Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 19.364
Filtrar
1.
BMC Cancer ; 22(1): 566, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35596224

RESUMO

BACKGROUND: The role of Berberine (BBR) in colorectal cancer (CRC) and gut microbiota has begun to appreciate. However, there was no direct evidence confirm that the gut microbiota regulated by BBR could inhibit CRC. This report investigated the effect of stool from BBR treated subjects and its effect on CRC. METHODS: A mouse model for CRC was developed using azoxymethane (AOM) and dextran sulfate sodium (DSS). Intestinal tissue from affected mice were used to determine the efficacy of BBR against CRC. Stool samples were collected for the 16s rRNA gene sequencing and fecal microbiota transplantation (FMT). Finally, the mechanism of gut microbiota from BBR treated mice on CRC was explored using immunohistochemistry, RNA-Sequencing, quantitative RT-PCR, and western blot analyses. RESULTS: BBR significantly reduced intestinal tumor development. The richness of gut microbiota were notably decreased by BBR. Specifically, the relative abundance of beneficial bacteria (Roseburia, Eubacterium, Ruminococcaceae, and Firmicutes_unclassified) was increased while the level of bacteria (Odoribacter, Muribaculum, Mucispirillum, and Parasutterella) was decreased by BBR treatment. FMT experiment determined that the mice fed with stool from BBR treated AOM/DSS mice demonstrated a relatively lower abundance of macroscopic polyps and a significantly lower expression of ß-catenin, and PCNA in intestinal tissue than mice fed with stool from AOM/DSS mice. Mechanistically, intestinal tissue obtained from mice fed with stool from BBR treated AOM/DSS mice demonstrated a decreased expression of inflammatory cytokines including interleukin 1ß (IL-1ß), tumor necrosis factor-α (TNF-α), C-C motif chemokine 1 (Ccl1), Ccl6, and C-X-C motif ligand (Cxcl9). In addition, the NF-κB expression was greatly suppressed in mice fed with stool from BBR treated AOM/DSS mice. Real-time PCR arrays revealed a down-regulation of genes involved in cell proliferation, angiogenesis, invasiveness, and metastasis in mice fed with stool from BBR treated AOM/DSS mice. CONCLUSIONS: Stool obtained from BBR treated AOM/DSS mice was able to increase colon length while simultaneously decreasing the density of macroscopic polyps, cell proliferation, inflammatory modulators and the expression of NF-κB. Therefore, it was concluded that suppression of pro-inflammatory genes and carcinogens factors by modulating gut microbiota was an important pathway for BBR to inhibit tumor growth in conventional mice.


Assuntos
Berberina , Colite , Microbioma Gastrointestinal , Animais , Azoximetano , Berberina/farmacologia , Berberina/uso terapêutico , Carcinogênese/metabolismo , Colite/patologia , Colo/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , RNA Ribossômico 16S/genética
2.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(3): 271-279, 2022 Mar 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-35545319

