Positive Effects of Oral Antibiotic Administration in Murine Chronic Graft-Versus-Host Disease.

Shinri Sato,Yutaka Kawakami,Eisuke Shimizu,Shinji Fukuda,Fan Yang,Kazuki Asai,Kazuo Tsubota,Yoko Ogawa,Jingliang He,Robert Rusch,Mamoru Ogawa,Hiroyuki Yazu,Mio Yamane

doi:10.3390/ijms22073745

Abstract

Chronic graft-versus-host disease (cGVHD) is one of the most frequent complications experienced after allogeneic hematopoietic stem cell transplantation. Reportedly, dysbiosis and severe damage to the microbiome are also closely associated with GVHD. Herein, we aimed to elucidate the positive and negative effects of the administration of various antibiotics in a murine model of cGVHD. For allogeneic bone marrow transplantation (allo-BMT), bone marrow from B10.D2 mice were transplanted in BALB/c mice to induce cGVHD. The cGVHD mice were orally administered ampicillin, gentamicin (GM), fradiomycin, vancomycin, or the solvent vehicle (control group). Among the antibiotic-treated mice, the systemic cGVHD phenotypes and ocular cGVHD manifestations were suppressed significantly in GM-treated mice compared to that in control mice. Inflammatory cell infiltration and fibrosis in cGVHD-targeted organs were significantly attenuated in GM-treated mice. Although regulatory T cells were retained at greater levels in GM-treated mice, there were significantly fewer Th17 cells and interleukin (IL)-6-producing macrophages in cGVHD-targeted organs in these mice. Collectively, our results revealed that orally administered GM may exert positive effects in a cGVHD mouse model.

Highlights

Allogeneic hematopoietic stem cell transplantation is an established treatment for hematologic malignancies and bone marrow failure disorders
At 4 weeks after bone marrow transplantation (BMT), among the antibiotic-treated Graft -versushost disease (GVHD) mice, the systemic GVHD scores of the GM-treated, ABPCtreated, and VCM-treated mice were significantly lower than the score of vehicle-treated mice (Figure 1b)
By 4 weeks post-BMT, the typical signs of the Chronic graft-versus-host disease (cGVHD) phenotype, including blepharitis, skin keratinization, and diarrhea, observed in the non-treated cGVHD mice were more severe than that observed in GM-treated cGVHD mice (Figure 1b, right)

Summary

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment for hematologic malignancies and bone marrow failure disorders. Graft -versushost disease (GVHD) is one of the major complications associated with allo-HSCT and can be categorized into acute (aGVHD) and chronic (cGVHD) types [1]. As the link between the gut microbiota and systemic immune systems has been elucidated in studies, the impact of the gut microbiota on GVHD has received increasing attention. These studies, most of which have been conducted since the 1970s, have shown that the gut microbiota plays an important role in the pathophysiology of GVHD [9,10,11]. The overall diversity of the gut microbiota reduces in patients undergoing allo-HSCT, and a high bacterial diversity is associated with improved overall survival after allo-HSCT [17,21]

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