Antibiotics, discovered in the early twentieth century, came into widespread use after the Second World War, with substantial public health benefits. Antibiotic use has increased markedly, now approximating one antibiotic course per year in the average child in the United States1,2
. However, there is increasing concern that antibiotic exposure may have long-term consequences3–5
For more than 50 years we have known that the administration of low doses of antibacterial agents promotes the growth of farm animals, consequently, in the United States, the largest use of antibiotics and related antimicrobial substances is within farms, with low doses fed to large numbers of animals used for food production to increase weight gain by as much as 15%6,7
. These effects are broad across vertebrate species, including mammals (cattle, swine, sheep) and birds (chickens, turkeys), and follow oral administration of the agents, either in feed or water, indicating that the microbiota of the gastrointestinal (GI) tract is a major target. That the effects are observed with many different classes of antibacterial agents (including macrolides, tetracyclines, penicillins and ionophores) indicates that the activity is not an agent-specific side effect, nor have the effects been observed with antifungals or antivirals.
The vertebrate GI tract contains an exceptionally complex and dense microbial environment, with bacterial constituents that affect the immune responses of populations of reactive host cells8
and stimulate a rich matrix of effecter mechanisms involved in innate and adaptive immune responses9
. The GI tract also is a locus of hormone production, including those involved in energy homeostasis (such as insulin, glucagon, leptin and ghrelin) and growth (for example, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1))10
. Alterations in the populations of the GI microbiota may change the intra-community metabolic interactions11
, modify caloric intake by using carbohydrates such as cellulose that are otherwise indigestible by the host12
, and globally affect host metabolic, hormonal and immune homeostasis13
. Full (therapeutic) dose antibiotic treatments alter both the composition of the gastrointestinal microbiota14
and host responses to specific microbial signals15
. In combination with dietary changes, antibiotic administration has been associated with changes in the population structure of the microbiome. However, the effects of exposure to subtherapeutic antibiotic dosages have not been described.
Early studies of the effects of gut microbiota on metabolism were limited by the use of culture-based technologies that interrogated <5% of the extant GI tract microbes16
. Culture-independent investigation of small subunit ribosomal RNA (ssrRNA) sequences allows the microbial population structure17
of the gut microbiota to be characterized with greater resolution. Despite inter-individual differences, substantial similarities exist18
among mammalian species in the GI microbiota at higher taxonomic levels and functional pathways, indicating a basis for the conserved responses to early-life subtherapeutic antibiotic treatment (STAT) within farms. Previous work has shown that obesity leads to variation in the GI microbiome12,19
; we use the insights provided from modern agricultural practices to suggest an alternative approach, using a murine model of STAT to explore how antibiotic exposure modulates host metabolic phenotypes.