Disruption of the Gut Microbiota With Antibiotics Exacerbates Acute Vascular Rejection

ABSTRACTBackgroundThe gut microbiota influences many immunological processes but how its disruption affects transplant rejection is poorly understood.MethodsInterposition grafting of aortic segments was used to examine vascular rejection. The gut microbiota was disrupted in graft recipients using an antibiotic cocktail (ampicillin, vancomycin, metronidazole, neomycin sulfate) in their drinking water.ResultsTreatment of mice with antibiotics severely reduced total bacterial content in the intestine and disrupted the bacterial composition. Short-term treatment of mice for only the first 3 weeks of life resulted in the population of the intestine in mature mice with bacterial communities that were mildly different from untreated mice, containing slightly more Clostridia and less Bacteroides. Antibiotic disruption of the gut microbiota of graft recipients, either for their entire life or only during the first 3 weeks of life, resulted in increased medial injury of allograft arteries that is reflective of acute vascular rejection but did not affect intimal thickening reflective of transplant arteriosclerosis. Exacerbated vascular rejection resulting from disruption of the gut microbiota was related to increased infiltration of allograft arteries by neutrophils.ConclusionDisruption of the gut microbiota early in life results in exacerbation of immune responses that cause acute vascular rejection. Background The gut microbiota influences many immunological processes but how its disruption affects transplant rejection is poorly understood. Methods Interposition grafting of aortic segments was used to examine vascular rejection. The gut microbiota was disrupted in graft recipients using an antibiotic cocktail (ampicillin, vancomycin, metronidazole, neomycin sulfate) in their drinking water. Results Treatment of mice with antibiotics severely reduced total bacterial content in the intestine and disrupted the bacterial composition. Short-term treatment of mice for only the first 3 weeks of life resulted in the population of the intestine in mature mice with bacterial communities that were mildly different from untreated mice, containing slightly more Clostridia and less Bacteroides. Antibiotic disruption of the gut microbiota of graft recipients, either for their entire life or only during the first 3 weeks of life, resulted in increased medial injury of allograft arteries that is reflective of acute vascular rejection but did not affect intimal thickening reflective of transplant arteriosclerosis. Exacerbated vascular rejection resulting from disruption of the gut microbiota was related to increased infiltration of allograft arteries by neutrophils. Conclusion Disruption of the gut microbiota early in life results in exacerbation of immune responses that cause acute vascular rejection. Address correspondence to: Jonathan Choy, PhD, Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6. E-mail: jonathan.choy@sfu.ca AUTHOR CONTRIBUTIONS: K.R., T.V., K.B., R.D.M., F.S.L.B and J.C.C designed the experiments; K.R., S.M., W.E., T.V., and K.B. performed the experiments; K.R., S.M., T.V., K.B., R.D.M., F.S.L.B., and J.C.C analyzed and interpreted the data; K.R., T.V., K.B., R.D.M., F.S.L.B., and J.C.C wrote the manuscript. DISCLOSURES: The authors declare no conflicts of interest. FUNDING: This work was supported by funding from the Heart and Stroke Foundation of Canada (J.C.C), Genome Canada and AllerGen NCE (F.S.L.B), and Natural Sciences and Engineering Research Council of Canada (T.V.R). J.C.C and R.D.M are recipients of Michael Smith Foundation for Health Research Scholar awards. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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