RESUMEN

BACKGROUND: Intestinal fibrosis, a complex complication of colitis, is characterized by excessive extracellular matrix (ECM) deposition. Estrogen receptor (ER) ß may play a role in regulating this process. METHODS: Intestinal tissue samples from stenotic and nonstenotic regions were collected from Crohn's disease (CD) patients. RNA sequencing was conducted on a mouse model to identify differentially expressed mRNAs. Histological, immunohistochemical, and semiquantitative Western blotting analyses were employed to assess ECM deposition and fibrosis. The roles of relevant pathways in fibroblast transdifferentiation, activity, and migration were examined. RESULTS: Estrogen receptor ß expression was found to be downregulated in the stenotic intestinal tissue of CD patients. Histological fibrosis score, collagen deposition, and profibrotic molecules in the colon of an intestinal fibrosis mouse model were significantly decreased after activation of ERß. In vitro, ERß activation alleviated transforming growth factor (TGF)-ß-induced fibroblast activation and migration, as evidenced by the inhibition of col1α1, fibronectin, α-smooth muscle actin (α-SMA), collagen I, and N-cadherin expression. RNA sequencing showed that ERß activation affected the expression of genes involved in ECM homeostasis and tissue remodeling. Enrichment analysis of differentially expressed genes highlighted that the downregulated genes were enriched in ECM-receptor interaction, TGF-ß signaling, and Toll-like receptor (TLR) signaling. Western blotting confirmed the involvement of TGF-ß/Smad and TLR4/MyD88/NF-κB signaling pathways in modulating fibrosis both in vivo and in vitro. The promoter activity of TGF-ß1 and TLR4 could be suppressed by ERß transcription factor. CONCLUSION: Estrogen receptor ß may regulate intestinal fibrosis through modulation of the TGF-ß/Smad and TLR4/MyD88/NF-κB signaling pathways. Targeting ERß activation could be a promising therapeutic strategy for treating intestinal fibrosis.

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Imagine your gut is like a garden hose. In Crohn's disease, parts of this "hose" get narrow and blocked. Scientists found less of a helpful protein, ERß, in these narrow areas. In an experiment with mice, boosting ERß lessened the gut damage and reduced the buildup of collagen­the "blockage" in our hose analogy. Also, ERß calmed overactive cells causing these issues, acting like a peacemaker. This protein "talks" to cells through channels called TGF-ß/Smad and TLR4/NF-κB, telling them to relax. This could be a new way to tackle such gut problems!

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PD-1 inhibitors, as one of commonly used immune checkpoint inhibitors, enable T-cell activation and prevent immune escape by blocking the PD-1/PD-L1 signaling pathway. They have transformed the treatment landscape for cancer in recent years, due to the advantages of significantly prolonging patients' survival and improving their life quality. However, the ensuing unpredictable immune-related adverse effects (irAEs) plague clinicians, such as colitis and even potentially fatal events like intestinal perforation and obstruction. Therefore, understanding the clinical manifestations and grading criteria, underlying mechanisms, available diverse therapies, accessible biomarkers, and basis for risk stratification is of great importance for the management. Current evidence suggests that irAEs may be a marker of clinical benefit to immunotherapy in patients, so whether to discontinue PD-1 inhibitors after the onset of irAEs and rechallenge after remission of irAEs requires further evaluation of potential risk-reward ratios as well as more data from large-scale prospective studies to fully validate. At the end, the rare gastrointestinal toxicity events caused by PD-1 inhibitors are also sorted out. This review provides a summary of available data on the gastrointestinal toxicity profile caused by PD-1 inhibitors, with the aim of raising clinicians' awareness in daily practice, so that patients can safely benefit from therapy.

