Primary Care Corner with Geoffrey Modest MD: Antibiotics, microbiome changes and colorectal adenoma

by Dr Geoffrey Modest

There been a few studies over the past suggesting a relationship between the gut microbiome and colorectal cancer, as well as between antibiotic exposure and colorectal cancer. An evaluation of the Nurses’ Health Study recently confirmed prospectively that there was a dose-response curve between women’s prior use of antibiotics and colorectal adenomas (see doi.org/10.1136/ gutjnl-2016-313413).

Details:

— 16,642 women aged at least 60 who had at least one colonoscopy between 2004 and 2010 and had reported their antibiotic use in a 2004 questionnaire, comparing antibiotic users versus nonusers

— mean age 70, family history of cancer in 20%, diabetes in 9%, BMI 25, hormone therapy 20%, regular use of aspirin in 40%, multivitamins in 78%, 20 pack-years of smoking in those who were ever-smokers, 2.3 g of alcohol per day, 6 servings of red meat per week.

Results:

— 1195 cases of adenomas were detected

— women who used antibiotics for more than 2 months between the ages of 20 and 39 had a 36% increased risk of adenomas by multivariate analysis, OR =1.36 (1.03-1.79)

— women who used antibiotics for more than 2 months between the ages of 40 and 59 had a 69% increased risk by multivariate analysis, OR = 1.69 (1.24 – 2.31)

— there was a trend between increasing antibiotic use at age 20-39 (p=0.002) and also at 40-59 (p=0.001), in each case with progressively more adenomas when increasing antibiotic use, from no use to 1-14 days, to 15 days-2 months, to >2 months.

— this association was similar for low risk versus high risk adenomas (high-risk being defined as size > 1 cm, with tubulovillous/villous histology, or > 2 detected lesions), though was slightly stronger for proximal lesions.

— there was no association between antibiotic use in the prior 4 years and risk of adenoma [ie, the microbiota were not influenced by recent antibiotic usage]

— women who used antibiotics for a longer duration were overall similar to those who did not in terms of family history, personal disease/screening history, and lifestyle factors, but were more likely to regularly use menopausal hormonal therapy, aspirin, and undergo colonoscopy for symptoms rather than routine screening.

Commentary:

–the Nurses’ Health Study is an ongoing prospective cohort study of 121,700 US female nurses aged 30 to 55 at enrollment in 1976. The advantage of looking at this cohort is the high quality of data collected (which had accurate data both on an array of lifestyle issues as well as medical problems/medications etc, as well as specifically on prior intermittent antibiotic use many years beforehand), and the long-term follow-up

— the presumed mechanism for a relationship between antibiotics and colorectal adenomas is through the effect of antibiotics on the microbiota. For unclear reasons antibiotics may induce either temporary, quasi-stable states, or alternative stable states. The specific microbiota changes associated with colon cancer include depletion of Bacteroides, Firmicutes (Clostridia), and Proteobacteria (Enterobacteriaceae) and enrichment of Fusobacteria.

— of course, though this was a really good prospective study following lots of items (a rather long questionnaire….), there could well be unaccounted-for differences between the antibiotic users and nonusers which could explain the microbiome differences as well as the increase in adenomas. The noted differences between these groups (eg, using postmenopausal hormones, aspirin, having nonscreening colonoscopies) were accounted for, but were there other issues? were there differences in psychosocial issues between the groups? were those on these meds and getting antibiotics more anxious or stressed out (and there is some evidence that increased cortisol levels, often found with stress, can effect changes in the microbiome)? Were these women on the above meds also taking other unassessed meds that could affect the microbiome and adenoma rate (and perhaps leading to the long-term changes in the microbiome)? As with all observational studies, one cannot attribute causality to an association.

–so, I bring this up mostly because this study has a great database, and long-term follow-up, and reinforces many of the articles brought up before regarding the effects of microbiota changes and human disease. And, it provides us with an even stronger imperative to try to decrease antibiotic use, except when clearly indicated. 

See here for an array of articles on the microbiome, including mechanism by which microbiota changes might lead to a variety of diseases including NAFLD, cancer, diabetes, metabolic syndrome, heart disease….  ​

See here for another array of articles, but dealing with the consequences of overuse of antibiotics in humans and livestock and microbial resistance