RESUMEN
To understand the role of T cells in the pathogenesis of ulcerative colitis (UC), we analyzed colonic T cells isolated from patients with UC and controls. Here we identified colonic CD4+ and CD8+ T lymphocyte subsets with gene expression profiles resembling stem-like progenitors, previously reported in several mouse models of autoimmune disease. Stem-like T cells were increased in inflamed areas compared to non-inflamed regions from the same patients. Furthermore, TCR sequence analysis indicated stem-like T cells were clonally related to proinflammatory T cells, suggesting their involvement in sustaining effectors that drive inflammation. Using an adoptive transfer colitis model in mice, we demonstrated that CD4+ T cells deficient in either BCL-6 or TCF1, transcription factors that promote T cell stemness, had decreased colon T cells and diminished pathogenicity. Our results establish a strong association between stem-like T cell populations and UC pathogenesis, highlighting the potential of targeting this population to improve clinical outcomes.
Asunto(s)
Colitis Ulcerosa , Factor Nuclear 1-alfa del Hepatocito , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Humanos , Animales , Ratones , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD4-Positivos/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Células Madre/inmunología , Células Madre/metabolismo , Femenino , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Ratones Noqueados , Colon/inmunología , Colon/patología , Masculino , Ratones Endogámicos C57BL , Traslado Adoptivo , Modelos Animales de Enfermedad , Adulto , Persona de Mediana EdadRESUMEN
BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD. METHODS: Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort). Clinical and serologic parameters were analyzed by means of univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations. RESULTS: Most EIMs occurred more commonly in female subjects (overall EIM: P = 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P = 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P = 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Smoking increased risk of EIMs except for PSC, where there was a "protective" effect. Multiple serologic associations were observed, including with PSC (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescens-associated sequence). We identified genome-wide significant associations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P = 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P = 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P = 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P = 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P = 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8). Genetic associations implicated tumor necrosis factor, JAK-STAT, and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated. CONCLUSIONS: We have identified demographic, clinical, and genetic associations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets-important steps toward a more personalized approach to IBD management.
Asunto(s)
Colangitis Esclerosante , Colitis Ulcerosa , Enfermedad de Crohn , Humanos , Femenino , Masculino , Adulto , Colangitis Esclerosante/inmunología , Colangitis Esclerosante/genética , Colangitis Esclerosante/diagnóstico , Colangitis Esclerosante/complicaciones , Persona de Mediana Edad , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/genética , Colitis Ulcerosa/diagnóstico , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/genética , Enfermedad de Crohn/diagnóstico , Adolescente , Factores de Riesgo , Niño , Espondilitis Anquilosante/genética , Espondilitis Anquilosante/inmunología , Espondilitis Anquilosante/diagnóstico , Espondilitis Anquilosante/complicaciones , Predisposición Genética a la Enfermedad , Adulto Joven , Factores Sexuales , Enfermedades de la Piel/etiología , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/genética , Oftalmopatías/etiología , Oftalmopatías/inmunología , Oftalmopatías/diagnóstico , Oftalmopatías/genética , Oftalmopatías/epidemiología , Fenotipo , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/diagnóstico , Modelos Logísticos , AncianoRESUMEN
Schistosome infection and schistosome-derived products have been implicated in the prevention and alleviation of inflammatory bowel disease by manipulating the host immune response, whereas the role of gut microbiota in this protective effect remains poorly understood. In this study, we found that the intraperitoneal immunization with Schistosoma japonicum eggs prior to dextran sulfate sodium (DSS) application significantly ameliorated the symptoms of DSS-induced acute colitis, which was characterized by higher body weight, lower disease activity index score and macroscopic inflammatory scores. We demonstrated that the immunomodulatory effects of S. japonicum eggs were accompanied by an influence on gut microbiota composition, abundance, and diversity, which increased the abundance of genus Turicibacter, family Erysipelotrichaceae, phylum Firmicutes, and decreased the abundance of genus Odoribacter, family Marinifilaceae, order Bacteroidales, class Bacteroidia, phylum Bacteroidota. In addition, Lactobacillus was identified as a biomarker that distinguishes healthy control mice from DSS-induced colitis mice. The present study revealed the importance of the gut microbiota in S. japonicum eggs exerting protective effects in an experimental ulcerative colitis (UC) model, providing an alternative strategy for the discovery of UC prevention and treatment drugs.
