Short-term antibiotic treatment immediately after weaning prevents spontaneous ileocolitis

Abstract

Abstract A spontaneous model of ileocolitis, a condition found in a majority of cases of Crohn’s Disease, allows for the study of processes that promote homeostasis within the ileum. Our system uses a “Bigenic” approach that combines TCR transgene mice with a transgenic line expressing the cognate antigen in ileal crypts. Bigenic mice exhibit decreased nTreg production that predisposes them to developing a chronic ileocolitic inflammatory disease in the weeks after weaning. Half of Bigenic mice accumulate ileal-reactive Treg cells and fail to develop colitis. In contrast, Ifng−/− Bigenic mice are unable to establish this homeostatic state, resulting in a fully penetrant and acute colitis. We aimed to identify time sensitive interventions capable of preventing colitis and restoring mucosal homeostasis in Ifng−/− Bigenic mice. Mice were started at weaning on a prophylactic treatment with ad libidum non-absorbable antibiotics in their drinking water and continued for three weeks. Alternately, mice were allowed to naturally progress into a disease state at which time the same antibiotic treatments were initiated and continued for nine weeks. We found that antibiotics prevented ileocolitic disease when initiated at weaning but were insufficient to reverse established disease measured by weight loss. Interestingly, this resistance to ileocolitis mediated by short-term early use of antibiotics was maintained, as these mice did not subsequently manifest either ileocolitis or the degree of breakthrough weight loss observed in antibiotic-rescued mice. Our findings suggest that in our model of ilieocolitis, there is a critical window of time after weaning where manipulation of the microbiome alone can facilitate resistance to spontaneous disease.