Early immunomodulatory program triggered by pro-tolerogenic Bifidobacterium pseudolongum drives cardiac transplant outcomes

BackgroundDespite ongoing improvements in regimens to prevent allograft rejection, most cardiac and other organ grafts eventually succumb to chronic vasculopathy, interstitial fibrosis, or endothelial changes, and eventually graft failure. The events leading to chronic rejection are still poorly understood and the gut microbiota is a known driving force in immune dysfunction. We previously showed that gut microbiota dysbiosis profoundly influences the outcome of vascularized cardiac allografts and subsequently identified biomarker species associated with these differential graft outcomes. MethodsIn this study, we further detailed the multifaceted immunomodulatory properties of pro-tolerogenic and pro-inflammatory bacterial species over time, using our clinically relevant model of allogenic heart transplantation. ResultsIn addition to tracing longitudinal changes in the recipient gut microbiome over time, we observed that Bifidobacterium pseudolongum (Bifido) induced an early anti-inflammatory phenotype within 7 days, while Desulfovibrio desulfuricans (Desulfo) resulted in a pro-inflammatory phenotype, defined by alterations in leukocyte distribution and lymph node (LN) structure. Indeed, in vitro results showed that Bifido and Desulfo acted directly on primary innate immune cells. However, by 40 days after treatment, these two bacterial strains were associated with mixed effects in their impact on LN architecture and immune cell composition and loss of colonization within gut microbiota, despite protection of allografts from inflammation with Bifido treatment. ConclusionsThese dynamic effects suggest a critical role for early microbiota-triggered immunological events such as innate immune cell engagement, T cell differentiation, and LN architectural changes in the subsequent modulation of pro-tolerant versus pro-inflammatory immune responses in organ transplant recipients.