期刊
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
卷 14, 期 1, 页码 35-53出版社
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2022.03.008
关键词
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资金
- American Gastroenterology Association Research Scholar Award
- NIDDK U34 Planning Grant [DK126626]
- Crohn's and Colitis Foundation through a Litwin IBD Pioneers Program Grant
- UCSD Collaborative Center for Multiplexed Proteomics
- San Diego Digestive Disease Center [P30 DK120515]
- UCSD Gastroenterology T32 training grant [DK 0070202]
- UCSD Graduate Training Program in Cellular and Molecular Pharmacology [T32 GM007752]
- NIH CTSA [1TL1TR001443]
- NIH [2UL1TR001442-06, UG3TR003355, AI155696, AI141630, AI123202, AI129973, AI132122, DK119724]
- Institutional Research and Academic Career Development Awards [K12GM068524]
- NIH Training grant (T32) [DK007202]
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [ERC-2018-StG-804135]
- Chaire d'Excellence from IdEx Universite de Paris [ANR-18-IDEX-0001]
- Kenneth Rainin Foundation
- ANR [EMULBIONT ANR-21-CE15-004201]
- INSERM
- Crohn's and Colitis Foundation [675191]
This study investigated the molecular mechanisms of hyperbaric oxygen therapy (HBOT) for moderate-to-severe ulcerative colitis. The findings indicate that HBOT reduces neutrophil STAT3 and azurophilic granule activity in UC patients, and improves colitis activity by altering microbial composition and metabolism. The strain-level variations in A muciniphila in the intestinal microbiota may contribute to the nonresponse to HBOT.
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-omit 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 mucusadherent 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 nonresponse.
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