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Non-small cell lung cancer (NSCLC) is a prevalent tumor and acidic tumor microenvironment provides an energy source driving tumor progression. We previously demonstrated significantly upregulated Integrin ß6 (ITGB6) in NSCLC cells. This study was designed to investigate the role of ITGB6 in NSCLC metastasis and explore the potential mechanisms. The expression of ITGB6 was evaluated in patients with NSCLC. Migration and invasion assays were utilized to investigate the role of ITGB6, and ChIP-qPCR and dual-luciferase reporter experiments preliminarily analyzed the relationship between ETS proto-oncogene 1 (ETS1) and ITGB6. Bioinformatics analysis and rescue models were performed to explore the underlying mechanisms. The results demonstrated that ITGB6 was upregulated in NSCLC patients and the difference was even more pronounced in patients with poor prognosis. Functionally, acidity-induced ITGB6 promoted migration and invasion of NSCLC cells in vitro, and epithelial-mesenchymal transition (EMT) and focal adhesion were the important mechanisms responsible for ITGB6-involved metastasis. Mechanistically, we revealed ETS1 enriched in the ITGB6 promoter region and promoted transcription to triggered the activation of subsequent signaling pathways. Moreover, ChIP-qPCR and dual-luciferase reporter experiments demonstrated that ETS1 played an important role in directly mediating ITGB6 expression. Furthermore, we found ITGB6 was responsible for the acidic microenvironment-mediated migration and invasion processes in NSCLC by performing rescue experiments with ITGB6 knockdown. Our findings indicated acidic microenvironment directly induced ETS1 to regulate the expression of ITGB6, and then the highly expressed ITGB6 further mediate EMT and activates the downstream focal adhesion pathways, eventually promotes the invasion and migration in NSCLC progression and metastasis.
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Carcinoma de Pulmón de Células no Pequeñas , Cadenas beta de Integrinas , Neoplasias Pulmonares , MicroARNs , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Transición Epitelial-Mesenquimal/genética , Adhesiones Focales/metabolismo , Luciferasas , Neoplasias Pulmonares/patología , MicroARNs/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: The indolent course of treatment-naive patients with inflammatory bowel disease (IBD) is confirmed predictable based on clinical characteristics. Current evidences supported that bile acids (BAs) alteration might be promising biomarkers in the field of IBD. We aimed to analyze the alterations of BAs as the disease progresses and explore their predictive value for indolent course of IBD. METHODS: The indolent course of IBD was defined as a disease course without need for strict interventions throughout the entire follow-up. A targeted metabolomics method was used to detect the concentration of 27 BAs from serum sample in treatment-naive patients with IBD (Crohn's disease [CD], n = 27; ulcerative colitis [UC], n = 50). Patients with CD and UC were individually divided into two groups for further study according to the median time of indolent course. The overall BAs profile and the clinical value of BAs in predicting indolent course of IBD were identified between different groups. RESULTS: For CD, the levels of deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycolithocholic acid-3-sulfate disodium salt and iso-lithocholic acid were significantly increased in patients with indolent course > 18 M (p < 0.05). These five BAs owned 83.5% accuracy for predicting indolent course over 18 months in CD. For UC, the concentration of deoxycholic acid and glycodeoxycholic acid were significantly higher, while dehydrocholic acid were lower in patients with indolent course > 48 M (p < 0.05). These three BAs predicted indolent course over 48 months of 69.8% accuracy in UC. CONCLUSION: The specific BAs alterations might be potential biomarkers in predicting disease course of IBD patients.