Asunto(s)

Antineoplásicos Inmunológicos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Estudios Prospectivos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico

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Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders of the gastrointestinal tract, mainly including Crohn's disease and ulcerative colitis. Epidemiological findings suggest that inadequate dietary fibers intake may be a risk factor for IBD. Oat beta-glucan is a type of fermentable dietary fiber and has been proved to reduce experimental colitis. However, the mechanism remains unclear. The aim of this study was to explore the role and possible mechanism of oat beta-glucan in reducing experimental colitis. We used a dextran sulfate sodium (DSS)-induced mice acute colitis model to explore the potential mechanism of oat beta-glucan in reducing experimental colitis. As a result, oat beta-glucan upregulated the expressions of Erythropoietin-producing hepatocyte receptor B6 (EPHB6) and transcription factor EB (TFEB), promoted autophagy flux and downregulated the expressions of interleukin 1 beta (IL-1ß), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in intestinal epithelial cells (IECs). The role of the EPHB6-TFEB axis was explored using a lipopolysaccharide-induced HT-29 cells inflammation model. The results revealed that EPHB6 regulated the expression of TFEB, and knockdown of EPHB6 decreased the protein level of TFEB. When EPHB6 or TFEB was knocked down, autophagy flux was inhibited, and the anti-inflammatory effect of sodium butyrate, a main metabolite of oat beta-glucan in the gut, was blocked. In summary, our findings demonstrated that oat beta-glucan reduced DSS-induced acute colitis in mice, promoted autophagy flux via EPHB6-TFEB axis and downregulated the expressions of IL-1ß, IL-6 and TNF-α in IECs, and this effect may be mediated by butyrate.

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Objective: To explore the clinical value of fecal calprotectin (FC) for evaluating disease activity in patients with Crohn's disease (CD) and its relationship with disease location. Methods: Patients with CD were enrolled retrospectively, and clinical data, including FC levels, were collected. Clinical activity was assessed using the Crohn's disease activity index (CDAI). Endoscopic activity was assessed using a simple endoscopic score for Crohn's disease (SES-CD). The partial SES-CD (pSES-CD) was scored for the size of ulcers in each segment as defined by the SES-CD and was calculated as the sum of segmental ulcer scores. Results: This study included 273 CD patients. The FC level was significantly positively correlated with the CDAI and SES-CD, with correlation coefficients of 0.666 and 0.674, respectively. The median FC levels in patients with clinical remission and mildly active and moderately-severely active disease were 41.01, 164.20, and 444.45 µg/g. These values were 26.94, 66.77, and 327.22 µg/g during endoscopic remission and mildly and moderately-severely active stages, respectively. Compared with c-reactive protein (CRP), the erythrocyte sedimentation rate (ESR), and other biomarker parameters, FC was better at predicting disease activity for CD patients. For an FC <74.52 µg/g, the area under the curve (AUC) for predicting clinical remission was 0.86, with a sensitivity of 89.47% and a specificity of 71.70%. Moreover, endoscopic remission was predicted with a sensitivity of 68.02% and a specificity of 85.53%. The AUC was 0.83, and the cutoff value was 80.84 µg/g. In patients with ileal and (ileo) colonic CD, FC was significantly correlated with the CDAI, SES-CD, and pSES-CD. The correlation coefficients were 0.711 (CDAI), 0.473 (SES-CD), and 0.369 (pSES-CD) in patients with ileal CD and 0.687, 0.745, and 0.714 in patients with (ileo) colonic CD, respectively. For patients in remission, those in the active stage, and those with large or very large ulcers, differences in FC levels were not significant between patients with ileal and (ileo) colonic CD. Conclusion: FC is a reliable predictor of disease activity in patients with CD, including those with ileal CD. FC is thus recommended for the routine follow-up of patients with CD.

