Protecting Intestinal Microenvironment Alleviates Acute Graft-Versus-Host Disease

Zhengcan Zhou; Ting Shang; Xiurong Li; Hongyan Zhu; Yu-Bo Qi; Xin Zhao; Xi Chen; Zhe-Xin Shi; Guixiang Pan; Yue-Fei Wang; Guanwei Fan; Xiumei Gao; Yan Zhu; Yuxin Feng

doi:10.3389/fphys.2020.608279

Protecting Intestinal Microenvironment Alleviates Acute Graft-Versus-Host Disease

Front Physiol. 2021 Feb 12:11:608279. doi: 10.3389/fphys.2020.608279. eCollection 2020.

Authors

Zhengcan Zhou^{1

2}, Ting Shang^{1

2}, Xiurong Li³, Hongyan Zhu^{1

2}, Yu-Bo Qi⁴, Xin Zhao¹, Xi Chen¹, Zhe-Xin Shi⁴, Guixiang Pan^{1

2}, Yue-Fei Wang^{1

2}, Guanwei Fan⁴, Xiumei Gao¹, Yan Zhu^{1

2}, Yuxin Feng^{1

2}

Affiliations

¹ State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
² Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin, China.
³ State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
⁴ First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.

Abstract

Acute gut graft-versus-host disease (aGVHD) is a leading threat to the survival of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Abnormal gut microbiota is correlated with poor prognosis in allo-HSCT recipients. A disrupted intestinal microenvironment exacerbates dysbiosis in GVHD patients. We hypothesized that maintaining the integrity of the intestinal barrier may protect gut microbiota and attenuate aGVHD. This hypothesis was tested in a murine aGVHD model and an in vitro intestinal epithelial culture. Millipore cytokine array was utilized to determine the expression of proinflammatory cytokines in the serum. The 16S rRNA sequencing was used to determine the abundance and diversity of gut microbiota. Combining Xuebijing injection (XBJ) with a reduced dose of cyclosporine A (CsA) is superior to CsA alone in improving the survival of aGVHD mice and delayed aGVHD progression. This regimen also reduced interleukin 6 (IL-6) and IL-12 levels in the peripheral blood. 16S rRNA analysis revealed the combination treatment protected gut microbiota in aGVHD mice by reversing the dysbiosis at the phylum, genus, and species level. It inhibited enterococcal expansion, a hallmark of GVHD progression. It inhibited enterococcal expansion, a hallmark of GVHD progression. Furthermore, Escherichia coli expansion was inhibited by this regimen. Pathology analysis revealed that the combination treatment improved the integrity of the intestinal tissue of aGVHD mice. It also reduced the intestinal permeability in aGVHD mice. Besides, XBJ ameliorated doxorubicin-induced intestinal epithelial death in CCK-8 assay. Overall, combining XBJ with CsA protected the intestinal microenvironment to prevent aGVHD. Our findings suggested that protecting the intestinal microenvironment could be a novel strategy to manage aGVHD. Combining XBJ with CsA may reduce the side effects of current aGVHD prevention regimens and improve the quality of life of allo-HSCT recipients.

Keywords: Chinese medicine; Xuebijing injection; acute graft vs. host disease; allogenic hematopoietic transplantation; biomarkers; cyclosporine A; gut microbiota; integrative medicine.