β-sitosterol alleviates dextran sulfate sodium-induced experimental colitis via inhibition of NLRP3/Caspase-1/GSDMD-mediated pyroptosis
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SUBMITTER: Zhang D
PROVIDER: S-EPMC10637366 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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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:Inflammatory bowel disease (IBD) has been reported to be associated with NLRP3 inflammasome activation. Therefore inhibiting inflammasome activation could be a new approach to treat IBD. Inflammasome inhibitors NLRP3-IN-2, JC124, and 3,4-methylenedioxy-β-nitrostyrene (MNS) were previously reported to exert anti-inflammatory effects in various disease models but not in the dextran sulfate sodium (DSS)-induced colitis model. Here, we showed that MNS was more efficient in inhibiting the secretion of interleukin-1β (IL-1β) by blocking oligomerization of apoptosis-associated speck-like protein (ASC) than NLRP3-IN-2 and JC124. To investigate the protective effects of MNS on enteritis, we administered intragastric MNS to DSS-induced colitis mice. The results demonstrated that MNS attenuated DSS-induced body weight loss, colon length shortening, and pathological damage. In addition, MNS inhibited the infiltration of macrophages and inflammatory cells and reduced IL-1β and IL-12p40 pro-inflammatory cytokines but had no significant effect on tumor necrosis factor α (TNF-α) and IL-6. Furthermore, we also found that the differentiation of IL-17A+interferon-γ (IFN-γ)+CD4+ T cell was decreased in the colon after MNS treatment, which might be mediated by IL-1β, etc. cytokine release. Taken together, MNS alleviated DSS-induced intestinal inflammation by inhibiting NLRP3 inflammasome activation, which may function as an effective therapeutic for IBD.
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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.
| S-EPMC10000425 | biostudies-literature
Project description:Colitis-associated cancer (CAC) is a subtype of inflammatory bowel disease (IBD)-associated colorectal cancer. Huoxiang Zhengqi (HXZQ) is a classical Chinese herbal medicine and has been used to treat intestinal disorders, however, anti-CAC effects and underlying mechanisms of HXZQ have not been reported. An azoxymethane/dextran sulfate sodium-induced CAC mice model was used to investigate the anti-CAC effect of HXZQ. HXZQ significantly reduced colonic inflammation, suppressed the size and number of tumors, and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-1α, IL-1β, IL-6, IL-17A, IL-21, IL-23, granulocyte macrophage-colony stimulating factor, and tumor necrosis factor-α) and oxidative stress markers (reactive oxygen species and malondialdehyde), and increased the levels of anti-inflammatory cytokines (IL-10 and IL-27) in CAC mice. Intestinal microbiota and serum metabolomics analyses indicated that HXZQ altered the gut microbial composition and the abundance of 29 serum metabolites in CAC mice. Additionally, HXZQ activated the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) signaling pathway and increased the levels of antioxidants such as catalase (CAT), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductases-1 (NQO-1), and superoxide dismutase-1 (SOD-1). HXZQ inhibited the activation of the nuclear factor kappa-B (NF-κB) signaling pathway and decreased the expression of NLR family pyrin domain containing 3 (NLRP3) by inhibiting the phosphorylation of inhibitor of nuclear factor kappa-B (IκB), inhibitor of nuclear factor kappa-B kinase (IKK), and NF-κB. In conclusion, HXZQ alleviated CAC in mice by modulating the intestinal microbiota and metabolism, activating Nrf2-mediated antioxidant response, and inhibiting NF-κB-mediated NLRP3 inflammasome activation against inflammation. The present data provide a reference for the use of HXZQ as a therapeutic or combination agent for clinical CAC treatment.
