Ambient oxygen levels regulate intestinal dysbiosis and GVHD severity after allogeneic stem cell transplantation

T-cell mediated gastro-intestinal (GI) diseases such as graft-versus-host host disease (GVHD) and inflammatory bowel diseases (IBD) cause significant morbidity and mortality. Multiple studies have correlated the changes in the gut microbiome composition with a decrease in microbial diversity caused by loss of obligate anaerobic commensals to the outcomes of these diseases. However, the mechanisms underpinning the changes in the microbial structure remain unknown. Furthermore, whether the associated change in the microbiome is a cause, a consequence, a regulator, or an amplifier of the disease severity remains unclear. Here we show that the changes in the structure of the gut microbiome is not a cause, but a consequence that regulates the intestinal damage initiated by pathogenic T cells. We found in multiple co-housed, gavaged, antibiotic treated, germ-free (GF) and in gnotobiotic models of GI GVHD that the initiation of the intestinal damage by the pathogenic T cells alters the ambient oxygen levels in the GI tract and droves dysbiosis. The change in oxygen levels contributed to the severity of intestinal pathology in host intestinal HIF-1a and microbiome dependent manner. Regulation of intestinal ambient oxygen levels with oral Fe chelation mitigated dysbiosis and reduced the severity of the GI GVHD. Our results thus provide a mechanism for the changes in microbiome that are correlated with GI GVHD and identify targeting of ambient oxygen levels with available Fe chelation methods as a relevant, novel strategy for treating non-infectious T-cell mediated intestinal diseases.