Gut toxin may be a ‘critical piece of the puzzle’ behind the rise in early-onset colorectal cancer
A gut toxin that’s been linked to colorectal cancers for more than two decades may be contributing to the sharp rise of the disease in younger people, according to landmark research published Wednesday in the journal Nature.
A number of species of harmful gut bacteria — including certain strains of E.coli, Klebsiella pneumoniae and Citrobacter koseri — produce a toxin called colibactin. Since the mid 2000s, studies have repeatedly shown that this toxin can inflict distinct DNA damage on colon cells that’s difficult to repair and can eventually lead to the development of cancer.
That DNA damage is particularly prominent in people who developed colorectal cancer at a younger age, researchers at the University of California San Diego said Wednesday. The new study sequenced the DNA of colorectal cancer tumors collected from 981 patients in 11 countries around the world, and found that colibactin-related DNA mutations were 3.3 times more common in patients under the age of 40, compared with those over 70.
“Around 50% of early-onset colorectal cancers in individuals under 40 carried the distinctive signature of colibactin exposure,” senior study author Ludmil Alexandrov, a bioengineering and cellular and molecular medicine professor at UC San Diego, said in an email interview.
The finding could have critical implications for public health amid rising rates of colorectal cancer in young people. Two years ago, the American Cancer Society reported that colorectal cancer diagnoses in patients under 55 had doubled between 1995 and 2019, with rates of advanced disease now increasing by roughly 3% every year in people younger than 50.
Christopher Johnston, associate professor and director of microbial genomics at MD Anderson Cancer Center, described the connection to colibactin as being potentially crucial to explaining this alarming trend.
“It may be a critical piece of the puzzle,” Johnston, who was not involved with the new research, said.
According to Alexandrov, the new findings indicate that colibactin’s damaging effects begin in childhood, with the initial DNA changes that lead to tumor formation seemingly occurring during the first decade of life. Lifestyle changes over the past 40 years may be predisposing more children to having a greater abundance of colibactin-producing strains of bacteria in their guts.
“There are several plausible hypotheses, including early-life antibiotic use, which may allow these strains to establish more easily; dietary shifts such as increased consumption of processed foods or reduced fiber consumption; increased rates of C-section births or reduced breastfeeding; and wider use of early group childcare which could facilitate microbial transmission during a critical developmental window,” Alexandrov said. “Collectively these shifts may be tipping the balance towards early-life acquisition of these microbes.”
At the same time, many questions remain unanswered.
Dr. Shuji Ogino, a professor of pathology and epidemiology at Harvard University, said it’s still unclear whether some people are simply more susceptible to the DNA-damaging effects of colibactin than others, or whether it can definitely be attributed to specific lifestyle patterns.
Colibactin-producing microbes are also not the only bacteria that have been linked to colorectal cancers. In recent years, both Ogino and Johnston have published studies implicating another gut microbe, called Fusobacterium nucleatum, in the development of the disease. Alexandrov suggested that while colibactin-producing species may cause the initial mutations that drive tumor formation, F. nucleatum may contribute to disease development by enabling the tumor to proliferate and evade the immune system.
However, Johnston said this is another area where more research is needed; the original cause of colorectal cancers may be the result of a combination of microbes and their toxins.
“Microbial interactions could amplify these effects,” he said. “For example, in patients with a hereditary colorectal cancer syndrome called familial adenomatous polyposis, studies have shown that when Bacteroides fragilis co-occurs with colibactin-producing E.coli, DNA damage is significantly enhanced.”
Over the next two to three years, Alexandrov said he and his colleagues are planning to develop a noninvasive test that uses stool samples to determine whether people have had prior exposure to colibactin-producing bacteria.
“The goal is to identify people who are at elevated risk for developing early-onset colorectal cancer, ideally before any disease has developed,” he said. “We would want to have these people regularly checked.”
Given the wealth of evidence for the role of colibactin in these diseases continues to grow, scientists say that it’s also now important to explore preventive approaches, such as targeted probiotics or vaccines.
“Considering the abundance of reproducible evidence, targeted interventions that seek to eliminate these specific microbes are now warranted,” Johnston said.
“Vaccination-based approaches are a logical next step, such as the development of a childhood vaccine, potentially with boosters, that generates immune memory against colibactin-producing E. coli,” he said. “The caveat here is that this is a long game, requiring examining the incidence of young-onset colorectal cancer over time in vaccinated individuals, which would take decades.”