TY - JOUR
T1 - Antibiotics promote inflammation through the translocation of native commensal colonic bacteria
AU - Knoop, Kathryn A.
AU - McDonald, Keely G.
AU - Kulkarni, Devesha H.
AU - Newberry, Rodney D.
N1 - Funding Information:
Supported by grants DK64798-RDN, AI009550-RDN, DK097317-RDN, DK097893-KAK. The High Speed Cell Sorter Core at the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO, provided flow cytometric cell sorting services. The Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant P30 CA91842. The Speed Congenics Facility of the Rheumatic Diseases Core Center, supported by NIH grant P30AR048335 bred the Myd88-/- mice onto the C57BL/6 background. The two photon imaging was performed at the In Vivo Imaging Core at Washington University School of Medicine. The authors wish to thank Dr. Mark J. Miller for advice and assistance with in vivo imaging. The Washington University Digestive Diseases Research Center Core (DDRCC), supported by NIH grant P30 DK052574 assisted with imaging services.
PY - 2016/7
Y1 - 2016/7
N2 - Objective Antibiotic use is associated with an increased risk of developing multiple inflammatory disorders, which in turn are linked to alterations in the intestinal microbiota. How these alterations in the intestinal microbiota translate into an increased risk for inflammatory responses is largely unknown. Here we investigated whether and how antibiotics promote inflammation via the translocation of live native gut commensal bacteria. Design Oral antibiotics were given to wildtype and induced mutant mouse strains, and the effects on bacterial translocation, inflammatory responses and the susceptibility to colitis were evaluated. The sources of the bacteria and the pathways required for bacterial translocation were evaluated using induced mutant mouse strains, 16s rRNA sequencing to characterise the microbial communities, and in vivo and ex vivo imaging techniques. Results Oral antibiotics induced the translocation of live native commensal bacteria across the colonic epithelium, promoting inflammatory responses, and predisposing to increased disease in response to coincident injury. Bacterial translocation resulted from decreased microbial signals delivered to colonic goblet cells (GCs), was associated with the formation of colonic GC-associated antigen passages, was abolished when GCs were depleted and required CX3 CR1+ dendritic cells. Bacterial translocation occurred following a single dose of most antibiotics tested, and the predisposition for increased inflammation was only associated with antibiotics inducing bacterial translocation. Conclusions These findings reveal an unexpected outcome of antibiotic therapy and suggest that bacterial translocation as a result of alterations in the intestinal microflora may provide a link between increasing antibiotic use and the increased incidence of inflammatory disorders.
AB - Objective Antibiotic use is associated with an increased risk of developing multiple inflammatory disorders, which in turn are linked to alterations in the intestinal microbiota. How these alterations in the intestinal microbiota translate into an increased risk for inflammatory responses is largely unknown. Here we investigated whether and how antibiotics promote inflammation via the translocation of live native gut commensal bacteria. Design Oral antibiotics were given to wildtype and induced mutant mouse strains, and the effects on bacterial translocation, inflammatory responses and the susceptibility to colitis were evaluated. The sources of the bacteria and the pathways required for bacterial translocation were evaluated using induced mutant mouse strains, 16s rRNA sequencing to characterise the microbial communities, and in vivo and ex vivo imaging techniques. Results Oral antibiotics induced the translocation of live native commensal bacteria across the colonic epithelium, promoting inflammatory responses, and predisposing to increased disease in response to coincident injury. Bacterial translocation resulted from decreased microbial signals delivered to colonic goblet cells (GCs), was associated with the formation of colonic GC-associated antigen passages, was abolished when GCs were depleted and required CX3 CR1+ dendritic cells. Bacterial translocation occurred following a single dose of most antibiotics tested, and the predisposition for increased inflammation was only associated with antibiotics inducing bacterial translocation. Conclusions These findings reveal an unexpected outcome of antibiotic therapy and suggest that bacterial translocation as a result of alterations in the intestinal microflora may provide a link between increasing antibiotic use and the increased incidence of inflammatory disorders.
UR - http://www.scopus.com/inward/record.url?scp=84973861100&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2014-309059
DO - 10.1136/gutjnl-2014-309059
M3 - Article
C2 - 26045138
AN - SCOPUS:84973861100
SN - 0017-5749
VL - 65
SP - 1100
EP - 1109
JO - Gut
JF - Gut
IS - 7
ER -