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Talaromyces marneffei is a thermally dimorphic fungus that affects multiple organs and frequently invades immunocompromised individuals. However, only a few studies have reported the presence of intestinal infection associated with T. marneffei. Herein, we reported a case of intestinal T. marneffei infection in a man who complained of a 1-month history of intermittent fever, abdominal pain, and diarrhea. The result of the human immunodeficiency virus antibody test was positive. Periodic acid-Schiff and Gomorrah's methylamine silver staining of the intestinal biopsy tissue revealed T. marneffei infection. Fortunately, the patient's symptoms rapidly resolved with prompt antifungal treatment. In addition, we summarized and described the clinical characteristics, management, and outcomes of patients with intestinal T. marneffei infection. A total of 29 patients were identified, the majority of whom (65.52%) were comorbid with acquired immunodeficiency syndrome. The main clinical features included anemia, fever, abdominal pain, diarrhea, weight loss, and lymphadenopathy. The transverse and descending colon, ileocecum, and ascending colon were the most common sites of lesions. A considerable number of patients (31.03%) developed intestinal obstruction, intestinal perforation, and gastrointestinal bleeding. Of the 29 patients, six underwent surgery, 23 survived successfully with antifungal treatment, five died of T. marneffei infection, and one died of unknown causes. T. marneffei intestinal infection should be considered when immunodeficient patients in endemic areas present with non-specific symptoms, such as fever, abdominal pain, and diarrhea. Appropriate and timely endoscopy avoids delays in diagnosis. Early aggressive antifungal therapy improves the clinical outcomes of patients.

Asunto(s)

Infecciones Oportunistas Relacionadas con el SIDA , Síndrome de Inmunodeficiencia Adquirida , Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Dolor Abdominal , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Antifúngicos/uso terapéutico , Diarrea , Fiebre/tratamiento farmacológico , Humanos , Masculino , Metilaminas , Micosis , Ácido Peryódico/uso terapéutico

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Background: Nonspecific terminal ileal ulcers are one of the common ulcerative diseases in terminal ileum. However, the studies about treatment efficacy are scarce. We aimed to investigate the efficacy of mesalazine in the treatment of this disease. Methods: Eighty-two patients with nonspecific terminal ileal ulcers who sought outpatient medical treatment in the Division of Gastroenterology, Wuhan Union Hospital, from April 2016 to January 2019 were enrolled and randomly divided into two groups. The experimental group took mesalazine orally, 4.0 g/d, once a day for 3 months. The control group was followed up without special intervention. The primary endpoint was the endoscopic remission rate at the 6th and 12th month. Secondary endpoints included the clinical remission rate at the 1st, 6th and 12th month and adverse events (ChiCTR1900027503). Results: About the endoscopic efficacy, the remission rate of the experimental group and control group was 73.2 versus 61.0% at the 6th month (RR = 1.20, 95%CI 0.88∼1.63, p = 0.24) and 87.8 versus 78.0% at the 12th month (RR = 1.13, 95%CI 0.92∼1.37, p = 0.24). About the clinical efficacy, the remission rate was 70.3 versus 43.8% at the 1st month (RR = 1.61, 95%CI 1.03∼2.51, p = 0.03), 83.8 versus 68.8% at the 6th month (RR = 1.22, 95%CI 0.93∼1.60, p = 0.14) and 91.9 versus 81.3% at the 12th month (RR = 1.13, 95%CI 0.93∼1.37, p = 0.34). During follow-up, no patients were diagnosed with Crohn's disease or intestinal tuberculosis, and no patients developed significant complications. Conclusion: For patients with nonspecific terminal ileal ulcers, there is no disease progression over a short term. In addition, there is no significant difference in clinical or endoscopic efficacy between patients who received mesalazine and patients who are followed up without special intervention.