Asunto(s)
Colitis Ulcerosa , Sulfato de Dextran , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Schistosoma japonicum , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/inmunología , Ratones , Schistosoma japonicum/inmunología , Sulfato de Dextran/toxicidad , Femenino , Inmunización/métodos , Óvulo , Ratones Endogámicos C57BLRESUMEN
This study aimed to analyze single-cell sequencing data to investigate immune cell interactions in ankylosing spondylitis (AS) and ulcerative colitis (UC). Vertebral bone marrow blood was collected from three AS patients for 10X single-cell sequencing. Analysis of single-cell data revealed distinct cell types in AS and UC patients. Cells significantly co-expressing immune cells (P < 0.05) were subjected to communication analysis. Overlapping genes of these co-expressing immune cells were subjected to GO and KEGG analyses. Key genes were identified using STRING and Cytoscape to assess their correlation with immune cell expression. The results showed the significance of neutrophils in both diseases (P < 0.01), with notable interactions identified through communication analysis. XBP1 emerged as a Hub gene for both diseases, with AUC values of 0.760 for AS and 0.933 for UC. Immunohistochemistry verified that the expression of XBP1 was significantly lower in the AS group and significantly greater in the UC group than in the control group (P < 0.01). This finding highlights the critical role of neutrophils in both AS and UC, suggesting the presence of shared immune response elements. The identification of XBP1 as a potential therapeutic target offers promising intervention avenues for both diseases.
Asunto(s)
Colitis Ulcerosa , Neutrófilos , Espondilitis Anquilosante , Proteína 1 de Unión a la X-Box , Humanos , Espondilitis Anquilosante/genética , Espondilitis Anquilosante/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/genética , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismo , Masculino , Adulto , Femenino , Análisis de la Célula IndividualRESUMEN
BACKGROUND: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvß6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis. METHODS: Serum anti-integrin αvß6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvß6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients. RESULTS: Anti-integrin αvß6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvß6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvß6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvß6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvß6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.
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Autoanticuerpos , Biomarcadores , Colitis Ulcerosa , Inhibidores de Puntos de Control Inmunológico , Integrinas , Humanos , Masculino , Femenino , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/sangre , Persona de Mediana Edad , Integrinas/inmunología , Integrinas/antagonistas & inhibidores , Anciano , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Biomarcadores/sangre , Adulto , Antígenos de Neoplasias/inmunología , Colitis/inducido químicamente , Colitis/inmunologíaRESUMEN
Ulcerative colitis (UC) is an idiopathic inflammatory disease of the large intestine, which impacts millions worldwide. Current interventions aimed at treating UC symptoms can have off-target effects, invoking the need for alternatives that may provide similar benefits with less unintended consequences. This study builds on our initial data, which showed that panaxynol-a novel, potent, bioavailable compound found in American ginseng-can suppress disease severity in murine colitis. Here we explore the underlying mechanisms by which panaxynol improves both chronic and acute murine colitis. Fourteen-week-old C57BL/6 female mice were either given three rounds of dextran sulfate sodium (DSS) in drinking water to induce chronic colitis or one round to induce acute colitis. Vehicle or panaxynol (2.5 mg/kg) was administered via oral gavage three times per week for the study duration. Consistent with our previous findings, panaxynol significantly (P < 0.05) improved the disease activity index and endoscopic scores in both models. Using the acute model to examine potential mechanisms, we show that panaxynol significantly (P < 0.05) reduced DSS-induced crypt distortion, goblet cell loss, and mucus loss in the colon. 16S Sequencing revealed panaxynol altered microbial composition to suppress colitis-enriched genera (i.e., Enterococcus, Eubacterium, and Ruminococcus). In addition, panaxynol significantly (P < 0.05) suppressed macrophages and induced regulatory T-cells in the colonic lamina propria. The beneficial effects of panaxynol on mucosal and crypt architecture, combined with its microbial and immune-mediated effects, provide insight into the mechanisms by which panaxynol suppresses murine colitis. Overall, this data is promising for the use of panaxynol to improve colitis in the clinic.NEW & NOTEWORTHY In the current study, we report that panaxynol ameliorates chemically induced murine colitis by improving colonic crypt and mucosal architecture, suppressing colitis-enriched microbes, reducing macrophages, and promoting the differentiation of regulatory T-cells in the colonic lamina propria. This study suggests that this novel natural compound may serve as a safe and effective treatment option for colitis patients.
