Mesenteric adipose-derived exosomal TINAGL1 enhances intestinal fibrosis in Crohn's Disease via SMAD4.

INTRODUCTION: Crohn's Disease (CD) is a chronic inflammatory condition characterized by intestinal fibrosis, severely impacting patient quality of life. The molecular mechanisms driving this fibrosis remain inadequately understood. Recent evidence implicates mesenteric adipose tissue (MAT) in CD pathogenesis, particularly through its exosome secretion, which may influence fibrogenic pathways. Understanding the role of MAT-derived exosomes is crucial for unraveling these molecular processes. OBJECTIVES: This study aims to elucidate the role of MAT-derived exosomes in CD-related intestinal fibrosis. We focus on investigating their molecular composition and the potential impact on fibrosis progression, with an emphasis on identifying novel therapeutic targets. METHODS: We induced chronic intestinal inflammation in mice using dinitrobenzene sulfonic acid (DNBS), simulating CD-like fibrosis. Exosomes were isolated from DNBS-treated mice (MG) and normal controls (NG) for characterization using electron microscopy and proteomic analysis. Additionally, human colonic fibroblasts were exposed to exosomes from CD patients and healthy individuals, with subsequent assessment of fibrogenesis through proteomic and RNA sequencing analyses. RESULTS: Proteomic analyses revealed a significant activation of the TGF-ß signaling pathway in MG-treated mice compared to controls, correlating with enhanced intestinal fibrosis. In vitro experiments demonstrated that colonic fibroblasts exposed to CD patient-derived exosomes exhibited increased fibrogenic activity. Protein docking and co-immunoprecipitation studies suggested a critical interaction between TINAGL1 and SMAD4, enhancing fibrosis. Importantly, in vivo experiments corroborated that recombinant TINAGL1 protein exacerbated DNBS-induced intestinal fibrosis. CONCLUSION: Our findings highlight the pivotal role of MAT-derived exosomes, particularly those carrying TINAGL1, in the progression of intestinal fibrosis in CD. The involvement of the TGF-ß signaling pathway, especially the SMAD4 protein, offers new insights into the molecular mechanisms of CD-related fibrosis and presents potential targets for therapeutic intervention.

Structural alterations of brain in different disease states of Crohn's disease: Results of a cross-sectional study in a Chinese hospital.

Rationale and objectives: To investigate alterations in the brain structure in patients with Crohn's disease in activity (CD-A) and in remission (CD-R) compared to healthy controls (HCs) and explore the relationship between gray matter volume (GMV) and psychological disorders. Materials and methods: A total of 127 CD patients (62 CD-A, 65 CD-R) and 92 healthy controls (HCs) were enrolled and analyzed in this study. The Crohn's disease activity index (CDAI) was used as the grouping criteria. Voxel-based morphometry (VBM) was applied to investigate gray matter volume (GMV), white matter volume (WMV) and global cerebrospinal fluid (CSF) volume alterations. Pearson correlation analysis was used to evaluate the relationships. Results: The CSF volume was negatively correlated with the disease duration in CD-R. Increased GMV of CD was observed in the parahippocampal gyrus, precentral gyrus, precuneous cortex, and subcallosal cortex, decreased was located in the occipital pole, precentral gyrus, inferior temporal gyrus, middle frontal gyrus, angular gyrus, frontal pole, lateral occipital cortex, and lingual gyrus. The GMV in the right temporal pole, left precuneous cortex, and left cingulate gyrus had a positive correlation with erythrocyte and hemoglobin in CD groups. The GMV in the right frontal pole, right postcentral gyrus, and left cingulate gyrus had a negative correlation with somatization in the CD groups. The GMV in the right temporal pole had a negative correlation with psychoticism and other in the CD groups. The GMV in the left cingulate gyrus was positive with bowel symptoms and systemic symptoms in the CD groups. Conclusion: Alterations of GMV in CD-A and CD-R and associated correlation with psychological disorders may provide evidence for possible neuro-mechanisms of CD with psychological disorders.

A potential brain functional biomarker distinguishing patients with Crohn's disease with different disease stages: a resting-state fMRI study.

