Ambient Oxygen Levels Regulate Intestinal Dysbiosis and GVHD Severity After Allogeneic Stem Cell Transplantation

Authors

Keisuke Seike
Anders Kiledal
Hideaki Fujiwara
Israel Henig
Marina Burgos da Silva
Marcel R M van den Brink
Robert Hein
Matthew Hoostal
Chen Liu
Katherine Oravecz-Wilson
Emma Lauder
Lu Li
Yaping Sun
Thomas M Schmidt
Yatrik M Shah
Robert R Jenq
Gregory Dick
Pavan Reddy

Publication Date

2-14-2023

Journal

Immunity

Abstract

The severity of T cell-mediated gastrointestinal (GI) diseases such as graft-versus-host disease (GVHD) and inflammatory bowel diseases correlates with a decrease in the diversity of the host gut microbiome composition characterized by loss of obligate anaerobic commensals. The mechanisms underpinning these changes in the microbial structure remain unknown. Here, we show in multiple specific pathogen-free (SPF), gnotobiotic, and germ-free murine models of GI GVHD that the initiation of the intestinal damage by the pathogenic T cells altered ambient oxygen levels in the GI tract and caused dysbiosis. The change in oxygen levels contributed to the severity of intestinal pathology in a host intestinal HIF-1α- and a microbiome-dependent manner. Regulation of intestinal ambient oxygen levels with oral iron chelation mitigated dysbiosis and reduced the severity of the GI GVHD. Thus, targeting ambient intestinal oxygen levels may represent a novel, non-immunosuppressive strategy to mitigate T cell-driven intestinal diseases.

Keywords

Animals, Mice, Dysbiosis, Hematopoietic Stem Cell Transplantation, Intestines, Graft vs Host Disease, Gastrointestinal Diseases

Comments

Supplementary Materials

PMID: 36736321