*Purpose: The gut microbiota driven inflammatory response and the host immune system engage bidirectional regulation of each other. These interactions are poorly characterized in organ transplantation. We hypothesized that changes in the gut microbiota and innate immunity will determine the outcome of allograft survival.

*Methods: Antibiotic pretreated mice received vascularized cardiac allografts and fecal microbiota transfer (FMT), along with tacrolimus. FMT samples were from normal, pregnant (immune suppressed), and spontaneously colitic (inflamed) mice, or cultured Bifidobacterium pseudolongum (Bifido) (a dominant member of pregnant gut microbiota). Fecal pellets collected post-transplant were analyzed by 16S rRNA gene sequencing. Grafts were assessed for inflammation by H&E and fibrosis by trichrome. Lymph nodes (LN) were assessed for ratio of laminin α4/α5 by immunohistochemistry, a determinant of immune reactivity or suppression. Macrophage (MΦ) and dendritic cells (DC) were stimulated with purified Bifido cells and extracellular polysaccharides (EPS), and cytokine responses measured by ELISA.

*Results: Pregnant FMT, abundant in Bifido, prolonged allograft survival and prevented graft inflammation and fibrosis. Normal or colitic FMT, abundant in Desulfovibrio (Desulfo), resulted in inferior survival and worse histology. Bifido remained abundant in pregnant FMT recipient samples for at least 40 days. Stimulation of MΦ and DC with Bifido cells or EPS induced the ant-inflammatory IL-10 and homestatic CCL19. In contrast LPS and Desulfo induced proinflammatory TNFα and IL-6. Analysis of mesenteric and peripheral LN structure showed Bifido gavage resulting in a higher ratio of laminin α4/α5 in the cortical ridge and around the high endothelial venules, indicatitive of a suppressive environment; while Desulfo resulted in a lower ratio of laminin α4/α5, supportive of inflammation. Bifido also resulted in increased Treg induction and decreased T cell activation, as compared to Desulfo or normal FMT.

*Conclusions: These results demonstrate gut microbiota stimulates innate immunity, which influences LN structure, alloantigen specific T cell fate, and allograft outcome. Definition of pro- and anti-inflammatory microbiota in the context of organ transplantation will help in determining allograft survival outcome. Therapeutic targeting of the microbiota or its functions could be beneficial in reducing inflammation and allograft scarring.

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