Asunto(s)
Colitis , Sulfato de Dextran , Microbioma Gastrointestinal , Mucosa Intestinal , Ratones Endogámicos C57BL , Animales , Femenino , Ratones , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/microbiología , Mucosa Intestinal/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/patología , Colitis/inmunología , Colitis/microbiología , Alcoholes Grasos/farmacología , Diinos/farmacología , Modelos Animales de Enfermedad , Colon/efectos de los fármacos , Colon/patología , Colon/inmunología , Colon/microbiología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/patología , Colitis Ulcerosa/microbiologíaRESUMEN
BACKGROUND: Recently, there has been an increase in the number of studies focusing on the association between the gut microbiome and obesity or inflammatory diseases, especially in adults. However, there is a lack of studies investigating the association between gut microbiome and gastrointestinal (GI) diseases in adolescents. METHOD: We obtained 16S rRNA-seq datasets for gut microbiome analysis from 202 adolescents, comprising ulcerative colitis (UC), Crohn's disease (CD), obesity (Ob), and healthy controls (HC). We utilized Quantitative Insights Into Microbial Ecology (QIIME) and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) to acquire Operational Taxonomic Units (OTUs). Subsequently, we analyzed Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology (KO) terms and pathway enrichment for the identified OTUs. RESULTS: In this study, we investigated the difference between the gut microbiomes in adolescents with GI diseases and those in healthy adolescents using 202 samples of 16S rRNA sequencing data. The distribution of the six main gut microbiota (i.e., unclassified Dorea, unclassified Lachnospiraceae, unclassified Ruminococcus, Faecalibacterium prausnitzii, Prevotella copri, unclassified Sutterella) was different based on the status of obesity and inflammatory diseases. Dysbiosis was observed within Lachnospiraceae in adolescents with inflammatory diseases (i.e., UC and CD), and in adolescents with obesity within Prevotella and Sutterella. More specifically, our results showed that the relative abundance of Faecalibacterium prausnitzii and unclassified Lachnospiraceae was more than 10% and 8% higher, respectively, in the UC group compared to the CD, Ob, and HC groups. Additionally, the Ob group had over 20% and over 3% higher levels of Prevotella copri and unclassified Sutterella, respectively, compared to the UC, CD, and HC groups. Also, inspecting associations between the six specific microbiota and KO terms, we found that the six microbiota -relating KO terms were associated with NOD-like receptor signaling. These six taxa differences may affect the immune system and inflammatory response by affecting NOD-like receptor signaling in the host during critical adolescence. CONCLUSION: In this study, we discovered that dysbiosis of the microbial community had varying degrees of influence on the inflammatory and immune response pathways in adolescents with inflammatory diseases and obesity.
Asunto(s)
Bacterias , Microbioma Gastrointestinal , Obesidad , Filogenia , ARN Ribosómico 16S , Humanos , Microbioma Gastrointestinal/genética , Adolescente , ARN Ribosómico 16S/genética , Obesidad/microbiología , Obesidad/inmunología , Femenino , Masculino , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/inmunología , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/inmunología , Disbiosis/microbiología , Prevotella/genética , Prevotella/clasificación , Prevotella/aislamiento & purificación , Faecalibacterium prausnitzii/genética , Heces/microbiologíaRESUMEN
PURPOSE OF REVIEW: To provide an overview of the current literature regarding the use of advanced combination therapy (ACT) in patients with inflammatory bowel disease (IBD). Although the treatment of IBD has come a long way, many patients do not respond or will lose response to currently available treatments over time. ACT has been proposed as a model to create sustained remission in difficult-to-treat IBD patient populations. This review discusses the available literature supporting the use of ACT, followed by practical tips for applying this model of treatment to clinical practice. RECENT FINDINGS: Both observational and controlled evidence have demonstrated that there may be an increased benefit of ACT in specific IBD patient populations compared to advanced targeted immunomodulator (TIM) monotherapy. Additional data is required to understand how to best use combination TIMs and the long-term risks associated with this strategy. SUMMARY: While the literature has demonstrated the potential for benefit in both Crohn's disease and ulcerative colitis, the use of ACT is currently off-label and long-term controlled data is needed. The successful application of ACT requires careful consideration of both patient and disease profiles as well as close monitoring of treatment response and adverse events.
