5 unintended consequences of antibiotic use

In recent years, the gut microbiome has received much attention. The microbiota plays an important role in health and pathology. Hard-to-treat nosocomial infections in hospitalized patients, for instance, often derive from the microbiome, where antibiotic use selects for antibiotic-resistant organisms.

Antibiotic use should always be carefully considered, in large part, because these drugs disrupt the microbiota in compromising ways. Antibiotics can lead to altered microbial composition and loss of colonization resistance, which contribute to a number of wide-ranging and negative effects.

Here’s a look at five unintended consequences of antibiotic use. 

Obesity

Those with obesity demonstrate differences in their mix of intestinal microbes compared with lean individuals. Authors of a review published in BMC Medicine suggested that such causal alterations in gut microbiota predate the development of obesity, with neonates at increased risk.

“The intestinal microbiota perturbation caused by antibiotic exposure in the perinatal period appears to program the host to an obesity-prone metabolic phenotype, which persists after the antibiotics have been discontinued and the gut microbiota has recovered,” the authors wrote.

“These observations may have serious implications in the clinical setting, since a substantial number of human infants are subjected to antibiotic treatment through the mother during delivery or directly in the immediate neonatal period. The clinical significance of these exposures remains unknown,” they added.

The authors suggested judicious use of antibiotics to curb the proliferation of antibiotic-resistant variants as well as metabolic repercussions of dysbiosis such as obesity. To this end, better screening of neonates with bacterial infections is imperative, with a focus of reducing exposure in those with nonspecific symptoms, signs, and risk factors. Neonates who are given antibiotic treatment, however, could benefit from healthy microbial contact.

Recurring infections

Emerging research has demonstrated that the overuse, prolonged use, or incorrect use of antibiotics can compromise the microbiome. These effects are unanticipated and undesirable, according to the authors of an article published in Immunological Reviews.

“Sequelae include antibiotic resistance, intestinal domination by pathogenic bacteria, transient or profound loss of microbial diversity, transient or profound loss of the number of microbial species, increased and prolonged susceptibility to infection and the risk of reoccurring infection,” the authors wrote.

In light of such concerns, the authors recommended careful consideration of the implications of antibiotic use and therapy to mitigate long-term effects.

Mood

Alterations in microbiota could increase the risk of several psychiatric illnesses via neurologic, metabolic, and immunologic pathways, according to the authors of a large nested case-control study published in the Journal of Clinical Psychiatry.

The investigators found that administration of a single course of antibiotics was related to a higher risk of depression. Specifically, the adjusted odds ratio (AOR) with penicillin was 1.23, and the AOR for quinolones was 1.25. Notably, the risk increased with more doses. Moreover, similar associations were observed with anxiety after exposure to sulfonamides and penicillins. Importantly, no change in psychosis risk was observed in any antibiotic group. 

Insulin sensitivity

In a preclinical study published in Nature Communications, researchers depleted the microbiome of mouse models using clinical antibiotics. Consequently, they observed a substantial decrease in gut microbiota, resulting in the mice clearing glucose much faster than usual. In other words, the antibiotics made the mice more sensitive to insulin.

They found that colonic tissue was acting like a glucose “sink,” thus reducing levels of sugar in the blood and leading to larger colons. These changes were linked to alterations in liver functions via bile acids. The mice, however, did not exhibit changes in body fat composition or dietary consumption, which typically affect glucose metabolism and diabetic pathology in humans. 

“We demonstrate that AIMD [antibiotic-induced microbiome depletion], which decreases luminal Firmicutes and Bacteroidetes species, decreases baseline serum glucose levels, reduces glucose surge in a tolerance test, and improves insulin sensitivity without altering adiposity,” the authors wrote.

These changes happen in the setting of decreased luminal short-chain fatty acids (SCFAs), especially butyrate, and the secondary bile acid pool, which affects whole-body bile acid metabolism, they noted. 

“In mice, AIMD alters cecal gene expression and gut glucagon-like peptide 1 signaling. Extensive tissue remodeling and decreased availability of SCFAs shift colonocyte metabolism toward glucose utilization. We suggest that AIMD alters glucose homeostasis by potentially shifting colonocyte energy utilization from SCFAs to glucose.” 

Kidney stones

Oxalobacter formigenes (OF) in the gut microbiome could protect against calcium oxalate stones. Intestinal colonization by OF is related to urinary oxalate excretion, with antibiotic exposure affecting colonization rates of this microbe.

In a novel prospective study published in the Journal of Endourology, researchers examined the effects of antibiotics on rates of OF colonization in an experimental group prescribed antibiotics for Helicobacter pylori (HP) infection and a control group including those without infection who received no antibiotics. The team determined OF colonization in stool by measuring oxalate degradation at baseline and after 1 and 6 months.

At baseline, OF colonization was 43.1% among all participants screened. In 12 patients who did not receive antibiotics, 11 (92%) harbored OF at 1 and 6 months compared with 7 of 19 (36.8%) of those who received antibiotics for HP infection. Specifically, amoxicillin and clarithromycin led to 62.5% of subject testing negative for OF at 1 month, with 56.2% of those receiving these antibiotics remaining negative for OF at 6 months.

“Antibiotics for HP infection effectively reduced colonization with OF, an effect present at 1 and 6 months after treatment,” the authors concluded. “The lasting elimination of OF could be associated with hyperoxaluria and be a factor in recurrent kidney stone disease.”

In a separate population-based study published in the Journal of the American Society of Nephrology, investigators examined the relationship between the administration of 12 classes of oral antibiotics and the frequency of kidney stones in the United Kingdom between 1994 and 2015. Data were adjusted for covariates, including the rate of health care encounters, comorbidities, and urinary tract infections, as well as the use of thiazide and loop diuretics, proton-pump inhibitors, and statins.

They found that exposure to any of five different antibiotic classes 3–12 months before testing was correlated with nephrolithiasis. The adjusted odds ratio was 2.33 for sulfas, 1.88 for cephalosporins, 1.67 for fluoroquinolones, 1.70 for nitrofurantoin/methenamine, and 1.27 for broad-spectrum penicillins. The degree of correlation was largest for exposure at younger ages and 3–6 months before testing. Importantly, results from exposure to all antibiotics sans broad-spectrum penicillins remained significant 3–5 years post-exposure.

“Oral antibiotics [were] associated with increased odds of nephrolithiasis, with the greatest odds for recent exposure and exposure at [a] younger age,” the authors concluded. “These results have implications for disease pathogenesis and the rising incidence of nephrolithiasis, particularly among children.”