By Gilang Cahya 
Toronto, ON – Researchers at the University of Toronto have unveiled a concerning link between low-carbohydrate diets and an increased risk of colorectal cancer, demonstrating how these dietary patterns can amplify the DNA-damaging capabilities of certain gut microbes. The groundbreaking study, published in the esteemed journal Nature Microbiology, sheds new light on the intricate interplay between diet, the gut microbiome, and the development of one of the most prevalent forms of cancer worldwide.
Unraveling the Gut-Microbe-Diet Nexus in Cancer Development
For decades, the scientific community has recognized colorectal cancer as a multifactorial disease, influenced by a complex web of genetic predispositions, environmental exposures, lifestyle choices, and the composition of the gut microbiome. However, the precise mechanisms by which these factors interact to initiate and promote cancer have remained a subject of intense investigation. The University of Toronto team, led by Professor Alberto Martin of the Department of Immunology at the Temerty Faculty of Medicine, set out to specifically address a critical question: how does dietary intake influence the carcinogenic potential of specific gut bacteria?
The research, spearheaded by postdoctoral fellow Bhupesh Thakur, employed a rigorous experimental model using mice. These mice were deliberately colonized with one of three bacterial species previously implicated in colorectal cancer. Crucially, the mice were then subjected to one of three distinct dietary regimens: a standard, balanced diet; a low-carbohydrate diet; or a Western-style diet characterized by high levels of fat and sugar. This experimental design allowed the researchers to meticulously isolate and observe the impact of specific dietary components in conjunction with particular microbial inhabitants.
A Potent Combination: Low-Carb Diet and Colibactin-Producing E. coli
The study’s most striking finding emerged from the combination of a low-carbohydrate diet and a specific strain of Escherichia coli (E. coli) bacteria. This particular strain of E. coli possesses the ability to produce colibactin, a potent genotoxin known to induce DNA damage in host cells. When exposed to a diet deficient in carbohydrates and soluble fiber, this colibactin-producing E. coli was observed to significantly drive the growth of polyps in the colon. Polyps are abnormal growths that, while often benign, can serve as precancerous lesions, holding the potential to develop into colorectal cancer over time.
"Colorectal cancer has always been thought of as being caused by a number of different factors including diet, gut microbiome, environment and genetics," stated Professor Martin. "Our question was, does diet influence the ability of specific bacteria to cause cancer? And our findings suggest that it absolutely can."
The Western-style diet, while high in fat and sugar, did not elicit the same concerning polyp formation when paired with the E. coli strain. This suggests that the absence of carbohydrates and soluble fiber, rather than the mere presence of fat and sugar, creates a more permissive environment for the bacteria’s carcinogenic activity.
The Gut’s Inner Defenses Compromised: Mucus Barrier and Inflammation
Further investigation revealed the underlying physiological changes that facilitate this heightened cancer risk. The researchers discovered that a diet low in fiber significantly exacerbated inflammation within the gut. This inflammatory environment not only altered the delicate balance of the gut microbial community but also created conditions that allowed the colibactin-producing E. coli to flourish unchecked.
Perhaps more critically, the study demonstrated that mice on the low-carbohydrate diet exhibited a thinner mucus layer lining their colons. This mucus layer serves as a vital protective barrier, physically separating the vast population of gut microbes from the underlying colon epithelial cells. When this barrier is weakened, it allows harmful compounds like colibactin to reach the colon cells more readily, leading to genetic damage and promoting the uncontrolled cell proliferation characteristic of tumor development.
The genotoxic effects of colibactin were particularly pronounced in mice with pre-existing genetic mutations in their DNA mismatch repair (MMR) pathway. The MMR pathway is a crucial cellular mechanism responsible for correcting errors that occur during DNA replication. Defects in this pathway, as observed in these mice, severely impair the cell’s ability to repair DNA damage, making them far more susceptible to the mutagenic effects of colibactin and, consequently, to cancer development.
Implications for Human Health and Cancer Prevention Strategies
While the study was conducted in mice, both Dr. Thakur and Professor Martin emphasized the urgent need to validate these findings in human populations. Nevertheless, the implications of their research are profound and offer promising avenues for cancer prevention.
Colorectal cancer is a significant public health concern, ranking as the fourth most commonly diagnosed cancer in Canada. Statistics reveal that approximately 15 percent of colorectal tumors exhibit mutations in MMR genes, highlighting the importance of this pathway in cancer development. Furthermore, mutations in these MMR genes are the underlying cause of Lynch syndrome, a hereditary condition that substantially elevates an individual’s risk of developing several cancers, including colorectal cancer.
"Can we identify which Lynch syndrome patients harbour these colibactin-producing microbes?" Professor Martin posed, underscoring a key direction for future research. He suggested that for individuals with Lynch syndrome, adopting a dietary approach that avoids low-carbohydrate regimens or exploring targeted antibiotic treatments to eradicate colibactin-producing bacteria could represent a potent strategy to mitigate their heightened cancer risk.
Intriguingly, Professor Martin also noted that a strain of E. coli known as Nissle, frequently found in popular probiotic supplements, also produces colibactin. This raises important questions about the long-term safety of such probiotics for individuals with Lynch syndrome or those adhering to low-carbohydrate diets. Ongoing research in Professor Martin’s laboratory is actively investigating this complex relationship.
The Crucial Role of Soluble Fiber
A particularly encouraging aspect of the study was the observation that supplementing the low-carbohydrate diet with soluble fiber significantly attenuated the negative effects. The researchers found that the addition of soluble fiber led to reduced levels of the cancer-causing E. coli, diminished DNA damage, and a lower incidence of tumors.
"We supplemented fibre and saw that it reduced the effects of the low-carb diet," Dr. Thakur explained. "Now we are trying to find out which fibre sources are more beneficial, and which are less beneficial."
To delve deeper into this aspect, Dr. Thakur and Professor Martin are collaborating with Heather Armstrong, a researcher at the University of Alberta. Their joint efforts aim to assess the efficacy of inulin, a type of soluble fiber, in reducing colibactin-producing E. coli and improving gut health in individuals at high risk for colorectal cancer, such as those with inflammatory bowel disease.
A Call for Dietary Awareness
The researchers’ findings serve as a critical reminder of the potential health risks associated with prolonged adherence to low-carbohydrate, low-fiber diets, which are often pursued for weight management.
"Our study highlights the potential dangers associated with long-term use of a low-carb, low-fibre diet, which is a common weight-reducing diet," Professor Martin stated. "More work is needed but we hope that it at least raises awareness."
This research represents a significant step forward in understanding the intricate mechanisms linking diet, the microbiome, and cancer. By elucidating how specific dietary patterns can empower harmful gut bacteria, the University of Toronto team has paved the way for more targeted and effective strategies to prevent colorectal cancer, particularly for individuals with a higher genetic predisposition. The focus now shifts to translating these vital laboratory findings into actionable public health recommendations and personalized dietary guidance.