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Quimioterapia Combinada , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/terapia , Agentes Inmunomoduladores/uso terapéutico , Agentes Inmunomoduladores/administración & dosificación , Enfermedad de Crohn/tratamiento farmacológico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/terapia , Inducción de Remisión/métodos , Resultado del Tratamiento , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Guías de Práctica Clínica como AsuntoRESUMEN
Ulcerative colitis (UC) is associated with changed dietary habits and mainly linked with the gut microbiota dysbiosis, necroptosis of epithelial cells, and mucosal ulcerations. Liver dysfunction and abnormal level of liver metabolism indices were identified in UC patients, suggesting a close interaction between gut and liver disorders. Methionine-choline deficient diet (MCD) has been shown to induce persistent alterations of gut microbiota and metabolome during hepatitis. In this study we further explored the disease phenotypes in UC patients and investigated whether MCD functioned as a trigger for UC susceptibility. After assessing 88 serum specimens from UC patients, we found significant liver dysfunction and dyslipidemia including abnormal ALT, AST, TG, TC, LDL-c and HDL-c. Liver dysfunction and dyslipidemia were confirmed in DSS-induced colitis mice. We fed mice with MCD for 14 days to cause mild liver damage, and then treated with DSS for 7 days. We found that MCD intake significantly exacerbated the pathogenesis of mucosal inflammation in DSS-induced acute, progressive, and chronic colitis, referring to promotion of mucosal ulcers, colon shortening, diarrhea, inflammatory immune cell infiltration, cytokines release, and abnormal activation of inflammatory macrophages in colon and liver specimens. Intraperitoneal injection of clodronate liposomes to globally delete macrophages dramatically compromised the pathogenesis of MCD-triggering colitis. In addition, MCD intake markedly changed the production pattern of short-chain fatty acids (SCFAs) in murine stools, colons, and livers. We demonstrated that MCD-induced colitis pathogenesis largely depended on the gut microbes and the disease phenotypes could be transmissible through fecal microbiota transplantation (FMT). In conclusion, this study supports the concept that intake of MCD predisposes to experimental colitis and enhances its pathogenesis via modulating gut microbes and macrophages in mice.
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Sulfato de Dextran , Microbioma Gastrointestinal , Macrófagos , Metionina , Ratones Endogámicos C57BL , Animales , Metionina/deficiencia , Macrófagos/metabolismo , Macrófagos/inmunología , Masculino , Ratones , Sulfato de Dextran/toxicidad , Humanos , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/patología , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/inmunología , Deficiencia de Colina/complicaciones , Femenino , Dieta , Colina/metabolismo , Colon/patología , Colon/microbiología , Colon/inmunología , Colitis/microbiología , Colitis/patología , Colitis/inducido químicamente , Hígado/patología , Hígado/metabolismoRESUMEN
Abnormalities in mucosal immunity are involved in the onset and progression of ulcerative colitis (UC), resulting in a high incidence of colorectal cancer (CRC). While high-mobility group box-1 (HMGB1) is overexpressed during colorectal carcinogenesis, its role in UC-related carcinogenesis remains unclear. In the present study, we investigated the role of HMGB1 in UC-related carcinogenesis and sporadic CRC. Both the azoxymethane colon carcinogenesis and dextran sulfate sodium colitis carcinogenesis models demonstrated temporal increases in mucosal HMGB1 levels. Activated CD8+ cells initially increased and then decreased, whereas exhausted CD8+ cells increased. Additionally, we observed increased regulatory CD8+ cells, decreased naïve CD8+ cells, and decreased mucosal epithelial differentiation. In the in vitro study, HMGB1 induced energy reprogramming from oxidative phosphorylation to glycolysis in CD8+ cells and intestinal epithelial cells. Furthermore, in UC dysplasia, UC-related CRC, and hyperplastic mucosa surrounding human sporadic CRC, we found increased mucosal HMGB1, decreased activated CD8+ cells, and suppressed mucosal epithelial differentiation. However, we observed increased activated CD8+ cells in active UC mucosa. These findings indicate that HMGB1 plays an important role in modulating mucosal immunity and epithelial dedifferentiation in both UC-related carcinogenesis and sporadic CRC.
