Challenges and opportunities targeting mechanisms of epithelial injury and recovery in acute intestinal graft-versus-host disease

Abstract

Despite advances in immunosuppressive prophylaxis and overall supportive care, gastrointestinal (GI) graft-versus-host disease (GVHD) remains a major, lethal side effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). It has become increasingly clear that the intestinal epithelium, in addition to being a target of transplant-related toxicity and GVHD, plays an important role in the onset of GVHD. Over the last two decades, increased understanding of the epithelial constituents and their microenvironment has led to the development of novel prophylactic and therapeutic interventions, with the potential to protect the intestinal epithelium from GVHD-associated damage and promote its recovery following insult. In this review, we will discuss intestinal epithelial injury and the role of the intestinal epithelium in GVHD pathogenesis. In addition, we will highlight possible approaches to protect the GI tract from damage posttransplant and to stimulate epithelial regeneration, in order to promote intestinal recovery. Combined treatment modalities integrating immunomodulation, epithelial protection, and induction of regeneration may hold the key to unlocking mucosal recovery and optimizing therapy for acute intestinal GVHD.

Gut microbiota, microbiota‐derived metabolites, and graft‐versus‐host disease

“…Disruptions to the gut microbial balance can lead to the loss of multiple host functions, including impaired intestinal barrier function, immune dysfunction, and inflammation, which are associated with various diseases 9,11,14,15 . In allo‐HSCT patients, a pretreatment regimen before transplantation including chemotherapy, radiotherapy, immunotherapy, and broad‐spectrum antibiotics followed by the activation of allogeneic T cells following transplantation can damage IECs and change the composition of the gut microbiota, resulting in decreased intestinal commensal bacteria 3,31–34 . The interaction between gut microbiota and GVHD has been studied for several decades.…”

“…9,11,14,15 In allo-HSCT patients, a pretreatment regimen before transplantation including chemotherapy, radiotherapy, immunotherapy, and broadspectrum antibiotics followed by the activation of allogeneic T cells following transplantation can damage IECs and change the composition of the gut microbiota, resulting in decreased intestinal commensal bacteria. 3,[31][32][33][34] The interaction between gut microbiota and GVHD has been studied for several decades. As early as the 1970s, it was shown that rearing mice in a sterile environment 35 or antibiotic-mediated intestinal purification 36 reduced aGVHD symptoms.…”

Mesenchymal (Stem) Stromal Cells Based as New Therapeutic Alternative in Inflammatory Bowel Disease: Basic Mechanisms, Experimental and Clinical Evidence, and Challenges

“…Nevertheless, it has been described that NOD2 contributes to intestinal crypt survival in vivo [ 37 ], but when stimulated by muramyl dipeptide, NOD2 in the non-hematopoietic compartment normalized the permeability [ 36 ]. So, NOD2 expression in hematopoietic or non-hematopoietic compartment could exhibit a protective role GVHD [ 38 ] and regulate intestinal barrier function.…”

IFNγ induces epithelial reprogramming driving CXCL11-mediated T cell migration

“…The immune system of the gut is remarkably complex and consists of a variety of innate and adaptive immune cells that act to oppose a variety of possible threats 2 . Among other immune cells, T cells play a major role in several pathologies affecting the gastrointestinal tract, for instance, inflammatory bowel disease (IBD), coeliac disease, and acute intestinal graft-versus-host disease (GVHD) [2][3][4][5][6][7][8][9] .…”