| S-EPMC9634060 | biostudies-literature
Project description:BackgroundPyroptosis is a form of proinfammatory gasdermin-mediated programmed cell death. Abnormal infammation in the intestine is a critical risk factor for Ulcerative colitis (UC). However, at present, it is not clear whether pyroptosis of colonic fibroblasts is involved in the pathogenesis and progression of UC.MethodsIn this study, key genes associated with UC were identified by bioinformatics analysis. Datasets were downloaded from the Gene Expression Omnibus (GEO) database (GSE193677). The differentially expressed genes were analyzed, and the hub genes were screened by weighted gene co-expression network analysis (WGCNA) and differentially expressed genes. We also downloaded the dataset from GEO for single-cell RNA sequencing (GSE231993). The expression of key genes was verified by immunohistochemistry, immunofluorescence and Western blot, and the specific pathways of key genes inducing pyroptosis in cell lines were explored.ResultsThe results of bioinformatics analysis showed that the expression of APOL1 and CXCL1 in UC tissues was significantly higher than that in normal tissues. The results of single-cell analysis showed that the two genes were co-localized to fibroblasts. These results were consistent with the results of immunohistochemistry and immunofluorescence colocalization in human intestinal mucosa specimens. Furthermore, APOL1 overexpression induced NLRP3-caspase1-GSDMD-mediated pyroptosis of fibroblasts, which was confirmed by Western blot.ConclusionAPOL1 induces pyroptosis of fibroblasts mediated by NLRP3-Caspase1-GSDMD signaling pathway and promote the release of chemokines CXCL1. Fibroblasts may play a crucial role in the pathogenesis and progression of UC.
| S-EPMC10757784 | biostudies-literature
Project description:Our previous study showed that bisdemethoxycurcumin (BUR) exerts anti-inflammatory properties in lipopolysaccharide-induced intestinal injury, and studies have revealed that NOD-like receptor superfamily, pyrin domain containing 3 (NLRP3) inflammasome activation plays a vital role in the pathogenesis of colitis. However, it is not clear whether BUR could attenuate colitis-mediated intestinal inflammation via NLRP3 inflammasome inactivation and modulate the gut microbiota dysbiosis. The results demonstrated that BUR attenuated DSS-induced body weight decrease, histopathological changes, and epithelial apoptosis. BUR significantly improved the intestinal barrier defects and abrogated DSS-induced inflammatory response. Consistently, BUR reduced the expression of NLRP3 family members, confirming its inhibitory effects on NLRP3 inflammasome activation and pyroptosis. BUR regulated microbiota dysbiosis and altered the gut microbial community. BUR supplementation enriched the relative abundance of beneficial bacteria (such as Lactobacillus and Bifidobacterium), which showed significant negative correlations with the pro-inflammatory biomarkers. Collectively, these findings illustrated that BUR could ameliorate DSS-induced colitis by improving intestinal barrier function, reducing apoptosis, inhibiting NLRP3 inflammasome activation, and regulating the gut microbiota.
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Project description:Inflammatory Bowel Disease is caused by an acute or chronic dysfunction of the mucosal inflammatory system in the intestinal tract. In line with the results of our previous study, wherein we found that the PKCα-LSD1-NF-κB signaling plays a critical role in the prolonged activation of the inflammatory response, we aimed to investigate the effect of signaling on colitis in the present study. Lsd1 S112A knock-in (Lsd1SA/SA) mice, harboring a deficiency in phosphorylation by PKCα, exhibited less severe colitis symptoms and a relatively intact colonic epithelial lining in dextran sulfate sodium (DSS)- induced colitis models. Additionally, a reduction in pro-inflammatory gene expression and immune cell recruitment into damaged colon tissues in Lsd1SA/SA mice was observed upon DSS administration. Furthermore, LSD1 inhibition alleviated colitis symptoms and reduced colonic inflammatory responses. Both LSD1 phosphorylation and its activity jointly play a role in the progression of DSS-induced colitis. Therefore, the inhibition of LSD1 activity could potentially protect against the colonic inflammatory response. [BMB Reports 2020; 53(7): 385-390].