RESUMO

OBJECTIVES: Liver disease is the most common extra-intestinal manifestation of ulcerative colitis (UC), but the underlying pathogenesis is still not clarified. It is well accepted that the occurrence of UC-related liver disease has close correlation with immune activation, intestinal bacterial liver translocation, inflammatory cytokine storm, and the disturbance of bile acid circulation. The occurrence of UC-related liver disease makes the therapy difficult, therefor study on the pathogenesis of UC-related liver injury is of great significance for its prevention and treatment. Glutathione (GSH) shows multiple physiological activities, such as free radical scavenging, detoxification metabolism and immune defense. The synthesis and the oxidation-reduction all contribute to GSH antioxidant function. It is reported that the deficiency in hepatic GSH antioxidant function participates in multiple liver diseases, but whether it participates in the pathogenesis of UC-related liver injury is still not clear. This study aims to investigate the feature and underlying mechanism of GSH synthesis and oxidation-reduction function during the development of UC, which will provide useful information for the pathogenesis study on UC-related liver injury. METHODS: UC model was induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS)-ethanol solution (5 mg/0.8 mL per rat, 50% ethanol) via intra-colonic administration in rats, and the samples of serum, liver, and colon tissue of rats were collected at the 3rd, 5th, and 7th days post TNBS. The severity degree of colitis was evaluated by measuring the disease activity index, colonic myeloperoxidase activity, and histopathological score, and the degree of liver injury was evaluated by histopathological score and the serum content of alanine aminotransferase. Spearman correlation analysis was also conducted between the degree of colonic lesions and index of hepatic histopathological score as well as serum aspartate aminotransferase level to clarify the correlation between liver injury and colitis. To evaluate the hepatic antioxidant function of GSH in UC rats, hepatic GSH content, enzyme activity of GSH peroxidase (GSH-Px), and GSH reductase (GR) were determined in rats at the 3rd, 5th, and 7th days post TNBS, and the protein expressions of glutamine cysteine ligase (GCL), GSH synthase, GSH-Px, and GR in the liver of UC rats were also examined by Western blotting. RESULTS: Compared with the control, the disease activity index, colonic myeloperoxidase activity, and histopathological score were all significantly increased at the 3rd, 5th, and 7th days post TNBS (all P<0.01), the serum aspartate aminotransferase level and hepatic histopathologic score were also obviously elevated at the 7th day post TNBS (all P<0.05). There was a significant positive correlation between the degree of liver injury and the severity of colonic lesions (P=0.000 1). Moreover, compared with the control, hepatic GSH content and the activity of GSH-Px and GR were all significantly decreased at the 3rd and 5th days post TNBS (P<0.05 or P<0.01), and the protein expressions of GCL, GSH-Px, and GR were all obviously down-regulated at the 3rd, 5th, and 7th days post TNBS (P<0.05 or P<0.01). CONCLUSIONS: There is a significant positive correlation between the degree of liver injury and the severity of colonic lesions, and the occurrence of reduced hepatic GSH synthesis and decreased GSH reduction function is obviously earlier than that of the liver injury in UC rats. The reduced hepatic expression of enzymes that responsible for GSH synthesis and reduction may contribute to the deficiency of GSH synthesis and oxidation-reduction function, indicating that the deficiency in GSH antioxidant function may participate in the pathogenesis of UC related liver injury.


Assuntos
Colite Ulcerativa , Colite , Animais , Antioxidantes , Aspartato Aminotransferases , Colite/induzido quimicamente , Colite Ulcerativa/metabolismo , Colo/patologia , Etanol/efeitos adversos , Etanol/metabolismo , Glutationa/efeitos adversos , Glutationa/metabolismo , Fígado/metabolismo , Peroxidase/metabolismo , Ratos , Ácido Trinitrobenzenossulfônico/efeitos adversos , Ácido Trinitrobenzenossulfônico/metabolismo
3.
Sci Immunol ; 7(71): eabf3717, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35522722

RESUMO

The expression of BTB-ZF transcription factors such as ThPOK in CD4+ T cells, Bcl6 in T follicular helper cells, and PLZF in natural killer T cells defines the fundamental nature and characteristics of these cells. Screening for lineage-defining BTB-ZF genes led to the discovery of a subset of T cells that expressed Zbtb20. About half of Zbtb20+ T cells expressed FoxP3, the lineage-defining transcription factor for regulatory T cells (Tregs). Zbtb20+ Tregs were phenotypically and genetically distinct from the larger conventional Treg population. Zbtb20+ Tregs constitutively expressed mRNA for interleukin-10 and produced high levels of the cytokine upon primary activation. Zbtb20+ Tregs were enriched in the intestine and specifically expanded when inflammation was induced by the use of dextran sodium sulfate. Conditional deletion of Zbtb20 in T cells resulted in a loss of intestinal epithelial barrier integrity. Consequently, knockout (KO) mice were acutely sensitive to colitis and often died because of the disease. Adoptive transfer of Zbtb20+ Tregs protected the Zbtb20 conditional KO mice from severe colitis and death, whereas non-Zbtb20 Tregs did not. Zbtb20 was detected in CD24hi double-positive and CD62Llo CD4 single-positive thymocytes, suggesting that expression of the transcription factor and the phenotype of these cells were induced during thymic development. However, Zbtb20 expression was not induced in "conventional" Tregs by activation in vitro or in vivo. Thus, Zbtb20 expression identified and controlled the function of a distinct subset of Tregs that are involved in intestinal homeostasis.


