Carlos G Gonzalez, Robert H Mills, Melissa C Kordahi, Marvic Carrillo-Terrazas, Henry Secaira-Morocho, Christella E Widjaja, Matthew S Tsai, Yash Mittal, Brian A Yee, Fernando Vargas, Kelly Weldon, Julia M Gauglitz, Clara Delaroque, Consuelo Sauceda, Leigh-Ana Rossitto, Gail Ackermann, Gregory Humphrey, Austin D Swafford, Corey A Siegel, Jay C Buckey Jr, Laura E Raffals, Charlotte Sadler, Peter Lindholm, Kathleen M Fisch, Mark Valaseck, Arief Suriawinata, Gene W Yeo, Pradipta Ghosh, John T Chang, Hiutung Chu, Pieter Dorrestein, Qiyun Zhu, Benoit Chassaing, Rob Knight, David J Gonzalez, Parambir S Dulai.
Published in April 2022, Cellular and molecular gastroenterology and Hepatology.
Background & Aims Hyperbaric oxygen therapy (HBOT) is a promising treatment for moderate-to-severe ulcerative colitis. However, our current understanding of the host and microbial response to HBOT remains unclear. This study examined the molecular mechanisms underpinning HBOT using a multi-omic strategy.
Methods Pre- and post-intervention mucosal biopsies, tissue, and fecal samples were collected from HBOT phase 2 clinical trials. Biopsies and fecal samples were subjected to shotgun metaproteomics, metabolomics, 16s rRNA sequencing, and metagenomics. Tissue was subjected to bulk RNA sequencing and digital spatial profiling (DSP) for single-cell RNA and protein analysis, and immunohistochemistry was performed. Fecal samples were also used for colonization experiments in IL10-/- germ-free UC mouse models.
Results Proteomics identified negative associations between HBOT response and neutrophil azurophilic granule abundance. DSP identified an HBOT-specific reduction of neutrophil STAT3, which was confirmed by immunohistochemistry. HBOT decreased microbial diversity with a proportional increase in Firmicutes and a secondary bile acid lithocholic acid. A major source of the reduction in diversity was the loss of mucus-adherent taxa, resulting in increased MUC2 levels post-HBOT. Targeted database searching revealed strain-level associations between Akkermansia muciniphila and HBOT response status. Colonization of IL10-/- with stool obtained from HBOT responders resulted in lower colitis activity compared with non-responders, with no differences in STAT3 expression, suggesting complementary but independent host and microbial responses.
Conclusions 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.