Main causes of Japanese colorectal cancer may be intestinal bacteria

A research group led by Professor Shinichi Yachida of the Graduate School of Medicine at the University of Osaka and Professor Tatsuhiro Shibata of the Institute of Medical Science at the University of Tokyo, in collaboration with the National Cancer Center and Institute of Science Tokyo, has revealed that certain strains of Escherichia coli that produce the toxin colibactin are involved in about half of colorectal cancer cases in Japan. In particular, they were involved in approximately 70% of early-onset colorectal cancer cases. The finding was made through large-scale analysis of the mutational scars left by colibactin-induced DNA damage in whole-genome analyses of colorectal cancer. The findings are expected to contribute to the development of new methods for the prevention and treatment of colorectal cancer. The results were published in Nature Genetics on August 10.

Colorectal cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in Japan, and the number of patients has increased sevenfold over the past 40 years. While incidence rates remain high among people aged 50 and older in Western countries, they have been declining, whereas they continue to rise in Japan. In addition, the number of patients under 50 is increasing worldwide.

Although the westernization of diets and changes in lifestyle have been cited as possible causes of the increase in colorectal cancer cases in Japan, the underlying molecular mechanisms, including those behind the rise in cases among people under 50, have remained unclear.

Previously, in an international collaborative study published in 2025, Professor Shibata and colleagues examined 1,000 colorectal cancer cases from multiple countries and found characteristic DNA damage patterns, known as mutational signatures, caused by the toxin colibactin produced by certain strains of E. coli in approximately 5% to 20% of cases.

Notably, the signatures were detected in about half of the 28 Japanese cases examined. However, because the number of cases was limited, it remained unclear whether this reflected a broader characteristic of the Japanese population. In addition, the relationship between these mutational signatures and the development of colorectal cancer had not been clearly established.

Although E. coli is generally a harmless symbiotic bacterium that inhabits the human colon, some strains carry the pks island gene cluster and produce the toxin colibactin, which damages host DNA.

Human DNA accumulates damage over time from cell-division errors and exposure to carcinogenic chemicals, and colibactin causes similar damage. Mutational signature analysis can be used to estimate the causes of such DNA damage. Colibactin induces interstrand DNA crosslinks, leaving characteristic mutational signatures known as SBS88 and ID18 during the DNA repair process.

The research group therefore performed whole-genome analyses of tumors from 200 colorectal cancer patients treated at the National Cancer Center Hospital and Osaka University Hospital, searching for SBS88 and ID18 and evaluating their frequencies. When a particular mutational signature accounts for 5% or more of all mutations, it is considered a major contributor to carcinogenesis. As a result, the researchers found that approximately 45% of colorectal cancer cases were attributable to colibactin.

Colorectal cancer typically progresses from a polyp to advanced cancer over the course of about 20 years, and in many cases the first mutation occurs in the APC gene. The researchers therefore examined whether colibactin-induced mutations occur in the APC gene. They found that colibactin directly damages the APC gene at an early stage of carcinogenesis. Further analysis by age at diagnosis showed that younger patients had higher positivity rates for both SBS88 and ID18. Among patients diagnosed before the age of 40, mutational signatures associated with colibactin were detected in approximately 70% of cases.

The findings strongly suggest that colibactin is one of the major causes of early-onset colorectal cancer. Analysis by birth year showed that these positivity rates were higher among individuals born in or after 1965.

The 1960s and 1970s were a period of rapid economic growth in Japan, when dietary habits changed dramatically and the use of antibiotics became widespread. Changes in the gut microbiota associated with these developments may have contributed to the trend.

The study also suggested that colibactin-induced DNA damage occurs at an early stage of colorectal carcinogenesis. The findings suggest that APC mutations acquired during childhood may accumulate additional mutations through long-term interactions with gut bacteria, ultimately contributing to the development of colorectal cancer in adulthood.

Yachida said, "This study has shown that colibactin is an important cause of colorectal cancer in Japan. However, many questions remain. First, when and where does colonization occur? We hope to clarify the routes involved, including mother-to-child transmission and dietary factors. Second, why is it more common in Japanese people? We would like to elucidate its relationship with dietary habits, the gut microbiota, and environmental factors. Ultimately, our goal is prevention. Just as the eradication of Helicobacter pylori dramatically changed the prevention of gastric cancer, a day may come when new preventive strategies targeting colibactin-producing bacteria transform colorectal cancer prevention. We will continue our research toward that goal."

Journal Information
Publication: Nature Genetics
Title: Prevalence and chronology of colibactin-associated mutational processes and their microbiome spectra in Japanese colorectal cancer
DOI: 10.1038/s41588-026-02692-x