Assuntos
Colite , Linfócitos T Reguladores , Fatores de Transcrição , Animais , Colite/induzido quimicamente , Homeostase , Intestinos , Camundongos , Camundongos Knockout , Linfócitos T Reguladores/metabolismo , Fatores de Transcrição/genética
4.
Cancer Cell ; 40(5): 509-523.e6, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35537412

RESUMO

Immune checkpoint blockade (ICB) therapy frequently induces immune-related adverse events. To elucidate the underlying immunobiology, we performed a deep immune analysis of intestinal, colitis, and tumor tissue from ICB-treated patients with parallel studies in preclinical models. Expression of interleukin-6 (IL-6), neutrophil, and chemotactic markers was higher in colitis than in normal intestinal tissue; T helper 17 (Th17) cells were more prevalent in immune-related enterocolitis (irEC) than T helper 1 (Th1). Anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) induced stronger Th17 memory in colitis than anti-program death 1 (anti-PD-1). In murine models, IL-6 blockade associated with improved tumor control and a higher density of CD4+/CD8+ effector T cells, with reduced Th17, macrophages, and myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) model with tumors, combined IL-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. IL-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.


Assuntos
Colite , Neoplasias , Animais , Colite/induzido quimicamente , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Interleucina-6 , Camundongos , Células Mieloides , Neoplasias/tratamento farmacológico
5.
Acta Biochim Biophys Sin (Shanghai) ; 54(3): 340-349, 2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35538040

RESUMO

Taraxasterol (TAX) has been proven to prevent and treat inflammatory diseases. However, the effects of TAX on intestinal barrier and the diversity, structure, and function of gut microbiota have yet to be elucidated in dextran sodium sulfate (DSS)-induced colitis mice. Our objectives are to evaluate the effect of TAX on intestinal barrier and its impact on gut microbiota. Herein, immunofluorescence analysis is conducted to determine the expressions of tight junction (ZO-1) and mucin (Mucin-2) proteins. The abundance, diversity, and function of fecal colonies are investigated by using 16S rDNA sequencing, and the influence of TAX on the gut microbiota in mice is also analyzed. Our results suggest that TAX attenuates the symptoms in DSS-induced colitis mice by reducing the DAI score, increasing colon length, alleviating histopathological damage of colon tissues, and improving intestinal barrier. 16S rDNA sequencing of fecal samples indicates that TAX intervention has a regulatory effect on DSS-induced gut microbiota dysbiosis at different taxonomic levels. TAX increases microbial diversity that is reduced by DSS. It normalizes the relative abundance of and the ratio of /. In addition, treatment with TAX has a better effect on the function of metabolisms, such as nucleotide, lipid, and bile acid metabolism. These findings suggest that TAX may be a good candidate for the remission of colitis, which is related to improving intestinal barrier and modulating gut microbiota.


Assuntos
Colite , Microbioma Gastrointestinal , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colo/metabolismo , DNA Ribossômico/metabolismo , DNA Ribossômico/farmacologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Disbiose/induzido quimicamente , Disbiose/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Esteróis , Sulfatos , Triterpenos
6.
Front Immunol ; 13: 695576, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35514976

RESUMO

Aberrant innate immune responses to the gut microbiota are causally involved in the pathogenesis of inflammatory bowel diseases (IBD). The exact triggers and main signaling pathways activating innate immune cells and how they modulate adaptive immunity in IBD is still not completely understood. Here, we report that the PI3K/PTEN signaling pathway in dendritic cells enhances IL-6 production in a model of DSS-induced colitis. This results in exacerbated Th1 cell responses and increased mortality in DC-specific PTEN knockout (PTENΔDC) animals. Depletion of the gut microbiota using antibiotics as well as blocking IL-6R signaling rescued mortality in PTENΔDC mice, whereas adoptive transfer of Flt3L-derived PTEN-/- DCs into WT recipients exacerbated DSS-induced colitis and increased mortality. Taken together, we show that the PI3K signaling pathway in dendritic cells contributes to disease pathology by promoting IL-6 mediated Th1 responses.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Células Dendríticas , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais
7.
Sci Rep ; 12(1): 7453, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35523978

