WIKIMEDIA, MATTOSAURUSA brief, low dose of antibiotics shortly after birth can have long-lasting consequences on gut microbes in mice and lead to obesity once the rodents reach middle age. These findings, published today (August 14) in Cell, suggest that the gut microbiome may influence the development of metabolic pathways during a critical time window early in life.
Low doses of antibiotics have been used to promote animal growth in agriculture for several decades, although the mechanism underlying the drugs’ fattening effect was unclear. Martin Blaser of the New York University Langone Medical Center and his colleagues showed in a 2012 Nature paper that early-life antibiotic therapy in mice altered hormone levels and the activities of genes involved in carbohydrate and lipid metabolism.
For this latest study, Blaser and his colleagues aimed to better understand how the timing of such treatment might mediate microbial effects on host metabolism, he told The Scientist. The researchers treated two groups of mice with low doses of penicillin either shortly before pups were born or while they were weaning. A third group of pups received the antibiotic after they had been weaned. The low doses of penicillin used in the experiments were not strong enough to decrease the overall gut microbial population, although the treatment did lead to increased body fat and skewed the proportions of dominant bacterial species in the gut.
Treated mice had significantly lower levels of Lactobacillus in their guts than untreated mice; Candidatus and Allobaculum, two other bacteria that typically reach peak proportions early in life, were suppressed by the small penicillin doses.
“We usually see that high doses of antibiotics decrease microbial diversity, but that’s typical of ‘antibiotic bombs,’” said microbiologist Federico Rey of the University of Wisconsin-Madison who was not involved with the work. “Here, this suppression of dominant bacteria may allow other species to flourish.”
Compared to untreated animals, mice treated with penicillin after they were weaned showed accelerated growth, altered bone mineral content, and increased fat and overall body weight. But the effect on the offspring was greater when their mothers received the treatment before giving birth and while nursing. “Putting mice on antibiotics for just four weeks was sufficient to get the full effect,” said Blaser. “Basically,” he added, “the earlier, the stronger.”
Combining the antibiotic treatment with a high-fat diet exacerbated these obesity-inducing effects. The antibiotic-induced microbiome changes also influenced host intestinal cells; the researchers found decreases in the expression of intestinal immune response genes, such as those involved in the production of Th17 populations and antimicrobial peptides.
“It appears as though the low-dose penicillin decreases microbial signals that help development of these immune responses,” said study coauthor Laura Cox, a postdoc in Blaser’s lab.
To determine whether these effects were triggered by changes to the microbiome, Cox, Blaser, and their colleagues transferred gut microbes from antibiotic-treated and untreated mice to germ-free animals. The transfer mimicked their initial treatment: mice that received penicillin-treated microflora gained weight, while control animals did not. The effects petered out when a second generation of germ-free mice received a gut microbiome transplant from this first treated generation. The transience may have been because these mice were treated later in life, according to Cox.
“We already knew antibiotics cause weight gain in other animals, so why wouldn’t they in mice?” asked microbiologist Brett Finlay of the University of British Columbia in Canada who was not involved with the study. Transferring the microbiota to recreate the weight gain effect “basically proves that it has to do with the microbes,” he added.
The data are “beautiful and thorough,” said Rey, and “the implications are huge, particularly when you put this in the context of epidemiological data.”
Moreover, the results of this controlled study in mice “bring a different level of proof” to the link between antibiotics and long-term health, he added.
“When babies develop, there are other critical developmental windows,” said Blaser. “Even though the effects we saw on microbes were transient, the [weight gain] was permanent, suggesting that there is a developmental window—a time when microbes are influencing the development of metabolism.”
L.M. Cox et al., “Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences,” Cell doi:10.1016/j.cell.2014.05.052, 2014.