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Delayed recovery from ulcerative colitis is mainly due to impaired healing of the intestinal epithelium after inflammation. The circadian rhythm controls cell proliferation and energy metabolism. However, the role of circadian genes in inflammatory bowel disease is largely unknown. The purpose of this study was to investigate whether disrupting the circadian rhythm in mice can worsen colitis by altering mitochondrial energy metabolism. Mice in the experimental groups were under physiologic stress with an 8-h light shift jet-lag schedule every 3 days, whereas those in the control group were not. Subsequently, half of the mice in the control and jet-lagged groups were given dextran sodium sulfate (DSS) to induce colitis. Mice in each group were euthanized at zeitgeber time (ZT)0, ZT4, ZT8, ZT12, ZT16, and ZT20. To investigate the effects of jet lag on the mice, colon specimens were subjected to hematoxylin and eosin staining to analyse mRNA and protein expression of core circadian clock genes (Bmal1, Clock, Per1, Per2, Cry1, Cry2, and Nr1d1). We analysed the mitochondrial morphology, adenosine triphosphate (ATP) levels, and the expression of dynamin-related protein 1 (Drp1) and ser637-phosphorylated (p)-Drp1, which are closely related to ATP production. We further investigated the effect of PER2 knock-down in the colon epithelial cells (CCD 841 CoN) by measuring ATP and cell proliferation levels. Disrupting the circadian rhythm changed the oscillation of clock genes in the colon of mice, altered the mitochondrial morphology of the colon specimens, decreased the expression of p-Drp1, reduced ATP production, and exacerbated inflammatory responses in mice with DSS-induced colitis. Additionally, silencing of PER2 in the colon epithelial cells reduced ATP production and cell proliferation. Disrupting the circadian rhythm in mice decreases mitochondrial energy metabolism in the colon and exacerbates symptoms of colitis.

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OBJECTIVES: Inflammatory bowel disease (IBD) usually present with systemic and gastrointestinal problems. This may result in both physical and psychological burden. The aim of the study was to investigate the association between psychological burden and Health Related Quality of Life (HRQoL), sleep quality and disease characteristics. METHODS: A total of 106 patients and 165 general populations were enrolled in this study. The demographic information, disease characteristics of participants were investigated. The SCL-90 was self-administered to evaluate psychometric properties. SF-36 and IBDQ were both used to the assessment of HRQoL, and PSQI to quality of sleep. RESULTS: The SCL-90 score of IBD was significantly higher than that of the control (p = .0007), especially in somatization, anxiety, depression, hostility and psychosis dimensions. Similar to IBDQ (p < .0001), the results of SF-36 (p < .0001) showed that the HRQoL of both Ulcerative colitis (UC) and Crohn's disease (CD) were somehow inferior to control. However, undifferentiated results were noted in patients between UC and CD. Good linear relationship between disease activity and SCL-90 (RUC = 0.53, pUC = .001; RCD = 0.36, pCD = .002), SF-36 (RUC = -0.42, pUC = .01; RCD = -0.49, pCD < .0001), IBDQ (RUC = -0.57, pUC = .0005; RCD = -0.52, pCD < .0001), PSQI (RUC = 0.50, pUC = .003; RCD = 0.27, pCD = .02) were observed. With the score of SCL-90 of patients increased, the SF-36 (R = -0.78, p < .0001) and IBDQ decreased (R = -0.74, p < .0001), PSQI increased (R = -0.70, p < .0001). Multiple stepwise regression analysis revealed that disease activity, extraintestinal manifestations, weight loss may contribute to identify the psychological anomalies. CONCLUSIONS: Altered psychological status can be found in IBD, reflecting the necessity of providing psychological care for them. The disease itself results in lower HRQoL. Better HRQoL and sleep quality are in concordance with better psychological health.

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Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Humanos , Calidad de Vida , Sueño , Encuestas y Cuestionarios

