Ulcerative Colitis Host-Microbiome Response to Hyperbaric Oxygen Therapy

Objective: This study examined the host-microbe changes underpinning treatment response to hyperbaric oxygen therapy (HBOT) in ulcerative colitis. Design: Pre- and post-intervention mucosal tissue and fecal samples from two clinical trials, along with fecal samples from healthy controls and fecal and mucosal tissue from disease severity matched UC controls. Mucosal tissue bulk-RNA sequencing, digital spatial profiling (DSP) for single-cell RNA and protein analysis, and immunohistochemistry was performed, in addition to 16S rRNA, shotgun metagenomics, metabolomics, and metaproteomics of fecal samples. Fecal colonization experiments in IL10-/- germ-free mice were performed to confirm observations. Results: Proteomics identified associations between HBOT response status and neutrophil degranulation, with specificity of effect for azurophilic granules. DSP identified a specific HBOT effect on reducing neutrophil STAT3, which was confirmed by immunohistochemistry. HBOT decreased microbial diversity with an accompanying proportional increase in Firmicutes and a secondary bile acid lithocholic acid. The reduction in diversity was due to reductions in mucinophiles, with differences in Akkermansia muciniphila strains being associated with HBOT response status. Proteomics observed an accompanying effect for HBOT on MUC2. Colonization of IL10-/- with stool obtained from HBOT responders resulted in lower colitis activity compared to stool obtained from HBOT non-responders, with no differences in STAT3 expression, suggesting complementary but independent host and microbial responses. Conclusion: HBOT reduces host neutrophil STAT3 and azurophilic granule activity in UC patients, and changes in microbial composition and metabolism in ways that improve colitis activity. Intestinal microbiota, especially strain level variations in A. muciniphila, may contribute to HBOT non-response.