Background: The previous studies have demonstrated that patients with Crohn's disease in remission (CD-R) have abnormal alterations in brain function. However, whether brain function changes in patients with Crohn's disease in activity (CD-A) and the relationship with CD-R are still unclear. In this study, we aimed to investigate whether the different levels of disease activity may differentially affect the brain function and to find the brain functional biomarker distinguishing patients with different disease stages by measuring the amplitude of low frequency fluctuations (ALFF). Methods: 121 patients with CD and 91 healthy controls (HCs) were recruited. The clinical and psychological assessment of participants were collected. The criteria for the disease activity were the Crohn's disease activity index (CDAI) scores. CD-R refers to CD patients in remission which the CDAI score is less than 150. Conversely, CD-A refers to CD patients in activity which the CDAI score is ≥150. The ALFF was compared among three groups by performing one-way analysis of variance, followed by a post hoc two-sample t-test. Differences among the groups were selected as seeds for functional connectivity analyses. We also investigated the correlation among clinical, psychological scores and ALFF. Binary logistic regression analysis was used to examine the unique contribution of the ALFF characteristics of the disease stages. Results: There were widespread differences of ALFF values among the 3 groups, which included left frontal pole (FP_L), right supramarginal gyrus (SG_R), left angular gyrus (AG_L), right cingulate gyrus (CG_R), right intracalcarine cortex (IC_R), right parahippocampal gyrus (PG_R), right lingual gyrus (LG_R), right precuneous cortex (PC_R), left occipital fusiform gyrus (OFG_L). Significant brain regions showing the functional connections (FC) increased in FP_L, SG_R, PC_R and OFG_L between CD-A and HCs. The erythrocyte sedimentation rate had a negative correlation with the ALFF values in PC_R in the patients with CD. The phobic anxiety values had a negative correlation with the ALFF values in OFG_L. The psychoticism values had a negative correlation with ALFF values in the IC_R. And the hostility values had a positive correlation with the ALFF values in CG_R. Significant brain regions showing the FC increased in FP_L, SG_R, CG_R, PG_R, LG_R and OFG_L between CD-R and HCs. In binary logistic regression models, the LG_R (beta = 5.138, p = 0.031), PC_R (beta = 1.876, p = 0.002) and OFG_L (beta = 3.937, p = 0.044) was disease stages predictors. Conclusion: The results indicated the significance of the altered brain activity in the different disease stages of CD. Therefore, these findings present a potential identify neuroimaging-based brain functional biomarker in CD. Additionally, the study provides a better understanding of the pathophysiology of CD.

A Comprehensive Global Population-Based Analysis on the Coexistence of Eosinophilic Esophagitis and Inflammatory Bowel Disease.

BACKGROUND: We explored inflammatory bowel disease (IBD) and eosinophilic esophagitis (EoE) coexistence using a global dataset. Investigating their epidemiology, risks, and impact, we aimed to enhance the understanding of concurrent diagnoses and patient outcomes. METHODS: A retrospective population-based cohort study was conducted using deidentified patient data from the TriNetX database (2011-2022). We estimated the incidence and prevalence of EoE in patients with IBD, including both Crohn's disease (CD) and ulcerative colitis (UC), and vice versa. Risks of select immune-mediated conditions and disease complications were compared among patients with EoE, IBD, or concurrent diagnoses. RESULTS: Our results included 174,755 patients with CD; 150,774 patients with UC; and 44,714 patients with EoE. The risk of EoE was significantly higher among patients with CD (prevalence ratio [PR] 11.2) or UC (PR 8.7) compared with individuals without IBD. The risk of IBD was higher in patients with EoE (CD: PR 11.6; UC: PR 9.1) versus those without EoE. A propensity-matched analysis of IBD patients revealed that, when comparing patients with and without EoE, the relative risk of immune-mediated comorbidities was significantly greater for celiac disease, IBD-related inflammatory conditions, eczema and asthma (CD: n = 1896; UC: n = 1231; p < 0.001). Patients with a concurrent diagnosis of EoE and IBD had a higher composite risk of IBD-related complications (CD: adjusted HR (aHR) 1.14, p < 0.005; UC: aHR 1.17, p < 0.01) and lower risk of food bolus impaction (aHR 0.445, p = 0.0011). CONCLUSION: Simultaneous EoE and IBD increased IBD-related complications risk, needing more treatment (glucocorticoids, biologic therapy, abdominal surgery), while reducing EoE-related issues like food bolus impaction.

Risk of Tuberculosis and Hepatitis B Reactivation in Patients With Crohn's Disease on Ustekinumab: A Nationwide Real-World Study.

