The Microbiome and Immune Regulation After Transplantation

Abstract

The trillions of microorganisms inhabiting human mucosal surfaces participate intricately in local homeostatic processes as well as development and function of the host immune system. These microorganisms, collectively referred to as the "microbiome," play a vital role in modulating the balance between clearance of pathogenic organisms and tolerance of commensal cells, including but not limited to human allografts. Advances in immunology, gnotobiotics, and culture-independent molecular techniques have provided growing insights into the complex relationship between the microbiome and the host, how it is modified by variables such as immunosuppressive and antimicrobial drugs, and its potential impact on posttransplantation outcomes. Here, we provide an overview of fundamental principles, recent discoveries, and clinical implications of this promising field of research.

Figure 1

Conceptual schematic of the multifaceted interaction between the enteric microbiome and the innate and adaptive human immune system. Luminal microorganisms express or metabolize a variety of molecules that can bind to and be recognized by pattern-recognition receptors PRRs such as toll-like receptors (TLRs) and NOD-like receptors (NLRs) on epithelial and other host cells. TLRs signal through MyD88 and MyD88-independent mechanisms and activate a series of signal transduction pathways which culminate in recruitment of effector cells, upregulation of costimulatory molecules on antigen presenting cells (D), enhancement of antigen presentation to T lymphocytes (D), and increased biosynthesis of cytokines and other signaling mediators. Segmented filamentous bacteria (a group of gram positive organisms related to clostridia) drive TH17 and TH1 differentiation (A, B) and compete with pathogenic microbes (eg S. enteritidis) in the intestinal tract. Various clostridial species promote expansion of Tregs with increased levels of TGF-β and IL-10 (C). Polysaccharide A from Bacteroides organisms has been shown to drive the differentiation of TH2 to TH1 T lymphocytes (A), enhance proliferation of Tregs, increase production of IL-10, and protect against experimental colitis (C). Short chain fatty acids (SCFAs), which are bacterial fermentation products of human ingesta, stimulate Treg proliferation, and help regulate Treg homeostasis (C). The enteric microbiota are a source of peptidoglycan that primes the innate immune system and enhances neutrophil function (eg bactericidal activity) via NOD1 NLR signaling (F). IgA from the intestinal lumen is transcytosed into the cytoplasm and plays a critical role in mucosal immunity as a first-line defense mechanism (E). Analogous molecular and cellular signaling occurs throughout other constituent anatomotical regions of the human microbiome (eg respiratory tract, skin) with local and systemic implications.

Figure 2

Diagram of dysbiotic alterations and associated host- and graft-level sequelae. Several factors pre-, intra-, and/or posttransplantation can result in an altered microbiome and consequent dysbiosis. As shown in this figure, these include use of antimicrobials and immunosuppressant drugs, chemotherapy (eg high-dose conditioning for hematopoietic stem cell transplantation [HSCT]), and the new post-surgical anatomy (which can pose anatomical as well as functional/neuromuscular changes). Dysbiosis may lead to or modify several posttransplantation complications such as risk of infection (urinary tract infection, infectious diarrhea), adverse immunologic phenomena (bronchiolitis obliterans postlung transplantation, autoimmune hemolytic anemia), graft-versus-host disease (post- HSCT), graft rejection, recurrence of underlying disease (eg recurrent primary sclerosing cholangitis post-liver transplantation), and increased mortality rates. Selectively avoiding these alterations and inducing eubiotic changes in the peri-transplantation setting may hold preventative and therapeutic potential.