Advances in Intestinal Barrier Preservation and Restoration in the Allogeneic Hematopoietic Cell Transplantation Setting

Abstract

The intestinal barrier consists of an epithelial lining covered with specialized mucus inhabited by intestinal microbiota. An intact gut barrier ensures a resistance to bacteria and toxins translocation. On the other hand, gut permeability allows the absorption of essential nutrients, fluids and ions. This balance is achieved only by the complex structure and functional characteristics of the intestinal barrier. Allogenic hematopoietic cell transplantation remains the only curative treatment for many hematological diseases, but its application is limited because of possible transplant-related mortality mainly due to graft-versus-host disease and infectious complications. The intestinal barrier has been extensively studied in recent years as the primary site of graft-versus-host disease initiation and propagation. In the present review, we focused on the physiological structure and function of the gut barrier and the evidence of how the disruption of the gut barrier and increased intestinal permeability affects transplant recipients. Finally, therapeutic strategies aiming at intestinal barrier protection with a special focus on microbiome preservation and restoration in the allogenic hematopoietic cell transplantation setting are discussed.

Keywords: allogeneic hematopoietic cell transplantation; graft-versus-host disease; gut permeability; intestinal barrier; microbiome.

Figure 1

Intestinal barrier. Apically placed tight junctions formed by transmembrane proteins (e.g., claudins and occludin) and peripheral scaffolding proteins (e.g., zonula occludens; ZO-1) seal the paracellular space between enterocytes and form the barrier limiting the intestinal microorganisms and pathogenic molecules (PAMPs) passage and, on the other hand, enabling the paracellular absorption of the essential nutrients and ions, depending on the size and charge. The lamina propria is inhabited by the cells of the immune system, e.g., T cells, plasma cells, macrophages and dendritic cells. Tregs modulate the immune system into a tolerance to self-antigens and chronic stimuli by the secretion of Il-10 and TGF-beta and suppression of effector T cells. The intestinal barrier is maintained by the SCFAs produced by the commensal bacteria and several protective molecules, i.e., lysozyme, defensins, REG3 and IgA, secreted by specialized cells of the intestinal lining. ZO-1, zonula occludens-1, DAMPs, damage-associated molecular patterns, PAMPs, pathogen-associated molecular patterns, IL-10. Interleukin 10, TGF-beta, transforming growth factor-beta, SCFAs, short-chain fatty acids, REG3, regenerating islet-derived protein 3 and IgA, Immunoglobulin A.

Figure 2

Intestinal barrier disruption after allo-HCT. Pretransplant conditioning results in enterocyte and Paneth cells apoptosis, leading to lower lactase and higher lactose concentrations and dysbiosis with the Enterococcus genus domination associated with lower SCFA concentrations. An increased MLCK expression results in loosening of the tight junctions and PAMPs translocation into the lamina propria. PAMPs (e.g., LPS) and DAMPs from damaged cells activate APCs. It results in donor T-cell activation, proinflammatory cytokines, i.e., IFN-γ, TNF-α, IL-5 release and GVHD. SCFAs, short-chain fatty acids, MLCK, myosin light chain kinase, PAMPs, pathogen-associated molecular patterns, LPS, lipopolysaccharide, DAMPs, damage-associated molecular patterns, APC, antigen-presenting cell, IFN-γ, interferon gamma, TNF-α, tumor necrosis factor alpha, IL-5, interleukin 5 and GVHD, graft-versus-host disease.