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Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Ácidos y Sales Biliares , Enfermedades Inflamatorias del Intestino/diagnóstico , Biomarcadores , Progresión de la EnfermedadRESUMEN
BACKGROUND: Short-chain fatty acids (SCFAs) and serotonin (5-hydroxytryptamine, 5-HT) may be associated with the pathogenesis of irritable bowel syndrome (IBS). There are some reports of alterations in SCFAs and 5-HT in IBS, but their results are inconsistent. We aimed to perform a meta-analysis to assess alterations in SCFAs and 5-HT in IBS patients and their potential role in the abnormal brain-gut-microbiota (BGM) axis. METHODS: Case-control studies detecting SCFAs and 5-HT in IBS patients were identified from PubMed, Web of Science, Cochrane Library, and Scopus databases to identify relevant articles up to September 2018. The standardized mean differences (SMDs) with 95% confidence intervals (CIs) of SCFAs and 5-HT were calculated by REVIEW MANAGER 5.3 to evaluate the alterations of 5-HT and SCFAs in IBS. RESULTS: Five studies on SCFAs and 5 on 5-HT in IBS patients were included. As compared to healthy controls (HCs), the SMDs of 5-HT in IBS patients was 2.35 (95% CI 0.46-4.24) and the SMDs of total SCFAs, acetic acid, propionic acid, and butyric acid in IBS patients were - 0.01 (95% CI - 0.57-0.55), - 0.04 (95% CI - 0.55-0.47), 0.07 (95% CI - 0.45-0.60), and - 0.00 (95% CI - 0.49-0.49), respectively. CONCLUSIONS: There was an increase in 5-HT in blood of IBS patients, indicating the increased 5-HT in blood may be involved in IBS pathogenesis. However, there were no significant differences in SCFAs in feces between IBS patients and HCs. But the study did not differentiate between subgroups of IBS. These findings might provide insight for future studies of the BGM axis in the pathogenesis of IBS. Mei Luo and Xiaojun Zhuang contributed equally to the writing of this article.
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Microbioma Gastrointestinal , Síndrome del Colon Irritable , Ácidos Grasos , Ácidos Grasos Volátiles , Humanos , SerotoninaRESUMEN
BACKGROUND: Short-chain fatty acids (SCFAs) alteration have been reported in irritable bowel syndrome (IBS), but the results are conflicting. Our study aims to explore the alteration of SCFAs in patients with diarrhea-predominant IBS (IBS-D) and their potential role in the occurrence and development of IBS. METHODS: We recruited patients with IBS-D defined by Rome IV criteria and age-and-gender matched healthy controls (HCs). A headspace solid-phase microextraction gas chromatography-mass spectrometric (HS-SPME-GC-MS) method was developed for the analysis of acetic, propionic and butyric acid in feces and serum. RESULTS: Compared with HCs, the levels of the serum propionate (2.957 ± 0.157 vs 2.843 ± 0.098 mmol/L, P = 0.012) and butyrate (2.798 ± 0.126 vs 2.697 ± 0.077 mmol/L, P = 0.012) were significantly higher in IBS-D group. No significant differences were found among two groups with regard to the concentration of fecal acetate (4.953 ± 1.065 vs 4.774 ± 1.465 mg/g, P = 0.679), propionate (6.342 ± 1.005 vs 6.282 ± 1.077 mg/g, P = 0.868) and butyrate (2.984 ± 0.512 vs 3.071 ± 0.447 mg/g, P = 0.607). CONCLUSIONS: Metabolites of gut microbiota, the propionic and butyric acid, are increased in patients with IBS-D in serum but not in feces. It suggests that propionic and butyric acid might be associated with the occurrence and development of IBS.
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Ácido Butírico/análisis , Diarrea/etiología , Síndrome del Colon Irritable/complicaciones , Propionatos/análisis , Acetatos/análisis , Adulto , Biomarcadores/análisis , Estudios de Casos y Controles , Heces/química , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Gut microbiota alterations including small intestinal bacterial overgrowth (SIBO) might play a role in pathogenesis of irritable bowel syndrome (IBS). Rifaximin could effectively and safely improve IBS symptoms. The aim of this study was to investigate the effect of rifaximin on Gastrointestinal (GI) symptoms, quality of life (QOL) and SIBO eradication in Chinese IBS-D patients. METHODS: This study included 78 IBS-D patients defined by the Rome IV criteria. Patients received 400 mg rifaximin twice daily for 2 weeks and 10-week follow-up. GI symptoms were assessed at week 0, 2, 4, 8 and 12. QOL and lactulose hydrogen breath test (LHBT) results were estimated at week 0 and 4. RESULTS: All participants showed significant improvements in GI symptom subdomains after rifaximin treatment (all P < 0.05), which could maintain at least 10 weeks of follow-up. Additionally, QOL scores were increased with concomitant improvement of clinical symptoms (all P < 0.05). The 45 rifaximin-responsive patients (57.7%) achieved significantly greater GI-symptom improvement than non-responders (all P < 0.05). No GI symptoms were associated with SIBO (all P > 0.05). SIBO normalization after rifaximin treatment measured by LHBT was found in 44.4% (20/45) of patients with SIBO before treatment. CONCLUSION: A short course (2 weeks) of rifaximin improved GI symptoms and QOL in Chinese IBS-D patients whether they had SIBO or not. However, the efficacy of rifaximin could not be explained by the successful eradication of SIBO. Further studies on the therapeutic mechanisms of rifaximin in IBS are urgently needed.