RESUMO

Intestinal homeostasis is highly dependent on optimal epithelial barrier function and permeability. Intestinal epithelial cells (IEC) regulate these properties acting as cellular gatekeepers by selectively absorbing nutrients and controlling the passage of luminal bacteria. These functions are energy demanding processes that are presumably met through mitochondrial-based processes. Routine methods for examining IEC mitochondrial function remain sparse, hence, our objective is to present standardized methods for quantifying mitochondrial energetics in an immortalized IEC line. Employing the murine IEC4.1 cell line, we present adapted methods and protocols to examine mitochondrial function using two well-known platforms: the Seahorse Extracellular Flux Analyzer and Oxygraph-2 k. To demonstrate the applicability of these protocols and instruments, IEC were treated with and without the murine colitogenic agent, dextran sulfate sodium (DSS, 2% w/v). Profound impairments with DSS treatment were found with both platforms, however, the Oxygraph-2 k allowed greater resolution of affected pathways including short-chain fatty acid metabolism. Mitochondrial functional analysis is a novel tool to explore the relationship between IEC energetics and functional consequences within the contexts of health and disease. The outlined methods offer an introductory starting point for such assessment and provide the investigator with insights into platform-specific capabilities.


Assuntos
Colite , Mucosa Intestinal , Animais , Colite/induzido quimicamente , Colite/metabolismo , Sulfato de Dextrana/toxicidade , Metabolismo Energético , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo
8.
JCI Insight ; 7(10)2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35503250

RESUMO

Aberrant epithelial differentiation and regeneration contribute to colon pathologies, including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Myeloid translocation gene 16 (MTG16, also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear. Here, we identified MTG16 as a central mediator of epithelial differentiation, promoting goblet and restraining enteroendocrine cell development in homeostasis and enabling regeneration following dextran sulfate sodium-induced (DSS-induced) colitis. Transcriptomic analyses implicated increased Ephrussi box-binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a mouse model with a point mutation that attenuates MTG16:E protein interactions (Mtg16P209T), we showed that MTG16 exerts control over colonic epithelial differentiation and regeneration by repressing E protein-mediated transcription. Mimicking murine colitis, MTG16 expression was increased in biopsies from patients with active IBD compared with unaffected controls. Finally, uncoupling MTG16:E protein interactions partially phenocopied the enhanced tumorigenicity of Mtg16-/- colon in the azoxymethane/DSS-induced model of CAC, indicating that MTG16 protects from tumorigenesis through additional mechanisms. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colon homeostasis, colitis, and cancer.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Transformação Celular Neoplásica/genética , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Sulfato de Dextrana/toxicidade , Humanos , Doenças Inflamatórias Intestinais/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição/genética
9.
Drug Des Devel Ther ; 16: 1383-1405, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35601674

RESUMO

Purpose: Ulcerative colitis (UC) is a chronic inflammatory bowel disease that starts with mucosal inflammation of the rectum and extends proximally in the colon in a continuous manner over a variable distance. Although it is more common in North America and Western Europe, its incidence is also increasing in Asia. Despite the introduction of several different classes of medications, the treatment options for UC may be insufficiently effective and burdened with significant side effects. In the present study, the therapeutic effects of Gancao Xiexin decoction (GCXX) were investigated on mice with dextran sulfate sodium (DSS)-induced colitis with exploration of the underlying mechanisms. Methods: Colitis was induced in C57BL/6 mice by administering 3% DSS in drinking water for 7 days. GCXX and (or) the standard of care anti-inflammatory drug, mesalazine (5-aminosalicylic acid) were then administered for 7 days. The gut microbiota was characterized by 16S rDNA high-throughput gene sequencing and gut metabolites were detected by untargeted metabolomics. Germ-free mice were subsequently used to determine whether GCXX ameliorated UC principally through modulation of the gut microbiota. Results: GCXX treatment was demonstrated to significantly reduce disease activity index (DAI) scores, prevent colonic shortening, ameliorate colonic tissue damage and reduce the levels of pro-inflammatory cytokines. Furthermore, analysis of the gut microbiota showed that GCXX-treated mice had higher relative quantity of Dubosiella (P<0.05) and lower relative quantity of Escherichia-Shigella (P<0.05). Metabolomics analysis indicated that GCXX could reduce the level of linoleic acid (P<0.05) and regulate its metabolism pathway. Moreover, in germ-free mice, GCXX failed to increase body weight, reduce DAI scores, or alleviate either colonic shortening or colonic damage. Conclusion: The present study demonstrated that GCXX ameliorated DSS-induced colitis principally through modulating the gut microbiota and metabolites. This information should be integrated into the overall mechanisms of GCXX treatment of UC.


Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Animais , Colite/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo/metabolismo , Sulfato de Dextrana/efeitos adversos , Sulfato de Dextrana/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Glycyrrhiza , Camundongos , Camundongos Endogâmicos C57BL
10.
Front Immunol ; 13: 830961, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35603158

RESUMO

Humans homozygous for inactivating LRBA (lipopolysaccharide (LPS)-responsive beige-like anchor) mutations or with compound heterozygous mutations exhibit a spectrum of immune-related pathologies including inflammatory bowel disease (IBD). The cause of this pathology remains undefined. Here we show that disruption of the colon epithelial barrier in LRBA-deficient mice by dextran sulfate sodium (DSS) consumption leads to severe and uniformly lethal colitis. Analysis of bone marrow (BM) chimeras showed that susceptibility to lethal colitis is primarily due to LRBA deficiency in the immune compartment and not the gut epithelium. Further dissection of the immune defect in LRBA-deficient hosts showed that LRBA is essential for the expression of CTLA4 by Treg cells and IL22 and IL17 expression by ILC3 cells in the large intestine when the gut epithelium is compromised by DSS. We further show that SHIP1 agonism partially abrogates the severity and lethality of DSS-mediated colitis. Our findings indicate that enteropathy induced by LRBA deficiency has multiple causes and that SHIP1 agonism can partially abrogate the inflammatory milieu in the gut of LRBA-deficient hosts.


Assuntos
Colite , Imunodeficiência de Variável Comum , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Colite/induzido quimicamente , Colite/genética , Camundongos , Mutação , Linfócitos T Reguladores
11.
Eur J Histochem ; 66(2)2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35603939

RESUMO

Recent evidence suggests that endoplasmic reticulum (ER) stress plays a vital role in inflammatory bowel disease (IBD). Therefore, the aim of this study was to investigate the mechanism by which ER stress promotes inflammatory response in IBD. The expression of Gro-α, IL-8 and ER stress indicator Grp78 in colon tissues from patients with Crohn's disease (CD) and colonic carcinoma was analyzed by immunohistochemistry staining. Colitis mouse model was established by the induction of trinitrobenzene sulphonic acid (TNBS), and the mice were treated with ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Then the body weight, colon length and colon inflammation were evaluated, and Grp78 and Gro-α in colon tissues were detected by immunohistochemistry. Epithelial cells of colon cancer HCT116 cells were treated with tunicamycin to induce ER stress. Grp78 was detected by Western blot, and chemokines were measured by PCR and ELISA. The expression levels of Grp78, Gro-α and IL-8 were significantly upregulated in intestinal tissues of CD patients. Mice with TNBS induced colitis had increased expression of Grp78 and Gro-α in colonic epithelia. TUDCA reduced the severity of TNBS-induced colitis. In HCT116 cells, tunicamycin increased the expression of Grp78, Gro-α and IL-8 in a concentration-dependent manner. Furthermore, p38 MAPK inhibitor significantly inhibited the upregulation of Gro-α and IL-8 induced by tunicamycin. In conclusion, ER stress promotes inflammatory response in IBD, and the effects may be mediated by the activation of p38 MAPK signaling pathway.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Colite/induzido quimicamente , Colite/patologia , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Interleucina-8/efeitos adversos , Camundongos , Ácido Trinitrobenzenossulfônico/toxicidade , Tunicamicina/efeitos adversos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/farmacologia
12.
Food Funct ; 13(10): 5626-5639, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35506498

RESUMO

This study aims to explore the protective effect of konjac oligosaccharides (KOS) on inflammatory bowel disease in colitis mice. During the experimental period, mice were administered 200 mg kg-1 or 600 mg kg-1 KOS, 200 mg kg-1 sulfasalazine and a combination of KOS and sulfasalazine for 14 days. The mice were then treated with drinking water containing 2.5% DSS for 9 days, while the intervention of KOS and sulfasalazine continued. At the end of the experiment, the phenotype, pathological lesion of the colon, parameters of cytokines and gut microbiota were evaluated. The results showed that mice treated with KOS exhibited alleviated pathological lesion of the colon tissue and significantly increased expression of tight junction proteins (p < 0.05). The level of inflammatory cytokines in the colon tissue of the colitis mice tended to be normal. Moreover, the analysis of the gut microbiota revealed that the structures and composition of the intestinal microorganisms were also regulated by KOS treatment. The possible internal mechanism is that KOS down-regulates the abundance of pro-inflammatory bacteria (Proteobacteria, Campilobacterota and Clostridiaceae) and up-regulates the abundance of anti-inflammatory bacteria (Bifidobacteriaceae and Akkermansiaceae). These findings provide new insights into dietary management for patients with inflammatory bowel disease.


