The Microbiome, Systemic Immune Function, and Allotransplantation

Abstract

Diverse effects of the microbiome on solid organ transplantation are beginning to be recognized. In allograft recipients, microbial networks are disrupted by immunosuppression, nosocomial and community-based infectious exposures, antimicrobial therapies, surgery, and immune processes. Shifting microbial patterns, including acute infectious exposures, have dynamic and reciprocal interactions with local and systemic immune systems. Both individual microbial species and microbial networks have central roles in the induction and control of innate and adaptive immune responses, in graft rejection, and in ischemia-reperfusion injury. Understanding the diverse interactions between the microbiome and the immune system of allograft recipients may facilitate clinical management in the future.

FIG 1

Bidirectional effects of the microbiome in allotransplantation. The process of allotransplantation disrupts the composition of the microbiome through a variety of mechanisms, including surgery, immunosuppressive agents, and antimicrobial therapies. Microbial dysbiosis has been associated with the development of chronic rejection, injury from ischemia-reperfusion, and infection. Conversely, microbiome homeostasis is associated with improved allograft outcomes. The role of microbial manipulation (e.g., by fecal transplantation) as a therapeutic measure to improve allograft outcomes is under investigation.

FIG 2

The microbiome in alloimmunity. Under normal conditions, inflammatory responses to gastrointestinal flora are muted via both innate and adaptive immune mechanisms. Subsets of Tregs include both natural, thymus-derived cells with T cell receptors targeting self-antigens and induced Tregs (iTregs) derived from circulating CD4⁺ cells activated in the presence of microbial antigens, transforming growth factor β (TGF-β), and retinoic acid. In the presence of noncommensal microbial antigens, such as those from Clostridium spp. and Gram-positive segmented filamentous bacteria (SFB), and proinflammatory cytokines, iTreg development is blocked and Tregs may be reprogrammed into proinflammatory Th1 and Th17 effector cells. These effects may be blocked by antibacterial agents. Recipient dysbiosis and receipt of antimicrobial agents may shift iTreg development toward proinflammatory adaptive alloimmune responses. GvHD, graft-versus-host disease.