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Síndrome del Asa Ciega/tratamiento farmacológico , Diarrea/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Síndrome del Colon Irritable/tratamiento farmacológico , Rifaximina/administración & dosificación , Adulto , Síndrome del Asa Ciega/complicaciones , Síndrome del Asa Ciega/microbiología , Pruebas Respiratorias/métodos , China , Diarrea/complicaciones , Diarrea/microbiología , Esquema de Medicación , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Síndrome del Colon Irritable/complicaciones , Síndrome del Colon Irritable/microbiología , Lactulosa/análisis , Masculino , Calidad de Vida , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Alterations of gut microbiota were assumed to be the etiology and pathogenesis of irritable bowel syndrome (IBS) in some studies. However, alterations of gut microbiota in IBS patients had not been systematically assessed with a meta-analysis. We performed a mate-analysis to explore and compare the alterations of gut microbiota in IBS patients from China and other regions around the world. METHODS: Case-control studies detecting gut microbiota in IBS patients were identified through English and Chinese databases. The standardized mean difference (SMD) with 95% confidence interval (CI) of bacterial counts was calculated. RESULTS: Ten studies from China and seven studies from other regions around the world were included in our study. As compared with healthy controls, the SMDs of Bifidobacteria, Lactobacillus, Escherichia Coli, and Enterobacter in Chinese IBS patients were -1.42 (CI: -2.10, -0.75), -0.91 (95% CI: -1.31, -0.52), 0.83 (95% CI: 0.26, 1.40), and 0.57 (95% CI: 0.33, 0.82), respectively. But the SMDs of Bacteroides and Enterococcus were found no significant differences in Chinese IBS patients. However, the SMDs of Bifidobacteria and Bacteroides in IBS patients from other regions were -0.76 (CI: -1.43, -0.09) and 1.17 (CI: 0.00, 2.35), while the SMDs of Lactobacillus, E. Coli, Enterobacter, and Enterococcus were found no significant differences. CONCLUSIONS: There were alterations of gut microbiota in IBS patients, and it implied that alterations of gut microbiota might be involved in the pathogenesis of IBS. However, the species-specific alterations of gut microbiota were different between IBS patients from China and other regions.
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Microbioma Gastrointestinal/fisiología , Síndrome del Colon Irritable/microbiología , Carga Bacteriana , Bifidobacterium/aislamiento & purificación , Estudios de Casos y Controles , Bases de Datos Bibliográficas , Enterobacter/aislamiento & purificación , Escherichia coli/aislamiento & purificación , Humanos , Síndrome del Colon Irritable/etiología , Lactobacillus/aislamiento & purificaciónRESUMEN
Intestinal stricture remains one of the most intractable complications in Crohn's disease (CD), and the involved mechanisms are poorly understood. Accumulating evidence suggests that the gut microbiota contributes to the pathogenesis of intestinal fibrosis. In this study, we investigated specific mucosa-associated microbiota related to intestinal strictures and their role in predicting postoperative disease course. Twenty CD patients who had undergone operative treatments were enrolled and followed up. Intestinal mucosa and full-thickness sections from stenotic and non-stenotic sites were sterilely collected. DNA extraction and bacterial 16s rRNA gene sequencing were conducted. Radiological and histological evaluations were performed to assess fibrosis. Microbial alpha diversity was significantly decreased in stenotic sites (p = 0.009). At the genus level, Lactobacillus, Oscillospira, Subdoligranulum, Hydrogenophaga, Clostridium and Allobaculum were decreased in stenotic segments (p < 0.1). The difference in Oscillospira sp. (stenotic vs. non-stenotic) was negatively correlated with the erythrocyte sedimentation rate (correlation coefficient (CC) -0.432, p = 0.057) and white blood cell count (CC -0.392, p = 0.087) and positively correlated with serum free fatty acids (CC 0.575, p < 0.05). This difference was negatively associated with intestinal fibrosis evaluated by imagological and histological methods (CC -0.511 and -0.653, p < 0.05). Furthermore, CD patients with a higher abundance of Oscillospira sp. in the residual intestine might experience longer remission periods (p < 0.05). The mucosa-associated microbiota varied between stenotic and non-stenotic sites in CD. Most notably, Oscillospira sp. was negatively correlated with intestinal fibrosis and postoperative disease course. It could be a promising biomarker to predict post-operative disease recurrence and a microbial-based therapeutic target.
