Intestinal Microbiota Influence Immune Tolerance Post Allogeneic Hematopoietic Cell Transplantation and Intestinal GVHD

Natalie Köhler, Robert Zeiser, Natalie Köhler, Robert Zeiser

Abstract

Under normal conditions our intestines are inhabited by trillions of diverse microorganisms composing the intestinal microbiota, which are mostly non-pathogenic anaerobic commensal bacteria vital for the maintenance of immune homeostasis. The composition and diversity of the intestinal microbiota can be disturbed by various factors including diet, antibiotics, and exposure to intestinal pathogens. Alterations of the intestinal microbiota contributes to many diseases including graft-vs.-host disease (GVHD), a life threatening complication that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) caused by an allogeneic reaction of donor T cells against recipient target tissues. Intestinal GVHD is most difficult to treat and connected to a high mortality. Due to recent advances in high-throughput sequencing technology, composition of the microbiome during allo-HCT has been characterized, and some common patterns have been identified. Metabolites produced by intestinal bacteria were shown to promote intestinal tissue homeostasis and immune tolerance post-allo-HCT. In this review, we discuss the role of the intestinal microbiota and metabolites in the context of acute GVHD. Moreover, novel therapeutic approaches that aim at protecting or regenerating intestinal cell populations will be highlighted.

Keywords: GVHD; Paneth cells; allo-HCT; intestinal inflammation; microbial metabolites; microbiota.

Figures

Figure 1
Figure 1
Microbial metabolites regulating gastrointestinal GVHD. IECs are damaged by the cytotoxic conditioning regimen as well as by GI GVHD, leading to disruption of the intestinal barrier. DAMPs released by the dying IECs as well as translocating bacteria and PAMPs activate host APCs via TLRs and the NLRP3 inflammasome, resulting in pro-inflammatory cytokine release, donor T cell activation, and GVHD. Microbial metabolites derived from intestinal microbiota can regulate IEC damage and mitigate GVHD. SCFAs mediate IEC protection via at least two different mechanisms. Firstly, binding of SCFAs to the G-protein-coupled receptor GPR43 on IECs leads to ERK phosphorylation and subsequent NLRP3 inflammasome activation, which promotes IEC integrity and repair by increasing IL-18 secretion. Secondly, the SCFA butyrate acts as a histone deacetylase inhibitor, thereby increasing expression of many different target genes, including anti-apoptotic BCL-B and the junctional protein JAM. This results in decreased IEC apoptosis and increased junctional integrity and hence IEC protection. MAIT cells located in the lamina propria respond to riboflavin metabolite antigens presented on the MHC class I-like molecule MR-1 to secrete large amounts of IL-17A, which enhances intestinal barrier integrity. Indoles and indole derivatives act via type I IFN signaling to protect and repair the mucosal barrier from damage and ameliorate GVHD. The exact molecular mechanisms and involved proteins remain to be elucidated. APC, antigen-presenting cell; DAMP, danger-associated molecular pattern; GI, gastrointestinal; GVHD, graft-vs.-host disease; IEC, intestinal epithelial cell; IFN, interferon; JAM, junctional adhesion molecule; MAIT cell, mucosal-associated invariant T cell; PAMP, pathogen-associated molecular pattern; SCFA, short chain fatty acid; siTCR, semiinvariant T cell receptor; TLR, Toll-like receptor; UA, uric acid.

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