Expansion of bacteriophages during disease worsens intestinal inflammation and colitis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA510809 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8354400.fastq.gz | Fastqsanger.gz | |||
| SRR8354401.fastq.gz | Fastqsanger.gz | |||
| SRR8354402.fastq.gz | Fastqsanger.gz | |||
| SRR8354403.fastq.gz | Fastqsanger.gz | |||
| SRR8354404.fastq.gz | Fastqsanger.gz |
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Project description:Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, which has been shown to increase the incidence of colorectal cancer. Recent studies have highlighted the role of ubiquitination, a post-translational modification, in the occurrence and development of colonic inflammation. Ovarian tumor deubiquitinase 6A (OTUD6A) is a deubiquitinating enzyme, which regulates cell proliferation and tumorigenesis. In this study, we investigated the expression and role of OTUD6A in IBD. Wide-type or Otud6a-/- mice were used to develop dextran sodium sulfate (DSS)- or 2,6,4-trinitrobenzene sulfonic acid (TNBS)-induced colitis model, as well as azoxymethane (AOM)/DSS-induced colitis-associated cancer model. Bone marrow-derived macrophages (BMDMs) were isolated from wild-type and Otud6a-/- mice to dissect molecular mechanisms. Our data show that OTUD6A deficiency attenuated DSS or TNBS-induced colitis, as well as AOM/DSS-induced colitis-related colon cancer in vivo. Bone marrow transplantation experiments further revealed that OTUD6A in myeloid cells was responsible for exacerbation of DSS-induced colitis. Mechanistically, OTUD6A directly bound to NACHT domain of NLRP3 inflammasome and selectively cleaved K48-linked polyubiquitin chains from NLRP3 at K430 and K689 to enhance the stability of NLRP3, leading to increased IL-1β level and inflammation. Taken together, our research identifies a new function of OTUD6A in the pathogenesis of colitis by promoting NLRP3 inflammasome activation, suggesting that OTUD6A could be a potential target for the treatment of IBD.
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Project description:Patho-mechanistic origins and disease dynamics of ulcerative colitis are still poorly understood. The actin-crosslinker Filamin A (FLNA) impacts cellular responses through interaction with cytosolic proteins. FLNA exists in two forms that differ only in one amino acid: genome-encoded FLNAQ and FLNAR - generated by post-transcriptional A-to-I editing. FLNA is edited in fibroblasts, smooth muscle- and endothelial cells in the colon. We identified the FLNA editing status as a key determinant of colitis severity. FLNA editing was highest in healthy colons and reduced during acute murine and human colitis. Mice that exclusively express edited FLNAR and do not downregulate editing upon challenge were highly resistant to DSS-induced colitis, whereas fully unedited FLNAQ animals developed severe inflammation. While the genetic induction of FLNA editing influenced transcriptional states of structural cells and the microbiome composition, we found that FLNAR exerts protection specifically via its influence on myeloid cells, which are not edited under physiological conditions. Introducing fixed, fully edited FLNAR did not hamper normal cell migration but reduced macrophage inflammation and rendered neutrophils less prone to NETosis. In conclusion, loss of FLNA editing correlates with colitis severity, and targeted FLNA editing of myeloid cells might serve as a novel therapeutic approach in intestinal inflammation.
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Project description:Objective: In this study, we aimed to evaluate the anti-inflammatory properties of nicotine and anatabine in a dextran sulfate sodium (DSS) mouse model of ulcerative colitis (UC). Methods: C57BL/6 male mice (10 groups with 8 animals each) were orally administered nicotine at a concentration of 5 or 20 mg/kg body weight or anatabine at a concentration of 5 or 20 mg/kg body weight for a total of 21 days. Colitis was induced by oral administration of 3.5% DSS in drinking water ad libitum during days 14–21. Colonic samples were collected for transcriptomic analysis and multi-analyte profiling (MAP). Results: Oral administration of anatabine, but not nicotine, reduced the clinical symptoms of DSS-induced colitis. The result of gene expression analysis suggested that anatabine had a restorative effect on global DSS-induced gene expression profiles, while nicotine only had limited effects. Accordingly, MAP findings revealed that anatabine reduced the colonic abundance of DSS-associated cytokines and increased IL‑10 abundance. Conclusions: Our results support the reduction of inflammatory effects by anatabine in the DSS mouse model of UC.
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