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OBJECTIVES: Our aims were to better understand the interplay of diet and gut microbiota in Crohn's disease [CD], taking advantage of a new-onset treatment-naïve CD cohort. We focus on phenylacetylglutamine [PAGln], a diet-derived meta-organismal prothrombotic metabolite. DESIGN: We collected faecal and serum samples from a CD cohort [nâ =â 136] and healthy controls [nâ =â 126] prior to treatment, and quantified serum PAGln using LC-MS/MS. Diet was assessed using food-frequency questionnaires. Mice [C57BL/6] were fed high/low-protein diets and administered dextran sodium sulphate [DSS] to examine plasma PAGly, thrombosis potential, and colitis severity. PAGly or saline was administered to DSS-induced colitis mice, and colitis severity and colonic tissue gene expression were examined. P-selectin and CD40L expression were determined in human platelet-rich plasma [nâ =â 5-6] after exposure to platelet agonists following PAGln priming. Bioinformatic analysis and bacterial culturing identified the main contributor of PAGln in CD. RESULTS: PAGln, a meta-organismal prothrombotic metabolite, is associated with CD. Administration of PAGly exacerbated colitis in a mouse model and upregulated coagulation-related biological processes. Antiplatelet medicine, dipyridamole, attenuated PAGly-enhanced colitis susceptibility. PAGln enhanced platelet activation and CD40L expression in platelet-rich plasma ex vivo. Further study revealed that high dietary protein intake and increased abundance of phenylacetic acid [PAA]-producing Proteobacteria mediated by phenylpyruvate decarboxylase act in concert to cause the elevated PAGln levels in CD patients. CONCLUSION: Taken together, ppdc-carrying Proteobacteria-generated PAGln from dietary protein is associated with CD and exacerbates colitis possibly via platelet-induced coagulation and inflammation These results suggest that PAGln is a potential early diagnostic marker and therapeutic target of CD.
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Colitis , Enfermedad de Crohn , Microbioma Gastrointestinal , Humanos , Animales , Ratones , Microbioma Gastrointestinal/genética , Proteínas en la Dieta/efectos adversos , Ligando de CD40 , Cromatografía Liquida , Ratones Endogámicos C57BL , Espectrometría de Masas en Tándem , Colitis/inducido químicamente , Colitis/metabolismo , Activación Plaquetaria , Sulfato de Dextran , Modelos Animales de EnfermedadRESUMEN
During the 21st century, the incidence and prevalence of inflammatory bowel disease (IBD) is rising globally. Despite the pathogenesis of IBD remaining largely unclear, the interactions between environmental exposure, host genetics and immune response contribute to the occurrence and development of this disease. Growing evidence implicates that food additives might be closely related to IBD, but the involved molecular mechanisms are still poorly understood. Food additives may be categorized as distinct types in accordance with their function and property, including artificial sweeteners, preservatives, food colorant, emulsifiers, stabilizers, thickeners and so on. Various kinds of food additives play a role in modifying the interaction between gut microbiota and intestinal inflammation. Therefore, this review comprehensively synthesizes the current evidence on the interplay between different food additives and gut microbiome alterations, and further elucidates the potential mechanisms of food additives-associated microbiota changes involved in IBD.
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Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Aditivos Alimentarios/efectos adversos , Microbioma Gastrointestinal/fisiología , Humanos , Enfermedades Inflamatorias del Intestino/microbiologíaRESUMEN
BACKGROUND: While the incidence of inflammatory bowel disease (IBD) has stabilised in the West, it is still increasing in several newly industrialised countries. AIMS: To investigate whether the environmental and dietary risk factors for IBD differ between Eastern and Western populations METHODS: We systematically searched PubMed, Embase, and Web of Science for studies published from inception through June 30, 2020. Data were pooled using a random effects model. RESULTS: Overall, 255 studies were assessed. We identified 25 risk factors for IBD, seven of which were noted in both Eastern and Western populations: family history of Crohn's disease [CD] or ulcerative colitis [UC], former smoking (CD/UC), smoking (CD), appendicectomy (CD), tonsillectomy (CD), meat and meat products (CD), and vitamin D deficiency (UC). The remaining factors, including urban living, current smoking, antibiotics, oral contraceptives, caesarean section, isotretinoin, total energy, fat, cholesterol, fatty acids and their sub-classifications, eggs, and soft drinks, were associated with an increased risk of IBD in Western or Eastern populations only. We identified 21 protective factors for IBD, among which eight were common in the East and West: farm animals (CD/UC), Helicobacter pylori infection (CD/UC), multiple births (CD), physical activity (CD), history of breastfeeding (CD), pets (UC), current smoking (UC), and coffee intake (UC). Ten factors conferred protection against IBD in Western populations only, whereas eight factors conferred protection against IBD in Eastern populations only. CONCLUSIONS: Numerous environmental and dietary factors influenced the development of IBD in both Western and Eastern populations, whereas certain factors influenced IBD risk differently in these populations.
