Background: Gut microbiota regulates systemic immunity and can activate pro- or anti-inflammatory pathways. We hypothesized that the gut microbiota influences the survival of mismatched murine cardiac transplants, and microbiota from colitic mice would be pro-inflammatory, while those from pregnant mice would be suppressive. Methods: C57BL/6 mice were fed an antibiotic cocktail on days -6 to -1, and then on d0 received fecal microbiota transfer (FMT) by oral gavage and BALB/c hearts. FMT samples were from healthy C57BL/6, pregnant C57BL/6, spontaneously colitic mice, or cultured Bifidobacterium pseudolongum (Bifido) (a major component of pregnant samples). Tacrolimus (2-3 mg/kg/d sc) was administered starting on d0. Fecal pellets were collected weekly post-transplant and analyzed via 16S rRNA gene sequencing for microbiota profiling and associations with transplant outcome. Cardiac allografts were assessed for survival, harvested at d40-60 or at rejection, and assessed for inflammation by H&E and fibrosis by Masson's Trichrome.Macrophage (MF) and dendritic cell (DC) lines were stimulated with purified Bifido cells in vitro and cytokine response measured. Results: Mice receiving pregnant FMT or Bifido had the highest graft survival rates with the least inflammation and fibrosis, indicating a possible anti-inflammatory and immune suppressive effect of Bifido. Bifido had almost no stimulatory effect on MF, while specifically stimulating DC production of IL-10 and chemokines associated with Treg migration. 16S rRNA analyses of gut microbiota from cardiac transplant recipients treated with normal, colitic, or pregnant FMT, or cultured Bifido., revealed significant differences in bacterial community structure (alpha- and beta-diversity). Bifido were absent in colitic, yet present in normal and pregnant source samples and remained abundant in pregnant transplanted samples for at least 40 days. In contrast, Desulfovibrio and Deferribacteraceae were more abundant in the colitic samples. In general, the microbiota of recipients of normal, colitic, and pregnant fecal samples became less different over time, but remained distinct for at least 40 days. Conclusions: The microbiota has a profound systemic effect on immunity with consequences for organ transplant outcome. Distinct species or genuses may both predict and modify immunity and allograft outcomes, with Bifidobacterium inducing anti-inflammatory effects. Therapeutics targeting the microbiota or its functions could be beneficial in reducing inflammation and subsequent graft rejection.

CITATION INFORMATION: Xiong Y, Brinkman C, Hittle L, Fricke W, Mongodin E, Bromberg J. The Gut Microbiota Regulates Murine Cardiac Transplant Outcome. Am J Transplant. 2017;17 (suppl 3).

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