Childhood Antibiotic Use Linked to Early-Onset Colorectal Cancer

A study in the International Journal of Cancer linked long-term or recurrent antibiotic use early in life with a higher risk of developing early-onset (before age 50) colorectal cancer (CRC) and precancerous polyps.

The joint Chinese-British research team found a particularly strong association among people carrying a defective form of a gene, FUT2.

FUT2 normally regulates the gut microbiome through its protein product, fucosyltransferase 2.

However, the defective form of FUT2 is inactive, so it does not generate the protein. This deficiency has been implicated in forms of cancer other than CRC.

Study details

Researchers used a survey on early-life antibiotic use and current life or lifestyle factors to screen subjects, ages 40-69, from a large U.K. patient database. Participants were recruited between 2006 and 2010 and followed up to February 2022.

Patients were evaluated for CRC and polyps at initial intake and during follow-up, with cases falling into either prevalent (present at initial assessment) or incident (during follow-up) categories.

Among the 113,256 participants who met the study’s inclusion criteria were 165 CRC cases (143 prevalent and 22 incident cases) and 719 instances of precancerous colorectal adenoma, or polyps.

Researchers defined long-term or recurrent antibiotic use as receiving more than three antibiotic prescriptions per year. Life/lifestyle factors included education level, family history of CRC and age at sexual maturity.

Investigators then ranked subjects according to high (above average) or low (below average) “polygenic risk score,” which combines the effects of genetic factors known to affect CRC risk.

Researchers hypothesized that factors affecting the gut microbiome — specifically antibiotic use and genetic factors — might work together to modify early-onset CRC risk.

Why this is important

Thanks to effective screening strategies, cases of CRC in adults over 50 have been falling slowly. However, rates in people under 50 have been rising.

Some experts attribute the overall rise in CRC diagnoses to diet, a “major” risk, or environmental and current lifestyle factors.

But diet, exercise and obesity cannot explain differences between over-50 and under-50 age groups.

CRC rates among under-50s are rising between 1-2% per year. This number may seem small. but over 10 years, a 2% yearly increase means an overall rise of 22%.

Based on these figures, one paper predicted that by 2030, between 10-12% of colon cancer and 25% of rectal cancer diagnoses will occur in people younger than 50.

Results

Long-term antibiotic use was associated with increased early-onset CRC risk when existing cases and those that occurred during the study were analyzed together, but not for cases that occurred during the study.

The associations with early-onset CRC were much stronger for high genetic risk subjects, in whom increases were seen for both prevalent-plus-incident occurrence and incident cases only.

When subjects were further grouped by low, medium and high genetic risk, participants in the middle and upper groups were much more likely to develop early-onset CRC than those in the lowest group.

Based on these preliminary findings one would expect subjects with the highest combined genetic risk and antibiotic exposure to have the highest risk for developing early-onset CRC, and this is what researchers found. Together, these factors increased the early-onset risk by more than 200%.

Associations between genes, antibiotic exposure and polyps followed similar patterns. Long-term antibiotic use was linked to higher rates for combined incident and prevalent cases regardless of genetic risk, but not for incident cases.

The polyp connection was strongest in individuals carrying a specific variation of the FUT2 gene.

Strengths and weaknesses

According to the authors, theirs was the first study to examine the connection between early-life antibiotic use and early-onset CRC. Their use of an extensive data set allowed them to find small but statistically significant differences between high-antibiotic and low-antibiotic use groups, and among subjects with varying genetics and family histories.

The main weakness was reliance on 30- and 40-year-old memories of events which, in the absence of a chronic condition requiring antibiotic treatment — for example, acne or tonsillitis — are not typically memorable.

Although questions on lifestyle were included in the intake survey, researchers were unable to match or compare study groups on the basis of lifestyle and diet at the time of antibiotic use.

Since diet, lifestyle and antibiotic use correlate to health or illness, children who take antibiotics may already be at greater risk for developing early-onset CRC or polyps — regardless of whether they take antibiotics.

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FUT2 and the microbiome

CRC is the second-leading cause of cancer death in the U.S., with approximately 147,950 diagnoses and 53,200 deaths in 2020. This includes 17,930 cases and 3,640 deaths (12% and 7%, respectively) in individuals younger than 50 years.

Hereditary, genetic and environmental factors contribute to CRC, as shown in Figure 1.

The connection between levels of the active FUT2 gene, gut microbiome and both precancerous and malignant colorectal growths is well-established.

The gut microbiome comprises large populations of microorganisms that interact with host cells to regulate energy utilization, metabolism and immune responses. Gene sequencing has revealed changes to the microbiome associated with CRC, and specific bacterial species involved in cancer including some, like E. coli, which when out of balance can cause a host of health issues.

Approximately 80% of humans carry a functional FUT2 gene, the precursor of the fucosyltransferase 2 enzyme that regulates the gut microbiome. FUT2 adds a sugar, fucose, to mucus in the digestive tract to help maintain healthy gut bacteria.

The 20% of humans who lack functional copies of this gene, and therefore lack the fucosyltransferase-2 protein, have greater susceptibility to common bacterial and viral colonization, including viral respiratory infections, stomach ulcers, and “stomach bugs.”

Under-expressed FUT2 has also been linked to Crohn’s disease and sclerosing cholangitis, or inflammation of the bile ducts.

FUT2 levels are low in colorectal tumors, whereas higher levels stop the spread of CRC and correlate to increased survival in patients. Test mice lacking the FUT2 gene naturally develop aggressive tumors.

The connection between antibiotics and cancer represents a medical conundrum because antibiotics are considered essential medicines. In a roundabout way, however, the connection has uncovered possible ways to prevent or treat CRC through noninvasive microbiome manipulation at the precancerous or polyp stage.