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Colitis Ulcerosa , Infecciones por Helicobacter , Helicobacter pylori , Enfermedades Inflamatorias del Intestino , Animales , Cesárea , Colitis Ulcerosa/epidemiología , Femenino , Infecciones por Helicobacter/complicaciones , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/etiología , Embarazo , Factores de RiesgoRESUMEN
Background: Behçet's disease (BD) is a relapsing systemic immune disorder, and intestinal BD is a significant cause of mortality in patients with BD. Conventional therapeutic strategies for intestinal BD showed unsatisfactory outcomes, especially in those patients with refractory subtypes. In recent years, biologic agents have exhibited promising results in this field. While the sample sizes of existing studies were limited, the results were heterogeneous. Objectives: This study aimed to observe the efficacy of different biologics in clinical symptomatic improvement and intestinal mucosal healing. Design: This is a study including the report of case series and meta-analysis. Data sources and methods: This meta-analysis was conducted following the PRISMA guidelines. Free-text words and subject terms, including 'Behcet's Syndrome', 'Biologics', 'Tumor Necrosis Factor Antagonist', were used to systematically research the relevant studies in the electronic databases (PubMed, Web of Science, Embase, and Cochrane Library). All retrieved articles were from inception to July 2021, and the data from our institution were also included in this meta-analysis. A double arcsine transformation was performed to stabilize the variance of the original ratio. Heterogeneity was evaluated via Q-test and I 2 statistics. Random-effects or fixed-effects model was used to calculate the pooled parameters, and the results were presented as forest plots with 95% confidence intervals. Results: Twelve studies were included, but only antitumor necrosis factor alpha (anti-TNF-α) agents were prescribed as biologicals for refractory intestinal BD. The symptom improvement rates at our institution ranged from 57.1 to 81.8%, and the mucosal healing rates were from 20 to 60% in different therapeutic periods. A total of 514 patients were enrolled in the meta-analysis, and the synthesized ratios showed that 59.8% (n = 377) and 73.7% (n = 317) of patients who received maintenance therapy with anti-TNF-α agents could achieve clinical symptomatic improvement during short-term (10-14 weeks) and long-term (48-54 weeks) periods, respectively. Furthermore, 77.8% (n = 229) of patients with intestinal BD maintained therapeutic efficacy for a longer time (100 weeks). In addition, 60.9% (n = 120) of the patients achieved sustained intestinal mucosal healing during a long-term follow-up (24-52 weeks). Conclusion: Anti-TNF-α treatment is effective in treating refractory intestinal BD but more studies are required to evaluate the effects of new biologics for intestinal BD in the near future. Registration: This study has been registered on PROSPERO, the ID is CRD42022329211. Plain language summary: Anti-TNF-α agents are effective and safe in patients with intestinal Behçet's disease Behçet's disease (BD) is a disease affecting several organs including the gastrointestinal tract. Nowadays, the efficacy of existing therapy strategies is still unsatisfactory and some patients are suffering from repeated attacks of the disease. We noticed that a new kind of medicine, called antitumor necrosis factor alpha (anti-TNF-α) agents, was applied to these patients recently. The therapeutic efficacy is not convincing enough to evaluate since the number of patients receiving this new medicine was small in every individual study. Regarding this, we conducted a research to learn about the efficacy of this medicine at our own institution. Besides, we composed the results of other studies in an appropriate way. Then, we drew a conclusion on the exact efficacy of anti-TNF-α agents after the data analysis. We unveiled that the anti-TNF-α agents appeared both effective and safe in the management of intestinal BD patients when the classical therapy failed. More than half of the patients could achieve discomfort remission when they got the therapy of the new medicine at our institution. We also found that intestinal ulcers in most patients improved after they received the treatment. All in all, it offered another foothold for getting relief in these patients who were caught in this mire.