RESUMEN

BACKGROUND: Clinical data suggest that enteral nutrition (EN) effectively decreases disease activity and maintains remission in patients with inflammatory bowel disease (IBD). However, the modulatory effects of EN on the intestinal mucosal immune system remain unclear. AIMS: This study first aimed at comparing the therapeutic effects of three EN formulas on ameliorating dextran sulfate sodium- (DSS-) induced chronic colitis; with the most effective formula, we then examined its influence on the mucosal inflammatory response and epithelial barrier function. METHODS: The effect of EN formulas on colitis in mice was assessed by body weight, disease activity index scores, colon length, and H&E staining for pathological examination. Colonic and circulating cytokine expression levels and the frequencies of immune cells were also analyzed. Intestinal epithelial barrier function was evaluated by detecting tight junction proteins. RESULTS: We found that among the three EN formulas, an elemental diet (ED) containing enriched amino acids restored the colitis-related reduction in body weight better than the other two EN formulas. ED amino acids suppressed the release of colonic proinflammatory mediators and maintained the expression of tight junction proteins in these mice. ED amino acid treatment mitigated the colitis-induced increase in CD103+CD11b+ dendritic cells and CD4+ and CD8+ T cells and inhibited the predominant Th1/Th17 responses particularly in the colonic mucosal lamina propria of mice with colitis. CONCLUSIONS: We showed that ED amino acids can be an effective immunomodulatory agent to reduce colitis-related inflammation by inhibiting proinflammatory mediators and Th1/Th17 cell responses and by repairing the disrupted epithelial barrier.

Asunto(s)

Aminoácidos/administración & dosificación , Alimentación Animal , Colitis/etiología , Colitis/metabolismo , Alimentos Formulados , Mucosa Intestinal/metabolismo , Animales , Biomarcadores , Colitis/dietoterapia , Colitis/patología , Colon/inmunología , Colon/metabolismo , Colon/patología , Citocinas/metabolismo , Sulfato de Dextran/efectos adversos , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Inmunohistoquímica , Mediadores de Inflamación/metabolismo , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/patología , Ratones , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Proteínas de Uniones Estrechas , Uniones Estrechas/metabolismo

RESUMEN

BACKGROUND: Pneumatosis cystoides intestinalis (PCI) is a low-incidence disease that confuses many doctors. A vast number of factors are suspected to contribute to its pathogenesis, such as Crohn's disease, intestinal stenosis, ulcerative colitis, drug use, extra-gastrointestinal diseases, and chronic obstructive pulmonary disease. Most consider its pathogenesis interrelated to an increase in intra-intestinal pressure and the accumulation of gas produced by aerogenic bacteria, and patients with atypical symptoms and imaging manifestations tend to be misdiagnosed. CASE PRESENTATION: A 64-year-old man complained of a 3-month history of bloody stool without mucopurulent discharge, abdominal pain, or diarrhea. Colonoscopy revealed multiple nodular projections into the segmental mucosa of the sigmoid colon. Crohn's disease and malignant disease ware suspected first according to the patient's history, but laboratory examinations did not confirm either. Endoscopic ultrasound (EUS) revealed multiple cystic lesions in the submucosa. Moreover, computer tomography scan showed multiple bubble-like cysts. Combined with ultrasonography, computed tomography, and pathology findings, we ultimately made a diagnosis of PCI. Instead of surgery, we recommended conservative treatment consisting of endoscopy and oral drug administration. His symptoms improved with drug therapy after discharge, and no recurrence was noted on follow-up. CONCLUSIONS: The incidence of PCI is low. Due to a lack of specificity in clinical manifestations and endoscopic findings, it often misdiagnosed as intestinal polyps, tumors, inflammatory bowel disease, or other conditions. Colonoscopy, computed tomography, and ultrasonography have demonstrated benefit in patients with multiple nodular projections in colon. Compared to the treatment of the above diseases, PCI treatment is effective and convenient, and the prognosis is optimistic. Therefore, clinicians should increase their awareness of PCI to avoid unnecessary misdiagnosis.

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Neumatosis Cistoide Intestinal/diagnóstico , Biopsia , Colonoscopía , Diagnóstico Diferencial , Humanos , Masculino , Persona de Mediana Edad , Neumatosis Cistoide Intestinal/diagnóstico por imagen , Neumatosis Cistoide Intestinal/tratamiento farmacológico , Neumatosis Cistoide Intestinal/patología , Tomografía Computarizada por Rayos X , Ultrasonografía