Altered gut bacteria may be culprit in middle-age adults
• by Jeff Minerd
Contributing Writer, MedPage Today April 06, 2017
Long-term antibiotic use in early-to-middle adulthood was linked with increased risk for colorectal adenomas after age 60 in a dose-dependent manner, in an analysis of data from the Nurses’ Health Study.
Be aware that the proposed link between exposure to antibiotics and development of colorectal neoplasia is biologically plausible, as antibiotics shift the gut microbiota and interactions of these dysbiotic microbiota with mucosal immune and epithelial cells may be critical in the initiation and/or promotion of colorectal carcinogenesis.
Long-term antibiotic use in early-to-middle adulthood was linked with increased risk for colorectal adenomas in a dose-dependent manner, researchers reported.
Among patients who took long-term antibiotics in their 40s and 50s, those who used them for more than 2 weeks had a 51% risk increase (odds ratio 1.51, 95% CI 1.14-1.99), and those who used them for more than 2 months had a 69% risk increase (OR 1.69; 95% CI 1.24-2.31) compared with those who never used long-term antibiotics (P=0.001 for both comparisons), said Andrew Chan, MD, of Massachusetts General Hospital in Boston, and colleagues.
For patients who used antibiotics long-term in their 20s and 30s, those who took them for more than 2 weeks had a 41% risk increase (OR 1.41, 95% CI 1.13-1.75) and those who used them for more than 2 months had a 36% risk increase, (OR 1.36, 95% CI 1.03-1.79) compared with never-users (P=0.002 for both), they wrote online in Gut.
For antibiotic courses lasting 2 weeks or less, there was a non-significant trend toward increased adenoma risk. However, recent long-term antibiotic use, defined as within the last 4 years, was not associated with greater risk regardless of the length of time the drugs were used (P=0.44), the study found.
“To the best of our knowledge, this study is the first to link duration of antibiotic use, in a dose-dependent fashion, to colorectal adenoma, the primary precursor of colorectal cancer,” Chan’s group wrote.
“Our study suggests caution with respect to the unnecessary long-term use of antibiotics,” Chan told MedPage Today via email. “Our data support the importance of one’s own normal bowel bacteria in maintaining health. Disrupting the composition of normal gut bacteria through the long-term use of antibiotics may predispose individuals to such conditions as colorectal polyps and cancer.”
As to why the study found no risk with recent long-term antibiotic use, Chan said, “It may be that there are critical time windows during one’s lifespan within which exposure to antibiotics may be more likely to have downstream health effects.”
The investigators analyzed data from the Nurses’ Health Study, a prospective cohort study of more than 121,000 female U.S. nurses, ages 30-55, at enrollment in 1976. The study focused on 16,642 participants who were 60 or older in 2004, had reported the history of their antibiotic use through age 59 on a 2004 questionnaire, and who had undergone at least one colonoscopy between 2004 and 2010. Recent antibiotic use was assessed via questionnaire in 2008.
Chan’s group documented 1,195 cases of adenoma. They used multivariate logistic regression analysis to explore links between long-term antibiotic use and colorectal adenoma, adjusting for variables that included age, family history of colorectal cancer, diabetes, BMI, alcohol intake, smoking, red and processed meat intake, and others.
The associations were similar for low-risk versus high-risk adenomas, but appeared modestly stronger for proximal compared with distal adenomas. For example, middle-aged women with a history of 2-plus months of antibiotic use had twice the risk for a proximal adenoma (OR 2.13, 95% CI 1.35-3.35, P=0.01) but only about a 50% increase in risk for distal adenomas (OR 1.49, 95% CI 0.96-2.29, P=0.02) compared with women who never used long-term antibiotics.
“The proposed link between exposure to antibiotics and development of colorectal neoplasia is biologically plausible,” the investigators said. “Antibiotics shift the gut microbiota to temporally quasi-stable or alternative stable states. Although it is unknown what factors influence either the recovery of gut microbiota to its native state or the development of alternative states after antibiotic exposure, this dysbiosis is generally marked by a loss of diversity, alternations in the abundance of specific taxa, shifts in metabolic capacity, and reduced resistance to colonisation by invading pathogens.”
“The interactions of these dysbiotic microbiota with mucosal immune and epithelial cells may be critical in the initiation and/or promotion of colorectal carcinogenesis,” they added.
In addition, inflammation might be another mechanistic link, as many of the pathogens antibiotics are used against are known to induce inflammation, they noted.
Study limitations included the fact that it did not differentiate between different classes of antibiotics, and that the results may not be generalizable to men or specific racial or ethnic groups.
“In conclusion, early-to-middle adulthood antibiotic use was associated with increased risk of colorectal adenoma, especially in the proximal colon. These data provide additional support for the association of antibiotics with colorectal cancer and the potential mediating role of the gut microbiome in carcinogenesis,” they stated. “Additional studies investigating the impact of antibiotic exposure with gut microbial composition and function, particularly in relation to the mechanisms underlying colorectal carcinogenesis, are warranted.”
The study was funded by the NIH, the Raymond P. Lavietes Foundation, the Project P Fund, the Friends of the Dana-Farber Cancer Institute, the Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance.
Altered gut bacteria may be culprit in middle-age adults