Asunto(s)
Linfocitos T CD8-positivos , Diferenciación Celular , Colitis Ulcerosa , Proteína HMGB1 , Inmunidad Mucosa , Mucosa Intestinal , Proteína HMGB1/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Colitis Ulcerosa/patología , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/inducido químicamente , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones , Masculino , Células Epiteliales/metabolismo , Células Epiteliales/patología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/inmunología , Ratones Endogámicos C57BL , Carcinogénesis/inmunología , Carcinogénesis/patología , Carcinogénesis/metabolismoRESUMEN
BACKGROUND: The strong connection between gut microbes and human health has been confirmed by an increasing number of studies. Although probiotics have been found to relieve ulcerative colitis, the mechanism varies by the species involved. In this study, the physiological, immune and pathological factors of mice were measured and shotgun metagenomic sequencing was conducted to investigate the potential mechanisms in preventing ulcerative colitis. RESULTS: The results demonstrated that ingestion of Lactobacillus fermentum GLF-217 and Lactobacillus plantarum FLP-215 significantly alleviated ulcerative colitis induced by dextran sulfate sodium (DSS), as evidenced by the increase in body weight, food intake, water intake and colon length as well as the decrease in disease activity index, histopathological score and inflammatory factor. Both strains not only improved intestinal mucosa by increasing mucin-2 and zonula occludens-1, but also improved the immune system response by elevating interleukin-10 levels and decreasing the levels of interleukin-1ß, interleukin-6, tumor necrosis factor-α and interferon-γ. Moreover, L. fermentum GLF-217 and L. plantarum FLP-215 play a role in preventing DSS-induced colitis by regulating the structure of gut microbiota and promoting the formation of short-chain fatty acids. CONCLUSIONS: This study may provide a reference for the prevention strategy of ulcerative colitis. © 2024 Society of Chemical Industry.
Asunto(s)
Colitis Ulcerosa , Microbioma Gastrointestinal , Lactobacillus plantarum , Limosilactobacillus fermentum , Probióticos , Animales , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/prevención & control , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/inmunología , Ratones , Probióticos/administración & dosificación , Probióticos/farmacología , Masculino , Humanos , Sulfato de Dextran/efectos adversos , Colon/microbiología , Colon/inmunología , Colon/patología , Mucosa Intestinal/microbiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Ratones Endogámicos C57BL , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunología , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Mucina 2/metabolismo , Mucina 2/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-6/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Interferón gamma/metabolismo , Interferón gamma/genética , Interferón gamma/inmunología , Proteína de la Zonula Occludens-1/metabolismo , Proteína de la Zonula Occludens-1/genética , Modelos Animales de EnfermedadRESUMEN
Ulcerative colitis(UC) is one of the common gastrointestinal diseases worldwide. In recent years, the incidence of UC has been continuously increasing, seriously threatening the health of people globally. It thus has become an urgent problem that needs to be addressed. There is research evidence that intestinal mucosal barrier dysfunction, including changes in intestinal stem cell secretion lineage, mucosal layer damage, disruption of cell junctions, overactive immune function, and imbalanced gut microbiota, is an important pathogenic factor and molecular basis of UC. The Notch signaling pathway is a highly conserved signaling pathway in eukaryotes during evolution, which transmits signals through cell connections between adjacent cells, affecting a series of processes such as cell proliferation, differentiation, development, migration, and apoptosis. Therefore, the Notch signaling pathway can regulate intestinal stem cells, CD4~+T cells, innate lymphoid cells(ILCs), macrophages(MØ), and intestinal microbiota and thus affect the chemical, physical, immune, and biological mucosal barriers of the intestinal mucosa. Its function is extensive and unique, different from those signaling pathways that mainly focus on anti-inflammatory and antioxidant stress. It can explain the therapeutic effects of traditional Chinese medicine from different perspectives. This article reviewed the role of the Notch1 signaling pathway in the pathogenesis of UC and the relevant literature on the targeted prevention and treatment of UC with traditional Chinese medicine, so as to provide new targets and theoretical support for further research on the effective prevention and treatment of UC.
