Gene expression profile at single cell level of intraepithelial neutrophils (IENs) and lamina propria neutrophils (LPNs) of the colon from dextran sulfate sodium (DSS)-treated mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE278437 | GEO | 2025/03/10
REPOSITORIES: GEO
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Project description:Uridine, one of the four components that comprise RNA, has attracted attention as a novel therapeutic modulator of inflammation. However, very little is known about its effect on intestinal inflammation. The aim of the present study was to investigate the potential protective effect of intracolonic administered uridine against DSS induced colitis in male C57BL/6 mice. Intracolonic instillation of 3 doses of uridine 1 mg/Kg (lower dose), 5 mg/Kg (medium dose), and 10 mg/Kg (higher dose) in saline was performed daily. Uridine at medium and high dose significantly reduced the severity of colitis (DAI score) and alleviated the macroscopic and microscopic signs of the disease. The levels of proinflammatory cytokines IL-6, IL-1β and TNF in serum as well as mRNA expression in colon were significantly reduced in the uridine treated groups. Moreover, colon tissue myloperoxidase activities, protein expression of IL-6, TNF- α, COX-2, P-NFkB and P-Ikk-βα in the colon tissues were significantly reduced in medium and high dose groups. These findings demonstrated that local administration of uridine alleviated experimental colitis in male C57BL/6 mice accompanied by the inhibition of neutrophil infiltration and NF-κB signaling. Thus, Uridine may be a promising candidate for future use in the treatment of inflammatory bowel disease.
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Project description:Previous studies have reported that anthocyanin (ACN)-rich materials have beneficial effects on ulcerative colitis (UC). Blackcurrant (BC) has been known as one of the foods rich in ACN, while studies demonstrating its effect on UC are rare. This study attempted to investigate the protective effects of whole BC in mice with colitis using dextran sulfate sodium (DSS). Mice were orally given whole BC powder at a dose of 150 mg daily for four weeks, and colitis was induced by drinking 3% DSS for six days. Whole BC relieved symptoms of colitis and pathological changes in the colon. The overproduction of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 in serum and colon tissues was also reduced by whole BC. In addition, whole BC significantly lowered the levels of mRNA and protein of downstream targets in the NF-κB signaling pathway. Furthermore, BC administration increased the expression of genes related to barrier function: ZO-1, occludin, and mucin. Moreover, the whole BC modulated the relative abundance of gut microbiota altered with DSS. Therefore, the whole BC has demonstrated the potential to prevent colitis through attenuation of the inflammatory response and regulation of the gut microbial composition.
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Project description:Spatially separated intraepithelial and lamina propria neutrophils present distinct functional identities in the inflamed colon mucosa
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Project description:BackgroundNecrotizing enterocolitis (NEC) is an inflammatory bowel disease of preterm human newborns with yet unresolved etiology. An established neonatal murine model for NEC employs oral administration of lipopolysaccharides (LPS) combined with hypoxia/hypothermia. In adult mice, feeding dextran sodium sulfate (DSS) represents a well-established model for experimental inflammatory bowel disease. Here we investigated the effect of DSS administration on the neonatal murine intestine in comparison with the established NEC model.Methods3-day-old C57BL/6J mice were either fed formula containing DSS or LPS. LPS treated animals were additionally stressed by hypoxia/hypothermia twice daily. After 72 h, mice were euthanized, their intestinal tissue harvested and analyzed by histology, qRT-PCR and flow cytometry. For comparison, adult C57BL/6J mice were fed with DSS for 8 days and examined likewise. Untreated, age matched animals served as controls.ResultsAdult mice treated with DSS exhibited colonic inflammation with significantly increased Cxcl2 mRNA expression. In contrast, tissue inflammation in neonatal mice treated with DSS or LPS plus hypoxia/hypothermia was present in colon and small intestine as well. Comparative analysis of neonatal mice revealed a significantly increased lesion size and intestinal Cxcl2 mRNA expression after DSS exposure. Whereas LPS administration mainly induced local neutrophil recruitment, DSS treated animals displayed increased monocytes/macrophages infiltration.ConclusionsOur study demonstrates the potential of DSS to induce NEC-like lesions accompanied by a significant humoral and cellular immune response in the small and large intestine of neonatal mice. The new model therefore represents a good alternative to LPS plus hypoxia/hypothermia administration requiring no additional physical stress.
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Project description:Akkermansia muciniphila has been proved to play a crucial role in the progression of colitis, but its underlying mechanism remains inconclusive. In this study, we aim to investigate the effect of A. muciniphila on the development of acute colitis and explore the underlying mechanism. We found that the fecal level of A. muciniphila was decreased in ulcerative colitis (UC) patients compared to the healthy people in the GMrepo database. Oral administration of A. muciniphila strain BAA-835 significantly ameliorated the symptoms in dextran sulfate sodium (DSS)-induced acute colitis, evidenced by decreased body weight loss, colon length shortening, and colon histological inflammatory score. In addition, the number of goblet cells and the mucin family were enhanced after A. muciniphila treatment. Furthermore, proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein 1 (MCP-1) had a downward trend. Mechanistically, the expression of NLRP3, caspase-1 p20, and IL-1β p17 were upregulated in A. muciniphila-treated mice. Additionally, the colon tissues from high-A. muciniphila UC patients had a higher NLRP3 expression than that from low-A. muciniphila UC patients. Moreover, the upregulation of NLRP3 was observed in mouse macrophage Raw264.7 cells and bone marrow-derived macrophage (BMDM) cells after incubation with A. muciniphila. To clarify whether the protective effect of A. muciniphila in colitis depends on NLRP3, we performed the NLRP3-deficient assay in NLRP3-/- mice in vivo. The evidence showed that NLRP3 deficiency eliminated the protective effects of A. muciniphila in acute colitis. In conclusion, A. muciniphila alleviates DSS-induced acute colitis by NLRP3 activation, which enriches the mechanism and provides a new prospect for the probiotic-based treatment of colitis. IMPORTANCE The gut microbiota and host immune response interaction influences the progression of intestinal inflammatory disease. As a well-recognized next-generation probiotic, Akkermansia muciniphila has been proved to play a crucial role in the progression of colitis, but its underlying mechanism remains inconclusive. We found that oral administration of A. muciniphila strain BAA-835 significantly ameliorated the symptoms of acute colitis. Mechanistically, the expression of NLRP3 was upregulated in the A. muciniphila group, and the protective effect of A. muciniphila in colitis depends on NLRP3 activation. This enriches the mechanism and provides a new prospect for the probiotic-based treatment of colitis, which would promote a deeper understanding of the complex characteristics of A. muciniphila and provide guidance for the treatment of human colitis in the future.
