The ketogenic diet (KD), characterized by high fat and very low carbohydrate content, has gained popularity for weight loss and its potential therapeutic effects in various conditions, including cancer. While some studies suggest that KD may offer benefits in colorectal cancer (CRC), others indicate potential risks, highlighting the complex relationship between this diet and CRC development. This article aims to explore the current research on the effects of KD on CRC, considering both its potential advantages and disadvantages.
What is the Ketogenic Diet?
The ketogenic diet is distinguished by its very low carbohydrate content (approximately 5% of total caloric intake), moderate protein intake (approximately 15% of total caloric intake), and high fat content (approximately 80% of total caloric intake). A common adaptation of this diet involves a 4:1 ratio of fat to carbohydrate and protein. The reduction in carbohydrate intake induces a metabolic state called ketosis, where the body shifts from using glucose as its primary energy source to using ketone bodies.
Normally, the body breaks down carbohydrates into glucose to fuel cells. When carbohydrate intake is insufficient, oxidation of fatty acids peaks, and production of acetyl-CoA increases in the mitochondria of hepatocytes. Acetyl-CoA then enters the citric acid cycle with oxaloacetate. When oxaloacetate is depleted, acetyl-CoA starts to produce ketone bodies, such as acetoacetate and β-hydroxybutyrate (βHB), as an alternative energy source for tissues outside the liver. This process is facilitated by the mitochondrial enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), which activates the first step of ketogenesis. Ketosis is achieved when blood βHB concentrations reach ≥ 0.5 mmol/L.
Potential Benefits of the Ketogenic Diet in Colorectal Cancer
Several studies suggest that the ketogenic diet may have beneficial effects in the context of colorectal cancer:
Reduced Tumor Growth: Some research indicates that KD can slow tumor growth by depriving cancer cells of glucose, their primary energy source. Cancer cells typically exhibit increased glucose uptake compared to normal cells, a phenomenon known as aerobic glycolysis or the Warburg effect. By limiting carbohydrate intake, KD reduces the amount of available glucose for tumors, potentially inhibiting their proliferation. In mice with pancreatic and colorectal cancer, keto diets slow the growth of tumors by a process called ferroptosis. This kills the cancer cells by causing a lethal buildup of toxic fatty molecules.
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Anti-tumor Potential of Ketone Bodies: The ketone body β-hydroxybutyrate (βHB) has been found to possess anti-tumor potential in colorectal cancer. Studies have shown that βHB can act on the surface receptor Hcar2, inducing the transcriptional regulator Hopx, which alters gene expression and inhibits cell proliferation.
Modulation of the Gut Microbiome: Recent studies suggest that KD can alter the composition and function of the gut microbiome, potentially contributing to its anti-cancer effects. KD consumption was associated with a decrease in colonic tumor burden. Stearate-producing members were enriched in ketogenic conditions, whereas consumers were depleted. Supplementation of stearic acid reduced tumor burden in vivo.
Inhibition of Key Signaling Pathways: KD or its products, such as βHB and the enzyme HMGCS2, can inhibit several genes and downstream effectors of pathways implicated in CRC, including the PI3K/AKT/mTOR pathway and the NF-κB pathway.
Potential Risks and Drawbacks of the Ketogenic Diet in Colorectal Cancer
Despite the potential benefits, the ketogenic diet also has some drawbacks and potential risks in the context of colorectal cancer:
Promotion of Tumor Metastasis: A study by researchers at the Herbert Irving Comprehensive Cancer Center (HICCC) found that KD may increase the risk of tumor metastasis. In a mouse model of breast cancer, mice fed with a ketogenic diet experienced significantly more lung metastases compared to those on a control diet. The ketogenic diet-induced metastasis is dependent on a protein called BACH1, which has been linked to enhanced metastatic potential in breast and lung cancers.
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Cachexia: In mice with pancreatic and colorectal cancer, KD accelerates a lethal wasting disease called cachexia. Patients and mice with cachexia experience loss of appetite, extreme weight loss, fatigue, and immune suppression. Keto causes toxic lipid byproducts to accumulate in and kill cancer cells by a process called ferroptosis. This slows tumor growth but also causes early-onset cachexia.
