FECAL TRANSPLANTATION RESTORES NEOINTIMAL HYPERPLASIA DEVELOPMENT AFTER ARTERIAL INJURY IN GERM-FREE MICE
Edmund Chen*1, Katherine E. Shapiro2, Betty Theriault4, Michael Nooromid1, Kelly Wun1, Vanessa Leone3, Katherine Harris3, Qun Jiang1, Melanie Spedale4, Liqun Xiong1, Owen Eskandari1, Eugene B. Chang3, Karen J. Ho2
1Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL; 2Department of Vascular Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL; 3Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL; 4Department of Surgery and Animal Resources Center, University of Chicago, Chicago, IL
Background: Neointimal hyperplasia development after vascular procedures such as angioplasty and stenting is a cellular proliferative process that is initiated and potentiated by inflammation and leads to arterial restenosis. However, the role of gut microbiota in regulating this process is unknown. We previously demonstrated that germ-free (GF) mice have diminished neointimal hyperplasia development after carotid ligation that is associated with increased M2 macrophage infiltration, reduced proportion of mature neutrophils, and altered systemic inflammatory cytokine profile compared to conventionally-raised (CONV-R) mice. To further understand the causative role of microbiota in neointimal hyperplasia development, we reconstituted bacterial colonization in GF mice with microbiota from CONV-R mice by fecal transplantation.
Methods: Fourteen-week-old C57BL/6 male GF mice underwent oral gavage of a fresh slurry of homogenized stool from donor CONV-R mice. Six weeks later, fecal transplanted GF (GF-FT) mice underwent unilateral carotid artery ligation. Age-, sex- and strain-matched CONV-R and GF mice served as the comparison groups. Neointimal hyperplasia was assessed by morphometric analysis of carotid artery sections four weeks after injury. Calculated measurements included neointima (NI) area, NI+media (NI+M) area, and NI/(NI+M). Maintenance of sterility in the GF cohort was confirmed by cultivation and 16S rRNA gene RT-PCR of stool. Morphometric parameters were compared using the Mann-Whitney U-test. P ≤ 0.05 was considered statistically significant.
Results: As anticipated, the GF cohort developed significantly less neointimal hyperplasia than the CONV-R cohort (mean NI, GF 0.005 ± 0.002 mm2 vs. CONV-R 0.021 ± 0.004 mm2, P = 0.01; mean NI+M, GF 0.029 ± 0.003 mm2 vs. CONV-R 0.055 ± 0.005 mm2, P = 0.005; and mean NI/[NI+M], GF 0.120 ± 0.031 vs. CONV-R 0.290 ± 0.047, P = 0.02). Fecal transplantation of donor CONV-R stool to GF mice attenuated this difference. GF-FT mice had similar neointimal hyperplasia to CONV-R mice, as assessed by NI (GF-FT, 0.014 ± 0.003 mm2; P=0.8), NI+M (GF-FT, 0.049 ± 0.007 mm2; P=0.5) and NI/(NI+M) (GF-FT, 0.249 ± 0.04; P=0.5). All GF mice remained sterile during the entire study period.
Conclusions: We provide evidence that strengthens the proposed connection between gut microbiota and arterial remodeling after injury. Further investigation into the impact of bacterial colonization on arterial inflammation and on the roles of specific microbial community members in arterial remodeling is warranted.
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