Assuntos
Amorphophallus , Colite Ulcerativa , Colite , Doenças Inflamatórias Intestinais , Amorphophallus/metabolismo , Animais , Colite/induzido quimicamente , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/microbiologia , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Oligossacarídeos/metabolismo , Sulfassalazina/farmacologia
13.
Food Funct ; 13(10): 5739-5751, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35527507

RESUMO

Soluble polysaccharides derived from microbial fermentation of agricultural by-products were considered as potential functional ingredients, primarily having probiotic properties. Herein, soluble polysaccharides (FSRP) were isolated from soybean residue fermented by Neurospora crassa, and FSRP mainly contained rhamnose, arabinose, fucose, mannose, glucose, and galactose, according to GC-MS analysis. To further investigate the protective effect of FSRP against colitis, dextran sulfate sodium induction (DSS)-treated mice were orally gavaged with FSRP (200 mg kg-1 d-1) or inulin (400 mg kg-1 d-1, a positive control) for 7 d. The results showed that DSS-treated mice displayed symptoms of body weight loss, atrophy, and histopathological changes of colon, as well as gut barrier damage, which were recovered after FSRP supplementation (similar to inulin). Furthermore, the beneficial effects of FSRP were linked to a decreased inflammatory response and increased protein expression of E-cadherin, claudin-1 and ZO-1. Illumina-MiSeq sequencing analysis revealed that FSRP increased microbial diversity and altered community structure. Specifically, FSRP could modulate the abundance of inflammation-related bacteria (such as Tenericutes, Clostridia, and Bacilli) to ameliorate colitis symptoms. Therefore, FSRP can relieve DSS-induced colitis, which is closely associated with reduced levels of inflammatory factors, improved gut barrier function and gut microbiota homeostasis.


Assuntos
Colite , Fabaceae , Microbioma Gastrointestinal , Neurospora crassa , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colo/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Inulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos/metabolismo , Polissacarídeos/farmacologia , Soja
14.
Food Funct ; 13(10): 5766-5781, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35536119

RESUMO

Ulcerative colitis (UC) is a modern, refractory disease, and studies have shown that UC is closely associated with the gut microbiota and intestinal immune barrier. This study evaluated the protective effects and regulatory mechanism of Chinese dwarf cherry [Cerasus humilis (Bge.) Sok.] fermentation juice (CFJ) on UC induced by dextran sulfate sodium (DSS). The results indicated that CFJ could significantly modulate the oxidative stress index in the serum and colon, observably reduce MPO and NO activity, and increase the SOD level. CFJ significantly downregulated the levels of TNF-α, IL-1ß and IL-6 and reduced inflammation caused by DSS. SIgA and short-chain fatty acids (SCFAs) levels were effectively improved in the CFJ group, especially the acetic acid and butyric acid levels. Intestinal flora analysis showed that DSS could enrich harmful bacteria such as Alistipes and Oribacterium and that CFJ could increase the abundance of beneficial bacteria (Parasutterella, Bacteroides, Roseburia and Blautia). SIgA in the colon was positively correlated with Lachnoclostridium, Blautia, Lachnospiraceae_UCG-004, Prevotellaceae_NK3B31_group and other beneficial bacteria. The results showed that DSS group rats had immunity and signalling pathway disorders and that CFJ could regulate immune disorders, mainly by regulating the expression of IgA pathway components. Taken together, our results demonstrated that CFJ could regulate changes in the gut microbiota, improve the expression of immune protein-related genes, further regulate intestinal mucosal immune function and maintain intestinal mucosal barrier homeostasis.