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Project description:Gene expression profile at single cell level of intraepithelial neutrophils (IENs) and lamina propria neutrophils (LPNs) of the colon from dextran sulfate sodium (DSS)-treated mice
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Project description:Family with sequence similarity 96 member A (FAM96A) is an evolutionarily conserved intracellular protein that is involved in the maturation of the Fe/S protein, iron regulatory protein 1 (IRP1), and the mitochondria-related apoptosis of gastrointestinal stromal tumor cells. In this study, we used a mouse model of chemically induced colitis to investigate the physiological role of FAM96A in intestinal homeostasis and inflammation. At baseline, colons from Fam96a -/- mice exhibited microbial dysbiosis, dysregulated epithelial cell turnover, an increased number of goblet cells, and disordered tight junctions with functional deficits affecting intestinal permeability. After cohousing, the differences between wild-type and Fam96a -/- colons were abrogated, suggesting that FAM96A affects colonic epithelial cells in a microbiota-dependent manner. Fam96a deficiency in mice resulted in increased susceptibility to dextran sulfate sodium (DSS)-induced colitis. Importantly, the colitogenic activity of Fam96a -/- intestinal microbiota was transferable to wild-type littermate mice via fecal microbial transplantation (FMT), leading to exacerbation of DSS-induced colitis. Taken together, our data indicate that FAM96A helps to maintain colonic homeostasis and protect against DSS-induced colitis by preventing gut microbial dysbiosis. This study used gene knockout animals to help to understand the in vivo effects of the Fam96a gene for the first time and provides new evidence regarding host-microbiota interactions.
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Project description:Akermansia muciniphila shows promise as a next-generation probiotic, however, its beneficial regulatory effects on mice ulcerative colitis (UC) has not been extensively investigated. We used an Akkermansia muciniphila strain (AKK ONE) isolated from healthy human feces to study its effect on DSS-induced colitis in mice. Our results demonstrate that AKK ONE supplementation significantly improves food intake, weight, colon length, disease activity index (DAI) score, organ index, and tissue damage of colitis mice. AKK ONE notably improved intestinal barrier integrity by significantly enhancing expression of occludin and claudin-1. Additionally, AKK ONE reduced inflammation by down-regulating IL-1β, IL-6, and TNF-α, and up-regulating IL-10. In addition to reducing excessive inflammation, AKK ONE also increased the abundance of Akkermansia and decreased the abundance of Bacteroides. Furthermore, the AKK ONE intervention markedly increased SCFAs in cecal contents. AKK ONE may be a potential therapeutic agent for improving UC, based on the findings of this study.
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Project description:UnlabelledUlcerative colitis (UC) is characterized by chronic inflammation of the colon. During inflammation, NF-κB is increased in colonic epithelial cells and in immune cells, leading to increases in proinflammatory cytokines. These events then increase DNA methyltransferases (DNMTs), which silence a subset of tumor suppressor genes by promoter methylation. Negative regulators of the Wnt pathway are frequently methylated in UC, leading to dysregulation of the pathway and, potentially, to colorectal cancer. We determined if black raspberries (BRBs) influence promoter methylation of suppressors in the Wnt pathway in dextran sodium sulfate (DSS)-induced UC. C57BL/6J mice received 1% DSS and were fed either control or 5% BRB diets. Mice were euthanized on days 7, 14 and 28, and their colons, spleen and bone marrow were collected. Berries reduced ulceration at day 28. This was accompanied by decreased staining of macrophages and neutrophils and decreased NF-κB p65 nuclear localization in the colon at all time points. At day 7, BRBs demethylated the promoter of dkk3, leading to its increased messenger RNA (mRNA) expression in colon, spleen and bone marrow. β-Catenin nuclear localization, c-Myc staining as well as protein expression of DNMT3B, histone deacetylases 1 and 2 (HDAC1 and HDAC2) and methyl-binding domain 2 (MBD2) were all decreased in colon; mRNA expression of these four proteins was decreased in bone marrow cells by BRBs. These results suggest that BRBs suppress colonic ulceration by correcting promoter hypermethylation of suppressor genes in the colon, as well as in the spleen and bone marrow that systematically regulate inflammation.SummaryOur results suggest that dietary BRBs suppress colonic ulceration by correcting promoter hypermethylation of suppressor genes in the colon, as well as in the spleen and bone marrow that systematically regulate inflammation in DSS-induced UC.
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