Retinoic Acid Signaling Modulates Recipient Gut Barrier Integrity and Microbiota After Allogeneic Hematopoietic Stem Cell Transplantation in Mice.

Pan Pan,Samantha N Atkinson,Philip Flejsierowicz,Chen Liu,Xiao Chen,Haojie Zhu,Matthew Morse,Li-Shu Wang,Brian Taylor,Ian L Gunsolus,Dian Zhou

doi:10.3389/fimmu.2021.749002

Pan Pan, Samantha N Atkinson + Show 9 more

Open Access

https://doi.org/10.3389/fimmu.2021.749002

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Abstract

Graft-versus-host disease (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). An impaired intestinal epithelial barrier is an important component of GVHD pathogenesis. However, contributing host factors that modulate mucosal barrier integrity during GVHD are poorly defined. We hypothesized that vitamin A and retinoic acid (RA) exert positive impacts on maintaining intestinal barrier function after HSCT, thus preventing or dampening GVHD severity. Unexpectedly, we found that exogenous RA increased intestinal permeability of recipient mice after allogeneic HSCT. Serum bacterial endotoxin levels were significantly higher in GVHD mice fed a vitamin A-high (VAH) diet compared to those fed a vitamin A-normal (VAN) diet, indicating a more compromised intestinal barrier function. Furthermore, VAH mice showed more severe lung GVHD with increased donor T cell infiltration in this tissue and died significantly faster than VAN recipients. 16S rRNA sequencing of fecal samples revealed significant differences in the diversity and composition of gut microbiota between VAN and VAH transplant recipients. Collectively, we show that retinoic acid signaling may negatively impact intestinal barrier function during GVHD. Mild vitamin A supplementation is associated with increased lung GVHD and more profound gut dysbiosis. Micronutrients such as vitamin A could modulate complications of allogeneic HSCT, which may be mediated by shaping gut microbiota.

Highlights

Graft-versus-host disease (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation (HSCT) [1, 2]
We first examined the effects of retinoic acid (RA), the active metabolite of vitamin A, on intestinal barrier function in a culture system
Gene expression of pro-apoptotic marker Bax and caspase family members (Caspase-3 and Caspase-9) was significantly increased in RA-treated mice (Figure 1F). These results indicate that exogenous RA can negatively impact intestinal barrier function of allogeneic Bone marrow transplantation (BMT) recipients by increasing Claudin-2 expression and promoting the apoptosis of intestinal epithelial cells

Summary

Introduction

Graft-versus-host disease (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation (HSCT) [1, 2]. Since the GI tract is home to an enormous amount of microbiota, its damage from the pretransplant conditioning regimen and subsequent alloimmunity can lead to leakage of immunostimulatory gram-negative bacterial fragments, such as lipopolysaccharide (LPS), into the circulation that can intensify the inflammatory responses characteristic of GVHD [6] In this regard, it has been shown that a breached mucosal epithelial barrier is an important component of GVHD pathogenesis [7, 8]. Accumulating evidence shows that protecting or restoring intestinal epithelial barrier function may be an effective approach in preventing or mitigating GVHD [9,10,11] Such a strategy is appealing because it deviates from conventional GVHD management by targeting recipient nonimmune cells instead of donor immune cells, such as T cells and antigen presenting cells [12,13,14]. Host factors that are involved in maintaining and modulating intestinal barrier function after allogeneic HSCT are not well defined

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