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Colitis Ulcerosa , Receptor Notch1 , Transducción de Señal , Humanos , Transducción de Señal/efectos de los fármacos , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Receptor Notch1/metabolismo , Receptor Notch1/genética , Animales , Medicamentos Herbarios Chinos/farmacología , Medicina Tradicional ChinaRESUMEN
BACKGROUND AND OBJECTIVE: Currently, there is no single golden standard for diagnosing ulcerative colitis (UC). Now serum αvß6 autoantibodies have shown promise as a diagnostic tool for UC. Here the aim was to determine the diagnostic performance of serum αvß6 autoantibodies for UC. METHODS: PubMed, the Cochrane Library, the Embase, and the Web of Science were searched comprehensively. STATA software was utilized to analyze the relevant data. RESULTS: 9 studies from 6 articles with 1827 subjects were eligible. The summary sensitivity and specificity of serum αvß6 autoantibodies to diagnose UC were 0.82 (95 % confidence interval (CI): 0.65-0.92) and 0.94 (95 % CI: 0.90-0.97) with an area under the summary receiver operating characteristic curve of 0.96 (95 % CI: 0.94-0.97). Subgroup analysis was conducted owning to substantial heterogeneity between studies (I2 = 97 % and P < 0.001). The aggregate sensitivity and specificity to diagnose UC in adults were 0.75 (95 % CI: 0.61-0.86) and 0.95 (95 % CI: 0.90-0.97), and when using a threshold of mean control+3SD, 0.80 (95 % CI: 0.60-0.91) and 0.96 (95 % CI: 0.90-0.99), respectively. Additionally, to differentiate UC from healthy participants, non-inflammatory bowel disease, and Crohn's disease, the overall specificity was 0.96, 0.88, and 0.80, respectively. CONCLUSIONS: serum αvß6 autoantibodies, as a non-invasive tool, demonstrated good diagnostic accuracy for UC. However, their application may be limited in some immune-related disorders, and further studies are needed for validation.
Asunto(s)
Autoanticuerpos , Colitis Ulcerosa , Humanos , Colitis Ulcerosa/sangre , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/inmunología , Autoanticuerpos/sangre , Sensibilidad y EspecificidadRESUMEN
Many immune-mediated diseases have the common genetic basis, as an autoimmune disorder, celiac disease (CeD) primarily affects the small intestine, and is caused by the ingestion of gluten in genetically susceptible individuals. As for ulcerative colitis (UC), which most likely involves a complex interplay between some components of the commensal microbiota and other environmental factors in its origin. These two autoimmune diseases share a specific target organ, the bowel. The etiology and immunopathogenesis of both conditions characterized by chronic intestinal inflammation, ulcerative colitis and celiac disease, are not completely understood. Both are complex diseases with genetics and the environmental factors contributing to dysregulation of innate and adaptive immune responses, leading to chronic inflammation and disease. This study is designed to further clarify the relationship between UC and CeD. The GEO database was used to download gene expression profiles for CeD (GSE112102) and UC (GSE75214). The GSEA KEGG pathway analysis revealed that immune-related pathways were significantly associated with both diseases. Further, we screened 187 shared differentially expressed genes (DEGs) of the two diseases. Gene Ontology (GO) and WikiPathways were carried out to perform the biological process and pathway enrichment analysis. Subsequently, based on the DEGs, the least absolute shrinkage and selection operator (LASSO) analysis was performed to screen for the diagnostic biomarkers of the diseases. Moreover, single-cell RNA-sequencing (RNA-seq) data from five colonic propria with UC showed that REG4 expression was present in Goblet cell, Enteroendocrine cell, and Epithelial. Finally, our work identified REG4 is the shared gene of UC and CeD via external data validation, cellular experiments, and immunohistochemistry. In conclusion, our study elucidated that abnormal immune response could be the common pathogenesis of UC and CeD, and REG4 might be a key potential biomarker and therapeutic target for the comorbidity of these two diseases.