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Background: Crohn's disease (CD) has a tendency for recurrence and requires adequate monitoring and personalized treatment. Since endoscopy is considerably invasive, serum biomarkers are required as alternatives for CD monitoring. Toward this, exosomal microRNAs (miRNAs) may serve as promising candidates. In this study, we aimed to assess the role of serum exosomal microRNA-144-3p (miR-144-3p) as a biomarker for CD monitoring. Methods: We prospectively recruited 154 patients without a history of surgery (Cohort 1) and 75 patients who were to undergo intestinal resection (Cohort 2). Serum samples were collected from Cohort 1 before colonoscopy and from Cohort 2 before surgery and during post-operative colonoscopic examination. The serum levels of exosomal miR-144-3p were measured using quantitative reverse-transcription polymerase chain reaction (PCR). Correlations between relative exosomal miR-144-3p levels, disease activity, and disease behavior were analysed. The area under the receiver-operating characteristic curve (AUC) was used to assess the predictive value of exosomal miR-144-3p regarding mucosal activity and post-operative recurrence. Results: A 3.33-fold increase in serum exosomal miR-144-3p levels was recorded in patients with CD compared with those in healthy controls (P < 0.001). The exosomal miR-144-3p levels were positively correlated with the simple endoscopic score of CD (ρ = 0.547, P < 0.001) as well as the Rutgeerts score (ρ = 0.478, P < 0.001). Elevated exosomal miR-144-3p levels were correlated with the penetrating disease with high specificity (100% [95% confidence interval, 95.1%-100%]). The accuracy of exosomal miR-144-3p for identifying post-operative recurrence was higher than that of C-reactive protein (CRP) (AUC, 0.775 vs 0.639; P < 0.001). Conclusions: Serum exosomal miR-144-3p is a reliable biomarker of mucosal inflammation and penetrating CD. It may identify endoscopic CD recurrence after intestinal resection with higher accuracy than CRP testing.
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Background: The natural disease course for patients with ulcerative colitis (UC) is heterogeneous and few data are available on the indolent course of UC and its related factors. We aimed to develop and validate a nomogram to predict indolent course in patients with UC. Methods: Data of patients diagnosed with UC in the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between April 2007 and February 2021 were retrospectively analysed. Indolent course was defined as a disease course without need for strict interventions (steroids, immunomodulators, biological agents, hospitalization, or surgery therapy) during the follow-up period. The whole cohort was randomly divided into training set and validation set. The nomogram was constructed in the training set based on the results of univariate and multivariate Cox regression analyses. The performance of the nomogram was assessed by the concordance index (C-index), area under the receiver-operating characteristic curve (AUC), and calibration plots. In addition, we internally validated the nomogram via the bootstrap method and the validation set. Results: Of 969 treatment-naive patients with UC, 771 (79.6%) had an indolent course after diagnosis. Of these, 313 patients were included in the development and validation of the nomogram. The nomogram incorporating age, disease activity, C-reactive protein, and platelet count showed good calibration and discrimination. The C-index was 0.759 (0.741 in bootstrap validation) and the AUC at 2, 4, and 6 years was 0.767, 0.782, and 0.775, respectively. The nomogram performed well when applied to the validation set. Conclusion: A majority of patients with UC had an indolent course after diagnosis. The nomogram developed in this study might be useful in therapeutic decision-making and follow-up management for patients with UC.
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BACKGROUND: Intestinal barrier impairment plays an essential role in the pathogenesis of Crohn's disease (CD), and claudins (CLDNs) dysfunction contributes to intestinal mucosa injury. SOX9, an important transcription factor, is upregulated in the disease-affected colon of patients with CD; however, its precise role in CD remains largely unknown. Our aim was to explore the interaction between SOX9 and CLDNs, and further elucidate the underlying mechanisms in CD. METHODS: SOX9 expression in patients with CD was evaluated using quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. The regulatory relationship between SOX9 and CLDNs was analyzed via a dual-luciferase reporter assay, chromatin immunoprecipitation, overexpression, and RNA interference methods. MicroRNAs (miRNAs) involved in the SOX9-CLDN pathway were predicted with bioinformatics analysis, and the upstream molecular mechanism was interpreted using MassARRAY methylation detection. FINDINGS: Upregulated expression of SOX9 in the disease-affected intestine mucosa was identified in both patients with CD and mice challenged with trinitrobenzene sulfonic acid (TNBS). SOX9 negatively regulated the expression of CLDN8, accompanying reduced intestinal permeability. MiR-145-5p downregulation was found in patients with CD and TNBS-induced colitis mice owing to an aberrant miR-145 promoter hypermethylation, which subsequently interfered the SOX9-CLDN8 pathway. MiR-145-5p agomir treatment alleviated TNBS-induced colitis in wild-type mice by inhibiting Sox9 expression and restoring Cldn8 expression, whereas similar findings were not apparent in the Cldn8-/- mice. INTERPRETATION: SOX9 mediates the crosstalk between upstream miR-145-5p and downstream CLDN8, and further impairs intestinal mucosal barrier homeostasis in CD. Targeting the miR-145-5p/SOX9/CLDN8 pathway represents a promising therapeutic strategy for CD. FUNDING: The National Natural Science Foundation of China (#81870374, #81670498, #81630018, #82070538, #8210031148), the Guangdong Science and Technology (#2017A030306021, #2020A1515111087), the Guangzhou Science and Technology Department (#202002030041), and the Fundamental Research Funds for the Central Universities (#19ykzd11).