Gastrointestinal Disorders and Weight Loss: The ketogenic diet can cause gastrointestinal disorders and weight loss, which may be detrimental to cancer patients, especially those already experiencing malnutrition or cachexia.
Nutrient Deficiencies: The restrictive nature of the ketogenic diet can lead to nutrient deficiencies if not carefully planned and supplemented.
Impact on Gut Microbiome Diversity: The ketogenic diet may negatively affect certain beneficial bacteria in the gut and increase levels of harmful bacteria. This can disrupt the balance of the gut microbiome and potentially promote inflammation and other adverse effects.
Research Findings and Studies
Several studies have investigated the effects of the ketogenic diet on colorectal cancer in both preclinical and clinical settings:
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Mouse Studies:
In mice with pancreatic and colorectal cancer, keto diets slow the growth of tumors by a process called ferroptosis. This kills the cancer cells by causing a lethal buildup of toxic fatty molecules.
In mice with pancreatic and colorectal cancer, keto accelerates a lethal wasting disease called cachexia.
A study in mice found that KD may increase the risk of tumor metastasis. In a mouse model of breast cancer, mice fed with a ketogenic diet experienced significantly more lung metastases compared to those on a control diet.
Mice fed either of the ketogenic diets had fewer tumors and smaller tumors than mice fed diets with a higher percentage of carbohydrates. Mice with colorectal cancer fed the ketogenic diets also lived longer. When mice were fed a ketogenic diet after tumors had already formed, their tumors grew very slowly or stopped growing altogether.
The scientists found that it increased the development of polyps. Some polyps have the potential to develop into colorectal cancer.
Researchers found that adding fiber to these mice’s diets reduced tumor formation and helped control inflammation.
Clinical Trials and Case Reports:
A recent clinical trial found that patients with breast cancer who followed a ketogenic diet for 12 weeks had a better response to chemotherapy, such as reduced tumor size and downstaging, compared to those in a control diet group.
The first attempt to treat cancer patients with a long-term controlled KD was reported by Nebeling et al. for two pediatric patients with astrocytoma. Results revealed a 21.8% average decrease in glucose uptake at the tumor site in both subjects. One of the patients exhibited significant clinical improvements in mood and new skill development during the study.
In another case, a female patient with glioblastoma multiforme was treated with a KD which clearly demonstrated that this intervention is capable of stopping tumor growth. However, the KD resulted in a 20% loss of weight over the treatment period of two months.
In a pilot trial by Schmidt et al., 16 patients with advanced metastatic tumors and no conventional therapeutic options were instructed to follow a KD (less than 70 g carbohydrates per day) over a three-month period. The trial demonstrated the feasibility of KD with improvement in nearly all standard blood parameters and some measures of quality of life. Severe side effects were not observed except for constipation and fatigue.
The Gut Microbiome's Role
Recent research has focused on the gut microbiome's role in maintaining the reported anti-cancer effects of KD in the context of CRC. CRC progression is often accompanied by dysbiosis of the gut microbiome. One study combined a humanized gut microbiome mouse model of CRC with a therapeutically administered KD and confirmed the cancer-suppressing properties of the KD. The causal role of the gut microbiome in maintaining this effect was demonstrated through transplantation of the microbial community.
Additional Considerations
Several other factors should be considered when evaluating the potential role of the ketogenic diet in colorectal cancer:
Individual Variability: The effects of KD can vary depending on individual factors such as genetics, metabolism, and overall health status.
Dietary Composition: The specific composition of the ketogenic diet, including the types of fats and proteins consumed, can influence its effects on CRC.
Combination with Conventional Treatments: KD may interact with conventional cancer treatments such as chemotherapy and radiation therapy, potentially enhancing or interfering with their efficacy.
Long-Term Sustainability: The long-term sustainability and safety of KD for cancer patients need to be carefully evaluated.