Asunto(s)
Enfermedad Celíaca , Colitis Ulcerosa , Análisis de la Célula Individual , Enfermedad Celíaca/genética , Enfermedad Celíaca/inmunología , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Humanos , Transcriptoma , Perfilación de la Expresión Génica , Análisis de Secuencia de ARNRESUMEN
Inflammatory bowel disease (IBD) is an immune-mediated inflammation of the gastrointestinal tract that includes Crohn disease and ulcerative colitis (UC). Although IBD is associated with elevated levels of innate and adaptive immunity, the relationship between circulating immune cells and IBD remains largely unknown. Therefore, we conducted a bidirectional 2-sample Mendelian randomization (MR) study to determine their causal relationship. Genome-wide association study summary statistics were extracted from publicly available databases regarding immune cell phenotypes and IBD traits (including IBD, Crohn disease, and UC). MR analysis was conducted using 5 MR methods, with inverse-variance-weighted (IVW) as the primary analysis method. False discovery rate correction (FDR) was used to reduce the likelihood of type 1 errors. We also conducted MR-Egger-intercept tests to evaluate horizontal pleiotropy. After FDR adjustment of the P values for the IVW method, the results indicated no causal relationship between immune cell phenotypes and IBD or UC, but 4 immune characteristics were causally associated with Crohn disease. The percentage of human leukocyte antigen DR+â CD4+â T cells in lymphocytes was positively associated with the development of Crohn disease (odd ratio [OR], 1.13; 95% confidence interval [CI], 1.07-1.21; Pâ <â .001; PFDRâ =â 0.019), whereas the percentage of IgD- CD27- B cells in lymphocytes (OR, 0.85; 95% CI, 0.79-0.92; Pâ <â .001; PFDRâ =â 0.014), CD28 on CD39+â secreting CD4 regulatory T cells (OR, 0.92; 95% CI, 0.89-0.96; Pâ <â .001; PFDRâ =â 0.019), and the percentage of naïve CD4+â T cells in all CD4+â T cells (OR, 0.90; 95% CI, 0.85-0.95; Pâ <â .001; PFDRâ =â 0.027) were negatively related to the risk of Crohn disease. MR analysis of the above 4 immune cell phenotypes revealed no horizontal pleiotropy. In the reverse MR analysis, Crohn disease was not causally associated with any of these immune cell phenotypes. The findings provide insight into the relationship between immune cells and IBD pathogenesis, and may serve as a basis for developing novel immunotherapies.
Asunto(s)
Enfermedad de Crohn , Estudio de Asociación del Genoma Completo , Enfermedades Inflamatorias del Intestino , Análisis de la Aleatorización Mendeliana , Humanos , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/sangre , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/sangre , Fenotipo , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/genética , Linfocitos T CD4-Positivos/inmunologíaRESUMEN
Inflammatory bowel diseases (IBDs), such as Crohn's disease (CD) and ulcerative colitis (UC), are chronic diseases of the digestive system with a multifactorial and not fully understood etiology. There is research suggesting that they may be initiated by genetic, immunological, and lifestyle factors. In turn, all of these factors play an important role in the modulation of intestinal microflora, and a significant proportion of IBD patients struggle with intestinal dysbiosis, which leads to the conclusion that intestinal microflora disorders may significantly increase the risk of developing IBD. Additionally, in IBD patients, Toll-like receptors (TLRs) produced by intestinal epithelial cells and dendritic cells treat intestinal bacterial antigens as pathogens, which causes a disruption of the immune response, resulting in the development of an inflammatory process. This may result in the occurrence of intestinal dysbiosis, which IBD patients are significantly vulnerable to. In this study, we reviewed scientific studies (in particular, systematic reviews with meta-analyses, being studies with the highest level of evidence) regarding the microflora of patients with IBD vs. the microflora in healthy people, and the use of various strains in IBD therapy.
Asunto(s)
Disbiosis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Humanos , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/inmunología , Probióticos/uso terapéutico , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/inmunologíaRESUMEN
The concept of inflammatory bowel disease (IBD), which encompasses Crohn's disease and ulcerative colitis, represents a complex and growing global health concern resulting from a multifactorial etiology. Both dysfunctional autophagy and dysbiosis contribute to IBD, with their combined effects exacerbating the related inflammatory condition. As a result, the existing interconnection between gut microbiota, autophagy, and the host's immune system is a decisive factor in the occurrence of IBD. The factors that influence the gut microbiota and their impact are another important point in this regard. Based on this initial perspective, this manuscript briefly highlighted the intricate interplay between the gut microbiota, autophagy, and IBD pathogenesis. In addition, it also addressed the potential targeting of the microbiota and modulating autophagic pathways for IBD therapy and proposed suggestions for future research within a more specific and expanded context. Further studies are warranted to explore restoring microbial balance and regulating autophagy mechanisms, which may offer new therapeutic avenues for IBD management and to delve into personalized treatment to alleviate the related burden.