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Enfermedad de Crohn , MicroARNs , Animales , Claudinas/genética , Enfermedad de Crohn/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Ácido Trinitrobencenosulfónico/metabolismo , Ácido Trinitrobencenosulfónico/toxicidadRESUMEN
BACKGROUND & AIMS: Pro-inflammatory diet interacting with gut microbiome might trigger for Crohn's disease (CD). We aimed to investigate the relationship between dietary inflammatory potential and microflora/metabolites change and their link with CD. METHODS: The dietary inflammatory potential was assessed using a dietary inflammatory index (DII) based on the Food Frequency Questionnaire from 150 new-onset CD patients and 285 healthy controls (HCs). We selected 41 CD patients and 89 HCs who had not received medication for metagenomic and targeted metabolomic sequencing to profile their gut microbial composition as well as fecal and serum metabolites. DII scores were classified into quartiles to investigate associations among different variables. RESULTS: DII scores of CD patients were significantly higher than HCs (0.56 ± 1.20 vs 0.23 ± 1.02, p = 0.017). With adjustment for confounders, a higher DII score was significantly associated with higher risk of CD (OR: 1.420; 95% CI: 1.049, 1.923, p = 0.023). DII score also was positively correlated with disease activity (p = 0.001). Morganella morganii and Veillonella parvula were increased while Coprococcus eutactus was decreased in the pro-inflammatory diets group, as well as in CD. DII-related bacteria were associated with disease activity and inflammatory markers in CD patients. Among the metabolic change, pro-inflammatory diet induced metabolites change were largely involved in amino acid metabolic pathways that were also observed in CD. CONCLUSIONS: Pro-inflammatory diet might be associated with increased risk and disease activity of CD. Diet with high DII potentially involves in CD by mediating alterations in gut microbiota and metabolites.
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Enfermedad de Crohn , Microbioma Gastrointestinal , Bacterias , Dieta/efectos adversos , Heces/microbiología , Humanos , Inflamación/microbiologíaRESUMEN
Fibrosis is a complex and difficult to elucidate pathological process with no available therapies. Growing evidence implicates intestinal microbiota in the occurrence and development of fibrosis, and the potential mechanisms involved in different organs have been explored in several studies. In this review, we summarize the causative and preventive effects of gut microbiota on intestinal fibrosis, as well as the relationships between gut microbiota and fibrosis in other organs. Interestingly, several colonized microbes are associated with fibrosis via their structural components and metabolic products. They may also play essential roles in regulating inflammation and fibroblast activation or differentiation, which modulates extracellular matrix formation. While the relationships between intestinal fibrosis and gut microbiota remain unclear, lessons can be drawn from the effects of gut microbiota on hepatic, cardiac, nephritic, and pulmonary fibrosis. Various intestinal microbes alterations have been detected in different fibrotic organs; however, the results were heterogeneous. Mechanisms by which the intestinal microbiota regulate fibrotic processes in other organs, such as novel metabolic products or specific microbes, are also discussed. The specific microbiota associated with fibrosis in other organs could instruct future studies aiming to discover prospective mechanisms regulating intestinal fibrosis.
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BACKGROUND: Approximately half of patients with Crohn's disease (CD) may inevitably receive surgical intervention as the disease progress. However, about 75% of CD patients will experience postoperative recurrence (POR). Biologics are appealing alternatives for the prevention of POR; however, it is still unclear which biological agents are more efficient. This meta-analysis aimed to investigate the efficacy of biologics for POR prevention and to compare the superiority of different biologics. METHODS: We conducted a thorough search of online databases and screened for studies on the efficacy of biologics in preventing POR (clinical, endoscopic, or histological) that were published until January 2021. The results were presented as forest plots and odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: We included 26 studies with 2,136 participants. Overall, biologics were more efficient over non-biological treatments in preventing endoscopic, severe endoscopic, and clinical POR without increasing the frequency of adverse events. Among the various types of biologics, anti-TNFα agents were better than vedolizumab in preventing endoscopic POR. Moreover, infliximab had a similar curative effect to adalimumab in preventing endoscopic, severe endoscopic, and clinical recurrence. CONCLUSION: Biologics, especially anti-TNFα agents, still play a vital role in preventing POR in the biological era.