Assuntos
Colite Ulcerativa , Colite , Prunus , Animais , Bactérias/genética , Bactérias/metabolismo , China , Colite/induzido quimicamente , Colo/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Fermentação , Imunoglobulina A/metabolismo , Imunoglobulina A Secretora/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Prunus/metabolismo , Ratos
15.
Cells ; 11(9)2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35563773

RESUMO

Recurrent chronic mucosal inflammation, a characteristic of inflammatory bowel diseases (IBD), perturbs the intestinal epithelial homeostasis resulting in formation of mucosal wounds and, in most severe cases, leads to colitis-associated colon cancer (CAC). The altered structure of epithelial cell-cell adhesions is a hallmark of intestinal inflammation contributing to epithelial injury, repair, and tumorigenesis. P-cadherin is an important adhesion protein, poorly expressed in normal intestinal epithelial cells (IEC) but upregulated in inflamed and injured mucosa. The goal of this study was to investigate the roles of P-cadherin in regulating intestinal inflammation and CAC. P-cadherin expression was markedly induced in the colonic epithelium of human IBD patients and CAC tissues. The roles of P-cadherin were investigated in P-cadherin null mice using dextran sulfate sodium (DSS)-induced colitis and an azoxymethane (AOM)/DSS induced CAC. Although P-cadherin knockout did not affect the severity of acute DSS colitis, P-cadherin null mice exhibited faster recovery after colitis. No significant differences in the number of colonic tumors were observed in P-cadherin null and control mice. Consistently, the CRISPR/Cas9-mediated knockout of P-cadherin in human IEC accelerated epithelial wound healing without affecting cell proliferation. The accelerated migration of P-cadherin depleted IEC was driven by activation of Src kinases, Rac1 GTPase and myosin II motors and was accompanied by transcriptional reprogramming of the cells. Our findings highlight P-cadherin as a negative regulator of IEC motility in vitro and mucosal repair in vivo. In contrast, this protein is dispensable for IEC proliferation and CAC development.


Assuntos
Caderinas , Neoplasias Associadas a Colite , Colite , Doenças Inflamatórias Intestinais , Animais , Caderinas/metabolismo , Colite/induzido quimicamente , Colite/complicações , Colite/metabolismo , Sulfato de Dextrana , Células Epiteliais/metabolismo , Humanos , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout
16.
Cells ; 11(9)2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35563847

RESUMO

In inflammatory bowel disease (IBD), the impaired intestinal barrier is mainly characterized by changes in tight junction protein expression. The functional role of the tight junction-associated MARVEL protein MARVELD3 (MD3) in IBD is yet unknown. (i) In colon biopsies from IBD patients we analyzed MD3 expression and (ii) in human colon HT-29/B6 cells we studied the signaling pathways of different IBD-relevant cytokines. (iii) We generated a mouse model with intestinal overexpression of MD3 and investigated functional effects of MD3 upregulation. Colitis, graded by the disease activity index, was induced by dextran sodium sulfate (DSS) and the intestinal barrier was characterized electrophysiologically. MD3 was upregulated in human ulcerative colitis and MD3 expression could be increased in HT-29/B6 cells by IL-13 via the IL13Rα1/STAT pathway. In mice DSS colitis, MD3 overexpression had an ameliorating, protective effect. It was not based on direct enhancement of paracellular barrier properties, but rather on regulatory mechanisms not solved yet in detail. However, as MD3 is involved in regulatory functions such as proliferation and cell survival, we conclude that the protective effects are hardly targeting the intestinal barrier directly but are based on regulatory processes supporting stabilization of the intestinal barrier.


Assuntos
Colite , Proteínas com Domínio MARVEL , Animais , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana/farmacologia , Humanos , Mucosa Intestinal/patologia , Proteínas com Domínio MARVEL/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Junções Íntimas/metabolismo
17.
Front Immunol ; 13: 853894, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35371051