Asunto(s)
Autofagia , Disbiosis , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/inmunología , Disbiosis/inmunología , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/inmunología , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/inmunología , Animales , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/inmunologíaRESUMEN
Background: It has been well documented that Takayasu arteritis (TAK) and ulcerative colitis (UC) coexist in the same patients. HLA-B*52 characterizes the co-occurrence, which is one of the common genetic features between these two diseases, indicating shared underlying pathologic mechanisms. Anti-integrin αvß6 antibody (Ab) is present in sera of UC patients in a highly specific manner. We investigated if there were any associations between anti-integrin αvß6 Ab and TAK, considering the risk HLA alleles. Methods: A total of 227 Japanese TAK patients were recruited in the current study and their serum samples were subjected to measurement of anti-integrin αvß6 Ab by ELISA. The clinical information, including the co-occurrence of UC, was collected. The HLA allele carrier status was determined by Luminex or genotype imputation. Results: The information about the presence of UC was available for 165 patients, among which eight (4.84%) patients had UC. Anti-integrin αvß6 antibody was identified in 7 out of 8 TAK subjects with UC (87.5%) while only 5 out of 157 (3.18%) TAK subjects without UC had the antibody (OR 121, p=7.46×10-8). A total of 99 out of 218 (45.4%) patients were HLA-B*52 carriers. There was no significant association between the presence of anti-integrin αvß6 Ab and HLA-B*52 carrier status in those without UC (OR 2.01, 95% CI 0.33-12.4, p = 0.189). Conclusions: The prevalence of anti-integrin αvß6 Ab was high in TAK patients with UC, but not in the absence of concomitant UC. The effect of HLA-B*52 on anti-integrin αvß6 Ab production would be minimal.
Asunto(s)
Antígenos de Neoplasias , Colitis Ulcerosa , Integrinas , Arteritis de Takayasu , Humanos , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/genética , Arteritis de Takayasu/inmunología , Arteritis de Takayasu/genética , Femenino , Integrinas/inmunología , Masculino , Adulto , Persona de Mediana Edad , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Antígeno HLA-B52/inmunología , Antígeno HLA-B52/genética , Alelos , Adulto Joven , Japón/epidemiología , Genotipo , Autoanticuerpos/sangre , Autoanticuerpos/inmunologíaRESUMEN
Background: Accumulating evidence reveals mitochondrial dysfunction exacerbates intestinal barrier dysfunction and inflammation. Despite the growing knowledge of mitochondrial dysfunction and ulcerative colitis (UC), the mechanism of mitochondrial dysfunction in UC remains to be fully explored. Methods: We integrated 1137 UC colon mucosal samples from 12 multicenter cohorts worldwide to create a normalized compendium. Differentially expressed mitochondria-related genes (DE-MiRGs) in individuals with UC were identified using the "Limma" R package. Unsupervised consensus clustering was utilized to determine the intrinsic subtypes of UC driven by DE-MiRGs. Weighted gene co-expression network analysis was employed to investigate module genes related to UC. Four machine learning algorithms were utilized for screening DE-MiRGs in UC and construct MiRGs diagnostic models. The models were developed utilizing the over-sampled training cohort, followed by validation in both the internal test cohort and the external validation cohort. Immune cell infiltration was assessed using the Xcell and CIBERSORT algorithms, while potential biological mechanisms were explored through GSVA and GSEA algorithms. Hub genes were selected using the PPI network. Results: The study identified 108 DE-MiRGs in the colonic mucosa of patients with UC compared to healthy controls, showing significant enrichment in pathways associated with mitochondrial metabolism and inflammation. The MiRGs diagnostic models for UC were constructed based on 17 signature genes identified through various machine learning algorithms, demonstrated excellent predictive capabilities. Utilizing the identified DE-MiRGs from the normalized compendium, 941 patients with UC were stratified into three subtypes characterized by distinct cellular and molecular profiles. Specifically, the metabolic subtype demonstrated enrichment in epithelial cells, the immune-inflamed subtype displayed high enrichment in antigen-presenting cells and pathways related to pro-inflammatory activation, and the transitional subtype exhibited moderate activation across all signaling pathways. Importantly, the immune-inflamed subtype exhibited a stronger correlation with superior response to four biologics: infliximab, ustekinumab, vedolizumab, and golimumab compared to the metabolic subtype. Conclusion: This analysis unveils the interplay between mitochondrial dysfunction and the immune microenvironment in UC, thereby offering novel perspectives on the potential pathogenesis of UC and precision treatment of UC patients, and identifying new therapeutic targets.