*Purpose: The gut microbiota is a driving force in host immune regulation, and thus a potential target for intervention and drug development. We previously showed that different microbiota and single bacterial species had specific immune stimulatory or regulatory effects on cardiac allograft outcomes. Microbiota components, such as cell wall and metabolites, interact with cells of the immune system. However, the mechanisms of these processes are mostly unknown. Our study aimed to characterize the specific immune stimulatory or suppressive effects of gut bacteria and their specific components on individual cells of the host immune system.

*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 isolated Bifidobacterium pseudolongum bacteria (Bifido), a dominant member of pregnant gut microbiota). Following transplant, characterization of the gut microbiota was assessed using 16S rRNA gene sequencing and bioinformatic analyses. Bone marrow derived dendritic cells (BMDC) and B cells were stimulated with UV-killed Bifido bacteria (strains from ATCC or isolated from pregnant mouse stools) or isolated Bifido exopolysaccharides (EPS), after which cytokine responses were measured by ELISA and activation markers by flow cytometry.

*Results: Bifido bacteria, abundant in pregnant FMT, prevented graft inflammation and fibrosis and prolonged allograft survival. Desulfovibrio (Desulfo), abundant in normal or colitic FMT, resulted in poor histology and reduced allograft survival. Stimulation of BMDC with Bifido cells or EPS induced the expression of anti-inflammatory cytokines IL-10 and CCL19, but induced lesser amounts of proinflammatory cytokines TNFα and IL-6. EPS did not affect expression of CD40, CD80, CD86, or MHC II on BMDC or B cells. EPS also prevented lipopolysaccharide (LPS) induced TNFα and IL-6 expression by BMDC.

*Conclusions: These results demonstrate the immunomodulatory properties of the gut microbiota, selected bacterial species, and specific bacterial components. Characterization of the anti- and pro-inflammatory properties of the microbiota, in the context of organ transplantation, provides a new avenue for assessing immune responses. Fully characterized microbiota and specific components may serve as both biomarkers and therapeutic targets to prolong allograft survival.

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