RESUMO

Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating inflammatory bowel disease (IBD), and intraperitoneal delivery of MSCs have become a more effective route for IBD treatment. However, the underlying mechanisms are still poorly understood. Here, we found that intraperitoneally delivered MSCs significantly alleviated experimental colitis. Depletion of peritoneal B cells, but not macrophages, clearly impaired the therapeutic effects of MSCs. Intraperitoneally delivered MSCs improved IBD likely by boosting the IL-10-producing B cells in the peritoneal cavity, and a single intraperitoneal injection of MSCs could significantly prevent disease severity in a recurrent mouse colitis model, with lower proinflammation cytokines and high level of IL-10. The gene expression profile revealed that thrombospondin-1 (THBS1) was dramatically upregulated in MSCs after coculture with peritoneal lavage fluid from colitis mice. Knockout of THBS1 expression in MSCs abolished their therapeutic effects in colitis and the induction of IL-10-producing B cells. Mechanistically, THBS1 modulates the activation of transforming growth factor-ß (TGF-ß), which combines with TGF-ß receptors on B cells and contributes to IL-10 production. Blocking the interaction between THBS1 and latent TGF-ß or inhibiting TGF-ß receptors (TGF-ßR) significantly reversed the THBS1-mediated induction of IL-10-producing B cells and the therapeutic effects on colitis. Collectively, our study revealed that intraperitoneally delivered MSCs secreted THBS1 to boost IL-10+Bregs and control the progression and recurrence of colitis, providing new insight for the prevention and treatment of IBD.


Assuntos
Linfócitos B Reguladores , Colite , Doenças Inflamatórias Intestinais , Células-Tronco Mesenquimais , Animais , Linfócitos B Reguladores/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Colite/terapia , Sulfato de Dextrana , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/terapia , Interleucina-10/genética , Interleucina-10/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Knockout , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/metabolismo
18.
J Exp Med ; 219(5)2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35363256

RESUMO

MicroRNAs are critical regulators of gene expression controlling cellular processes including inflammation. We explored their role in the pathogenesis of inflammatory bowel disease (IBD) and identified reduced expression of miR-374a-5p in IBD monocytes that correlated with a module of up-regulated genes related to the inflammatory response. Key proinflammatory module genes, including for example TNFα, IL1A, IL6, and OSM, were inversely correlated with miR-374a-5p and were validated in vitro. In colonic biopsies, miR-374a-5p was again reduced in expression and inversely correlated with the same inflammatory module, and its levels predicted subsequent response to anti-TNF therapy. Increased miR-374a-5p expression was shown to control macrophage-driven inflammation by suppressing proinflammatory mediators and to reduce the capacity of monocytes to migrate and activate T cells. Our findings suggest that miR-374a-5p reduction is a central driver of inflammation in IBD, and its therapeutic supplementation could reduce monocyte-driven inflammation in IBD or other immune-mediated diseases.


Assuntos
Colite , Doenças Inflamatórias Intestinais , MicroRNAs , Humanos , Doenças Inflamatórias Intestinais/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Monócitos/metabolismo , Inibidores do Fator de Necrose Tumoral
19.
Nat Microbiol ; 7(4): 590-599, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35365791

RESUMO

Experimental mouse models are central to basic biomedical research; however, variability exists across genetically identical mice and mouse facilities making comparisons difficult. Whether specific indigenous gut bacteria drive immunophenotypic variability in mouse models of human disease remains poorly understood. We performed a large-scale experiment using 579 genetically identical laboratory mice from a single animal facility, designed to identify the causes of disease variability in the widely used dextran sulphate sodium mouse model of inflammatory bowel disease. Commonly used treatment endpoint measures-weight loss and intestinal pathology-showed limited correlation and varied across mouse lineages. Analysis of the gut microbiome, coupled with machine learning and targeted anaerobic culturing, identified and isolated two previously undescribed species, Duncaniella muricolitica and Alistipes okayasuensis, and demonstrated that they exert dominant effects in the dextran sulphate sodium model leading to variable treatment endpoint measures. We show that the identified gut microbial species are common, but not ubiquitous, in mouse facilities around the world, and suggest that researchers monitor for these species to provide experimental design opportunities for improved mouse models of human intestinal diseases.


Assuntos
Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Animais , Bacteroidetes , Colite/induzido quimicamente , Colite/microbiologia , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/microbiologia , Camundongos
20.
Front Immunol ; 13: 856966, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35401533

RESUMO

Introduction: In colitis, macrophage functionality is altered compared to normal homeostatic conditions. Loss of IL-10 signaling results in an inappropriate chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice. Methods: We performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence and absence of lipopolysaccharide (LPS) with and without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization. Results: Treatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo resulted in a mild reduction in colitis severity as compared with vehicle-treated mice. Conclusion: We identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis.


Assuntos
Colite , Microbiota , Animais , Cromatina/genética , Cromatina/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Proteínas do Tecido Nervoso , Receptores de Superfície Celular , Fatores de Transcrição/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...