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Enfermedad de Crohn , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/prevención & control , Enfermedad de Crohn/cirugía , Humanos , Infliximab/efectos adversos , Recurrencia , Prevención Secundaria , Resultado del Tratamiento , Factor de Necrosis Tumoral alfaRESUMEN
Background and Aim: Accumulating evidence have implicated gut microbiota alterations in pediatric and adult patients with inflammatory bowel disease (IBD); however, the results of different studies are often inconsistent and even contradictory. It is believed that early changes in new-onset and treatment-naïve pediatric patients are more informative. We performed a systematic review to investigate the gut microbiota profiles in pediatric IBD and identify specific microbiota biomarkers associated with this disorder. Methods: Electronic databases were searched from inception to 31 July 2020 for studies that observed gut microbiota alterations in pediatric patients with IBD. Study quality was assessed using the Newcastle-Ottawa scale. Results: A total of 41 original studies investigating gut microbiota profiles in pediatric patients with IBD were included in this review. Several studies have reported a decrease in α-diversity and an overall difference in ß-diversity. Although no specific gut microbiota alterations were consistently reported, a gain in Enterococcus and a significant decrease in Anaerostipes, Blautia, Coprococcus, Faecalibacterium, Roseburia, Ruminococcus, and Lachnospira were found in the majority of the included articles. Moreover, there is insufficient data to show specific microbiota bacteria associated with disease activity, location, and behavior in pediatric IBD. Conclusions: This systematic review identified evidence for differences in the abundance of some bacteria in pediatric patients with IBD when compared to patients without IBD; however, no clear overall conclusion could be drawn from the included studies due to inconsistent results and heterogeneous methodologies. Further studies with large samples that follow more rigorous and standardized methodologies are needed.
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Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder closely related to gut dysbiosis, which is associated with alterations in an important bacterial metabolite, bile acids (BAs). Although certain findings pertinent to BA changes in IBD vary among studies owing to the differences in sample type, quantitated BA species, study methodology, and patient characteristics, a specific trend concerning variations of BAs in IBD has been identified. In elaborating on this observation, it was noted that primary BAs and conjugated BAs are augmented in fecal samples but there is a reduction in secondary BAs in fecal samples. It is not entirely clear why patients with IBD manifest these changes and what role these changes play in the onset and development of IBD. Previous studies have shown that IBD-associated BA changes may be caused by alterations in BA absorption, synthesis, and bacterial modification. The complex relationship between bacteria and BAs may provide additional and deeper insight into host-gut microbiota interactions in the pathogenesis of IBD. The characteristic BA changes may generate profound effects in patients with IBD by shaping the gut microbiota community, affecting inflammatory processes, causing BA malabsorption associated with diarrhea, and even leading to intestinal dysplasia and cancer. Thus, therapeutic strategies correcting the alterations in the composition of BAs, including the elimination of excess BAs and the supplementation of deficient BAs, may prove promising in IBD.
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Ácidos y Sales Biliares/metabolismo , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Disbiosis/etiología , Heces , HumanosRESUMEN
Diet is one of the most critical factors for inflammatory bowel disease (IBD). A whole dietary pattern should be considered when doing nutrient-based research to preserve the potential for synergism between nutrients. Dietary indices are important tools to evaluate diet quality, and we investigated the associations of it with IBD. Fourteen studies on the relation between index-based dietary patterns and IBD were included. 6 studies showed the relation between index-based dietary patterns and IBD risk, 7 studies explored the dietary indices and progression of IBD, and 1 study investigated the relationship between index and all-cause mortality in IBD patients. These results implied that a high score on the Mediterranean diet was negatively associated with risk and progression of IBD. However, a diet with high inflammatory potential could increase risk and aggravate disease activity in IBD. Dietary scores have the potential to evaluate the association between overall diet quality and risk and progression of IBD. Future randomized controlled trials are required to confirm the effect of the change in dietary score. This review was registered at www.crd.york.ac.uk/prospero/ as CRD42020220926.