[HTML][HTML] Gut microbiota can impact chronic murine lung allograft rejection

Q Wu, B Turturice, S Wagner, Y Huang… - American journal of …, 2019 - atsjournals.org
Q Wu, B Turturice, S Wagner, Y Huang, PK Gupta, C Schott, A Metwally, R Ranjan
American journal of respiratory cell and molecular biology, 2019atsjournals.org
The role of the microbiome in regulation of immune homeostasis is well established, and its
alteration underlies the immunopathogenesis of a variety of diseases (1, 2). Clinical and
animal studies have recently found that derangement in the microbiome may impact
transplant outcomes by contributing to allograft dysfunction after liver, small bowel, and skin
transplantation (3–5). Clinical studies have also shown that lung transplantation alters the
composition of the lung microbiome (6, 7). However, whether the gut microbiome can …
The role of the microbiome in regulation of immune homeostasis is well established, and its alteration underlies the immunopathogenesis of a variety of diseases (1, 2). Clinical and animal studies have recently found that derangement in the microbiome may impact transplant outcomes by contributing to allograft dysfunction after liver, small bowel, and skin transplantation (3–5). Clinical studies have also shown that lung transplantation alters the composition of the lung microbiome (6, 7). However, whether the gut microbiome can modulate lung transplant outcomes remains unknown. Lung allografts are limited by the development of chronic lung allograft rejection (8), and transplant-associated ischemia–reperfusion injury is a major risk factor for chronic lung allograft rejection (9–11). A recent animal study showed that administration of broadspectrum antibiotics to reduce gut microbiota can ameliorate lung ischemia–reperfusion injury (12). In a previous report, we found that CD4 1 T lymphocytes were required for the expansion of an IL-17A response in the lung allograft that is necessary for the development of obliterative bronchiolitis, the histological correlate of chronic lung allograft rejection (13). Gut microbiota can regulate T-helper cell type 17 (Th17) cell homeostasis (14), raising the possibility that alterations in the gut microbiota can impact lung allograft rejection. Hence, we hypothesized that alterations in microbiota may also impact lung transplant outcomes, particularly chronic lung allograft rejection, which is characterized by airway remodeling and fibrosis.
To address this question, we used a minor mismatch model of orthotopic lung transplantation with C57BL/10 mice as donors and C57BL/6N mice as recipients in a pathogen-free facility, as we previously described (13). To alter the microbiota at the time of transplantation, both donor and recipient mice were treated by daily oral gavage (200 ml) with a cocktail of broad-spectrum antibiotics we previously reported (5), including gentamycin (0.35 mg/ml), kanamycin (5.25 mg/ml), colistin (8,500 U), metronidazole (2.15 mg/ml), and vancomycin (0.5 mg/ml) diluted in autoclaved water, starting 10 days before transplantation and ending the day before transplantation. In the control group, mice were treated with 200 ml of autoclaved water orally. This treatment timing was intended to reduce microbial diversity at the priming phase of the alloresponse, when T cells first encounter donor antigens, so that we could investigate whether dysbiosis at the priming stage affected Th17 differentiation after lung transplantation. We also hypothesized that the microbiota from not only the recipient but also the donor would modulate the alloresponse after lung
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