New manuscript: Antibiotics cause metabolic changes in mice primarily through microbiome modulation rather than behavioral changes

Just published in PLOS ONE: a new study by Kale Bongers and our group teasing out how much of the effects of antibiotics on murine metabolism are due 1) to changes in gut microbiota vs 2) behavioral changes (e.g. food and water aversion due to bad-tasting antibiotics.

A common approach in murine microbiome studies is to put a cocktail of antibiotics (often ampicillin, metronidazole, vancomycin, neomycin) into their drinking water and ascribe all biologic consequences to perturbation of the microbiome. But this overlooks important off-target effects of antibiotics, including food and water avoidance. Metronidazole especially is extremely bitter. Your mice are thus potentially dehydrated and starved at the time of your measurements or experimental exposures.

In this study, we systematically studied the effects of multiple antibiotic regimens (both oral and systemic) on mice: their food and water consumption, their body composition (via NMR), their organ- and tissue-specific metabolism, and their gut bacterial density and community composition.

We found that mice are even more avoidant of water when it contains metronidazole than when it contains a commercial bitterant (denatonium benzoate, the stuff they put antifreeze and animal deterrents and nail-polish). Much of the metabolic consequences previously reported in that common four-drug regimen (ampicillin, metronidazole, vancomycin, neomycin) may actually be due to dehydration and starvation. But we did find that other enteral regimens (cefoperazone, enrofloxacin/ampicillin) can effectively deplete gut bacteria without causing nearly as much food and water avoidance. Interestingly, systemic antibiotics (intraperitoneal ceftriaxone) also result in decreased food and water consumption, suggesting that the microbiome plays a role in behavior (food and water aversion) independent of the direct aversive effects of taste.

The gut microbiome is an important and overlooked player in systemic metabolism, both in health and critical illness. Kale’s study gives us a firm methodological footing for future work determining how the microbiome modulates tissue-specific and organismal metabolism.

Manuscript: Antibiotics cause metabolic changes in mice primarily through microbiome modulation rather than behavioral changes (PLOS ONE)

Kale Bongers MD PhD