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National Geographic

Colon cancer is rising in young people. Finally, scientists have a clue about why.

As scientists question the rise in early colon cancer cases, a new study is offering some potential answers. Colored scanning electron micrograph (SEM) of a macrophage white blood cell (center) that is being destroyed by toxins released by E. coli bacteria (red). Some strains of E. coli release colibactin, a toxin which damages the DNA of cells, and may contribute to the development of colorectal cancer. Micrograph by Steve Gschmeissner, Science Photo Library Colorectal cancer should be on your radar: Today, one in five people under the age of 54 is diagnosed with the disease, marking an 11 percent uptick in this age group over the past two decades. What, exactly, is fueling the surge in younger patients has perplexed scientists and medical professionals alike. (Colon cancer is rising among young adults. Here are signs to watch for.) For years, however, experts have suspected that colibactin, a toxin produced by E. coli and other bacteria that can damage DNA, could be involved. Now, a new study published in Nature has identified a strong link between childhood exposure to colibactin and colorectal cancer in patients under the age of 40. Here's how the study expands scientists' understanding of the microbiome's influence on colorectal cancer development, plus how a focus on colibactin could pave the way for earlier detection and new prevention strategies. What researchers discovered in colon cancer patients The researchers initially designed the study to broadly explore why people in different countries develop colorectal cancer at different rates, so the colibactin observation was 'somewhat incidental,' says lead study author Ludmil Alexandrov, a professor of cellular and molecular medicine at the University of California, San Diego. He and his team analyzed blood and tissue samples from the tumors of nearly 1,000 colorectal cancer patients across 11 countries, including Canada, Japan, Thailand, and Colombia. They used DNA sequencing technology to identify cellular mutations, or genetic changes that can help cancer form, grow, and spread. 'Different carcinogens leave this characteristic pattern of mutations, which we call mutational signatures,' Alexandrov explains. 'The simplest example is if you smoke cigarettes, you get a specific pattern of mutations across your lung cells.' Alexandrov and his team found that people diagnosed with colorectal cancer under the age of 50 had a 'striking enrichment' of mutations associated with colibactin. The younger the person was, on average, the higher the prevalence of these signatures. Those diagnosed with colorectal cancer under age 40 were about three times more likely to have colibactin-driven mutations than those diagnosed after age 70. 'When we sequence cancers, we see this archeological record of everything that happened in that person's lifetime,' Alexandrov says. Meaning, scientists can figure out the approximate timing of when specific mutations took hold in the gut. The study's results suggest that the participants' colibactin exposure happened before they turned 10. This early 'hit' to the gut microbiome seemed to put people 20 to 30 years ahead of schedule for developing colorectal cancer, Alexandrov says. Rather than being diagnosed in their 60s or 70s, they faced the disease in their 30s or 40s. Cynthia Sears, an infectious disease expert and professor of oncology at the Johns Hopkins University School of Medicine, who was not involved in the study, believes the study was done 'carefully and thoroughly,' but also leaves questions unanswered. 'We don't understand the biology of these organisms and the circumstances that allow them to be mutational,' she says. Alexandrov agrees. He says this new study shows a 'strong association' between childhood colibactin exposure and early-onset colorectal cancer. However, proving that colibactin actually causes colorectal cancer would be 'very complicated.' How colibactin could lead to colorectal cancer Colibactin is a genotoxin—think of it as a weapon certain bacteria deploy to protect themselves against other microbes. Experts theorize that, in some people, these bacteria become dominant and then start hurting their hosts, Alexandrov explains. Once they colonize the colon, they can latch onto healthy tissues, attack cells, and generate DNA mutations. Fluorescence micrograph of human colon cancer cells in a three-dimensional extracellular matrix, where the cells organize into cancer organoids as they would in human tissue. Micrograph by Dr Torsten Wittmann, Science Photo Library A colored 3D computed tomography (CT) scan of the colon of a 54-year-old male patient, showing extensive narrowing (stenosis) in the left colon (highlighted, upper right), suggesting the presence of a cancerous lesion. Image by Zephr/Science Photo Library But not everyone with colibactin-producing bacteria winds up with colorectal cancer—estimates show 20 to 30 percent of people harbor these strains. So what's prompting the bugs to go rogue in certain individuals? 'We think something is happening to give them an advantage over the other bacteria,' Alexandrov says. He cites previous studies that suggest people in Westernized countries (particularly urban areas), like the U.S. and parts of Europe, tend to have a higher prevalence of colibactin-producing bacteria in their guts than those in more rural or non-industrialized regions. 'To me, this is a window of opportunity to zero in on environmental influences in different sectors of the world,' Sears says. In particular, evidence suggests that a Western diet—typically higher in red and processed meats, added sugar, and refined grains and lower in fruits and vegetables—is associated with a higher risk of colorectal cancer. As for the reason why colibactin, specifically, could be more 'mutagenic' in the setting this diet creates in the gut? 'We just don't have this information,' Sears says. The new study didn't analyze the participants' individual cancer risk or track changes in their environment or diet, so any combination of these components could be at play. Alexandrov and his team suspect factors that can substantially alter a person's immune system and microbiome in their earliest years, like whether they were born via a C-section or vaginally, took antibiotics, were breastfed or formula-fed, or were fed a lot of processed foods. (How your fiber intake impacts your colon cancer risk) Some colibactin-producing bacteria may also trigger an immune response that further injures the cells. Those are the strains that 'get us into trouble,' Sears says. But it's 'extremely complex' to figure out what makes these bacteria stick in different parts of the gut. 'The rectum is different than the sigmoid colon,' she explains. 'Each of these regions has a somewhat different biology and predilection to tumor formation.' Where the research goes from here Alexandrov and Sears agree that longitudinal data is needed. Ideally, researchers would follow people in early life, give them probiotics designed to target colibactin-producing bacteria, and then track whether participants develop the associated mutations, and thus, early-onset colorectal cancer. 'If we can create the right probiotic that would bump off the bad actors, that might be a prevention strategy that would be easy and not harmful to people,' Sears says. Alexandrov and his team are looking into future studies that explore this possibility. He also believes they could design a stool test that pinpoints colibactin-related mutations. If this DNA damage is detected in the test, then the individual would be encouraged to start colorectal cancer screening earlier—say, in their 20s versus their 40s. (Will a new colon cancer blood test replace your colonoscopy?) All that said, Sears believes focusing on colibactin alone likely isn't the 'holy grail' solution to the rise in early-onset cases. 'We don't want to be too short-sighted about the spectrum of the research that we do,' she says. Until we have more data, focusing on the lifestyle changes you can control is key; Sears points to eating a Mediterranean-style diet, staying active, quitting smoking, and cutting back on alcohol. Awareness is also paramount: Young adults—as well as many medical professionals—are quick to brush off colorectal cancer symptoms like persistent abdominal pain, unexplained weight loss, and rectal bleeding. As Alexandrov stresses, 'they should be aware that it may be something quite serious,' because the sooner the tumors are detected, the easier they will be to treat.