Nature 2022;605(7908):160–165. Epidemiologic studies suggest that dietary habits play a strong predisposing role in colorectal cancer (CRC). However, a key challenge in interpreting the pathogenic link between dietary patterns and CRC risk stands in the multiplicity of factors that can affect CRC tumorigenesis either separately or co-dependently with dietary composition. Western dietary patterns leave little room for protracted periods of fasting and intermittent fasting or time-restricted feeding is being actively investigated as a disease preventing or modulating strategy across several disease states, including cancer. Metabolic reprogramming mediated by increased ketogenesis is postulated to promote the beneficial effects of these approaches. However, evidence has so far failed to convincingly inform clinical practice. A study published recently in Nature provides compelling evidence for the central role of β-hydroxybutyrate (BHB) as a key metabolic modulator of the pathogenesis and progression of CRC. In this study, Dmitrieva-Posocco et al demonstrated that mice fed ketogenic diets (KDs), (diets containing a higher fat-to-carbohydrate ratio) had a reduction in tumor size and number compared with those fed a carbohydrate-rich diet, despite exposure of each group to an identical chemical or genetic carcinogenic stimulus and equal overall caloric intake. Using organoids derived from the various experimental conditions, the authors demonstrated that the beneficial effects of KD were largely dependent on BHB, a metabolite that is released after oxidation of fatty acids in the fasting state. This study adds important preclinical evidence in support of the role of BHB as a metabolite capable of preventing the formation of tumors and progression of established ones, paving the way for a potential chemopreventative, as well as therapeutic, role of BHB supplementation. The activity of BHB is, in fact, dependent on interaction with the HCAR2 receptor and with the homeodomain-only protein Hopx, a DNA binding protein that mediates the antiproliferative capacity of BHB. Although this study provided evidence that patients with CRC with higher circulating BHB levels have increased levels of Hopx within their tumor, several questions remain unanswered as to the true clinical meaning of this pathway in patients with CRC. Chemopreventative studies are extremely difficult and expensive to run due to the need for long-term follow-up, risk of high dropout rates, and requirement to dynamically adjust observations for confounding factors that may be introduced at any point during the study. From a therapeutic perspective, dietary interventions and time-restricted feeding might be difficult in patients with advanced malignancies, where often anorexia, cachexia, and nutritional decline are fueled by an unopposed cancer-driven systemic inflammatory response. Lastly, the combination of BHB supplementation with currently available anticancer therapies requires adequately powered prospective studies—a clear challenge in a setting where several effective therapeutic agents exist and where the activity of BHB may not be measured by standard oncological efficacy end points used commonly in clinical trials. Despite these limitations, the seminal article by Dmitrieva-Posocco et al represents a high-quality attempt to dissect the molecular mechanisms underlying dietary patterns and CRC pathogenesis; a relationship that is highly impactful but notoriously difficult to describe and understand.