Non-therapeutic administration of a model antimicrobial growth promoter modulates intestinal immune responses

C. rodentium was transformed with the tetracycline resistance gene, tetO, and continuous oral administration of a non-therapeutic dose of chlortetracycline to mice did not affect densities of C. rodentium CFU in feces throughout the experiment or associated with mucosal surfaces in the colon (i.e. at peak and late infection). However, chlortetracycline regulated transcription levels of Th1 and Th17 inflammatory cytokines in a temporal manner in C. rodentium-inoculated mice, and ameliorated weight loss associated with infection. In mice inoculated with C. rodentium, those that received chlortetracycline had less pathologic changes in the distal colon than mice not administered CTC (i.e. relative to untreated mice). Furthermore, chlortetracycline administration at a non-therapeutic dose did not impart either prominent or consistent effects on the colonic microbiota.Data support the hypothesis that AGP function by modulating the intestinal immune system in mammals. This finding may facilitate the development of biorationale-based and efficacious alternatives to AGP.The in-feed administration of non-therapeutic doses of antimicrobial growth promoters (AGP) has been successfully used to promote animal growth for more than 60 years [1]. Unfortunately, the indiscriminate use of AGP [2] has contributed to the emergence of antimicrobial resistance (AMR) in zoonotic pathogens [3-5], and the European Union (EU) implemented a precautionary ban on administration of all AGP (i.e. at non-therapeutic doses) to livestock [6,7]. The AGP ban in the EU increased the therapeutic administration of antimicrobial agents [6], as well as the cost of animal production, and resulted in a general decline in livestock production [8]. A recent guidance document issued by the United States Food and Drug Administration recommended restrictions that would limit the use of AGP [9]. Thus, it is anticipated that an AGP ban will progressively be imposed in North America, adversely affecting the sustaina