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Disruption of the Gut Microbiota With Antibiotics Exacerbates Acute Vascular Rejection

Rey, Kevin, BSc1; Manku, Sukhbir, BSc1; Enns, Winnie, BSc1; Van Rossum, Thea, PhD1; Bushell, Kevin, MSc1; Morin, Ryan D., PhD1; Brinkman, Fiona S.L., PhD1; Choy, Jonathan C., PhD1

doi: 10.1097/TP.0000000000002169
Original Basic Science—General

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.

Conclusions Disruption of the gut microbiota early in life results in exacerbation of immune responses that cause acute vascular rejection.

Disruption of mice gut microbiota, either for their entire life or only during the first 3 weeks of life, results in increased acute vascular rejection of allograft arteries due to infiltration of the media by neutrophils. Intima thickening of the arteries reflecting chronic rejection is not affected.

1 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.

Received 4 December 2017. Revision received 8 February 2018.

Accepted 16 February 2018.

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.

The authors declare no conflicts of interest.

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 article.

Correspondence: Jonathan Choy, PhD, Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6. (jonathan.choy@sfu.ca).

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

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