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Project description:BackgroundLicorice is one of the most ubiquitous herbs in traditional Chinese medicine, with notable anti-inflammatory and antiulcerative effects as well as potent digestive disease therapeutic impacts; yet, its active components and mechanisms remain unclear. There is a lot of evidence that Glycyrrhiza polysaccharide (GPS) has antioxidants, improving intestinal flora, anti-inflammatory effects, etc. Hypothesis/Purpose. Here, we investigated the effects of GPS on dextran sulfate sodium (DSS)-induced acute ulcerative colitis (UC) mice and its possible mechanisms.MethodsGPS (100, 200, and 400 mg/kg) or the positive control drug sulfasalazine (SASP) (200 mg/kg) were orally administered to mice for 8 days. Body weight was recorded daily. Symptoms associated with UC, such as disease activity index (DAI), colon length, spleen weight, and mucosal damage were detected. The possible mechanism of GPS ameliorating enteritis symptoms was explored by detecting intestinal permeability and serum levels of inflammatory factors, and changes in intestinal permeability were expressed by serum concentration of FITC-dextran and D-lactic acid.ResultsThe results demonstrated that GPS administration alleviated UC symptoms in colitis mice, including weight loss, DAI index, shorting colon length, and mucosal damage. Mechanistic evaluation revealed that GPS treatment reduced intestinal permeability and serum levels of inflammatory factors: IL-1, IL-6, and TNF-α, while increasing serum levels of the anti-inflammatory factor IL-10, suggesting that GPS's mechanism in UC is related to reducing intestinal permeability and inhibiting the inflammatory response, with intestinal permeability implicated as the initiating mechanism.ConclusionThis study highlights GPS as a promising therapeutic agent, with high therapeutic efficacy and a good safety profile, for enteritis and beyond.
| S-EPMC9012628 | biostudies-literature
Project description:Evidence indicates that gut microbiota is crucial in ulcerative colitis (UC) development. Increased Peptostreptococcus species abundance is linked to UC, but its role and mechanisms in intestinal inflammation are not well understood. This study used a dextran sulfate sodium (DSS)-induced colitis model in mice, and different bacterial strains were administered via gavage. We assessed clinical manifestations, colonic barrier function, gut microbiota composition, and levels of inflammatory cytokines, NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling molecules, and pyroptosis-related proteins. Mouse bone marrow-derived macrophages (BMDMs) were infected with Peptostreptococcus anaerobius at different time points and multiplicities of infection (MOI). Cell viability and the expression of NLRP3 signaling molecules and pyroptosis-associated proteins were assessed. The inhibitors C29, TAK-242, and MCC950 were employed for Toll-like receptor (TLR) and NLRP3 signaling pathways. It was observed that P. anaerobius exacerbated intestinal inflammation and barrier injury in DSS-induced colitis in mice. Additionally, P. anaerobius contributed to gut microbiota dysbiosis during colitis progression. P. anaerobius induced the expression of NLRP3 signaling molecules and pyroptosis-associated proteins in mouse colitis tissues. In vitro assays demonstrated that P. anaerobius activated NLRP3 inflammasome and evoked gasdermin D-mediated pyroptosis and interleukin (IL)-1β secretion in macrophages. Furthermore, TLR2 and TLR4 were identified as key mediators of P. anaerobius-induced macrophage pyroptosis via activation of the Nuclear Factor-kappa B (NF-κB)-NLRP3 pathway. In conclusion, P. anaerobius promotes macrophage pyroptosis and IL-1β secretion through the TLR2/4-NF-κB-NLRP3 signaling axis, thereby aggravating colitis. P. anaerobius may represent a potential risk factor for UC development.
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Project description:Phytosterols, the plant analogues of cholesterol, widely occur in the human diet. In this study, we investigated and compared the effects of stigmasterol and ?-sitosterol (both with purities ?95%) on dextran sulfate sodium (DSS)-induced colitis in C57BL/6J male mice fed a high fat Western-style diet. Mice treated with DSS developed severe mucosal colitis, with a marked distortion and crypt loss of colonic surface epithelium. Both ?-sitosterol and stigmasterol significantly inhibited colon shortening, lowered fecal hemoglobin content, and reduced the severity of colitis in the middle and distal colon (p < 0.05). These phytosterols also significantly suppressed the activation of nuclear factor-kappa B. They also significantly decreased colony stimulating factor-1 and the nuclear translocation of inflammatory master regulator nuclear factor-kappa B. Stigmasterol significantly lowered the colonic inflammation score and the expression of cyclooxygenase-2 and colony stimulating factor-1, while ?-sitosterol was less or not effective. These results suggest that dietary intake of stigmasterol and ?-sitosterol ameliorates colitis. Such activities of stigmasterol and ?-sitosterol in humans remain to be investigated.
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