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.
Original language | English (US) |
---|---|
Pages (from-to) | 353-368.e6 |
Journal | Immunity |
Volume | 56 |
Issue number | 2 |
DOIs | |
State | Published - Feb 14 2023 |
Keywords
- T cell-mediated gastrointestinal (GI) diseases
- allogeneic
- germ-free
- graft-versus-host host disease
- hypoxia
- iron chelation
- microbiome
- oxygen
- tissue tolerance
- transplantation
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases
MD Anderson CCSG core facilities
- Research Animal Support Facility