BACKGROUND: Ustekinumab (UST) was approved in China for moderate-to-severe Crohn's disease (CD) in 2020. The prevalence rates of tuberculosis and hepatitis B virus (HBV) infection are high in China, and no guideline clearly states that tuberculosis chemoprophylaxis or prophylactic anti-HBV therapy should be prescribed before UST administration. This study aimed to assess the risk of tuberculosis and HBV reactivation in CD patients with latent tuberculosis infection (LTBI) and previous HBV infection receiving UST. METHODS: A multicenter retrospective cohort study was carried out at 68 hospitals in China to assess 721 adult CD cases administered UST between May 1, 2020, and December 31, 2021. CD and concurrent LTBI or HBV carrier were included. Hepatitis B serology, T-SPOT.TB, and tuberculin skin tests were performed at baseline. The primary outcome was tuberculosis or HBV reactivation. RESULTS: Patients with CD-concomitant LTBI or who were HBV carriers receiving UST therapy were retrospectively enrolled from 15 hospitals in China. A total of 53 CD with LTBI patients and 17 CD with HBV carrier patients receiving UST were included. Treatment and follow-up durations were 50 ± 20 weeks and 50 ± 15 weeks in the LTBI and HBV carrier groups, respectively. A total of 25 CD patients with LTBI underwent chemoprophylaxis and 28 did not. A total of 11 HBV carriers had antiviral prophylaxis and 6 did not. No patient experienced tuberculosis or HBV reactivation or liver dysfunction during follow-up. CONCLUSIONS: UST was safe for treatment of CD because no patient developed tuberculosis, persistent hepatitis, or acute liver failure during therapy, whether with a prophylactic regimen or not, based on our sample size and limited follow-up time.

Is disease activity associated with social support and psychological distress in Crohn's disease patients? Results of a cross-sectional study in a Chinese hospital population.

OBJECTIVES: This study aims to assess the relative of social support and psychological distress in disease activity among patients with Crohn's disease (CD) in China, and explore whether sex moderates the relationship between disease activity and social support and psychological distress in CD. DESIGN: Our study has a cross-sectional design. SETTING: This was a single-centre study, which was conducted in Wuhan, China. PARTICIPANTS: A total of 184 patients with CD at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology were enrolled in this study; of these,162 patients were included in the final analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The main study outcome was the CD patients' clinical and questionnaire data. The association of disease activity, social support and psychological distress with patients with CD was also evaluated based on the collected data. RESULTS: A total of 162 patients with CD were enrolled. Compared with patients with CD in remission (CD-R), the patients with CD in activity (CD-A) had higher C reactive protein (CRP) (p=0.001), anaemia (p<0.001) and relapse rates in the last year (p<0.001). Independent samples t-tests indicated that the CD-A group reported lower Social Support Rating Scale scores and higher Symptom Checklist-90 scores than the CD-R group. Moreover, men with CD had lower somatisation (p=0.030) and anxiety (p=0.050) scores than women. In binary logistic regression models, the subjective support (beta=0.903, p=0.013), the clinical factors of CRP (beta=1.038, p=0.001) and psychological distress factors of anxiety (beta=1.443, p=0.008) and other (beta=1.235, p=0.042) were disease activity predictors. CONCLUSION: The findings highlight the importance of the psychological distress and social support factors that may play a role in CD patients' health. Interventions to address these issues should be part of management in CD.

Exploring the relationship between urinary phthalate metabolites and Crohn's disease via oxidative stress, and the potential moderating role of gut microbiota: A conditional mediation model.

OBJECTIVE: Interactions between phthalic acid esters (PAEs) exposure and Crohn's disease (CD) were unknown. This study aims to examine the association between exposure to PAEs and CD activity and to explore the roles of oxidative stress and microbiota. METHODS: A cross-sectional study with 127 CD patients was conducted. The disease activity was evaluated based on symptoms (Harvey-Bradshaw index, HBI), endoscopy findings (Simple Endoscopic Score for CD, SES-CD), and computed tomography enterography (CTE-scores). Ten urinary PAEs metabolites (mPAEs), two urinary oxidative stress biomarkers, including 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α), as well as 16S rRNA sequencing of stool samples were determined. Multiple linear regression models and Hayes's PROCESS macro for SPSS were used to evaluate the interplays between urinary PAEs metabolites, CD activities, oxidative stress, and microbiota diversity. RESULTS: There were positive associations between most mPAEs and HBI. Oxidative stress mediated 20.69-89.29% of the indirect associations between low molecular weight (LMW) mPAEs and HBI, while the majority of the high molecular weight (HMW) mPAEs were directly associated with HBI. In addition, microbiota diversity moderated the indirect associations of LMW mPAEs on HBI. CONCLUSIONS: PAEs exposure was related to CD activity, and the association could be mediated by oxidative stress and reversed or alleviated by rich gut microbiota.

Uncovering the Novel Role of NR1D1 in Regulating BNIP3-Mediated Mitophagy in Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic, incurable condition characterized by mucosal inflammation and intestinal epithelial cell (IEC) damage. The circadian clock gene NR1D1, implicated in UC and the critical mitophagy process for epithelial repair, needs further exploration regarding its role in mitophagy regulation in UC. METHODS: We created a jet lag mouse model and induced colitis with dextran sulfate sodium (DSS), investigating NR1D1's role. Intestinal-specific Nr1d1 knockout mice were also generated. RNA sequencing, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays helped ascertain NR1D1's regulatory effect on BNIP3 expression. The mitochondrial state in IECs was assessed through transmission electron microscopy, while confocal microscopy evaluated mitophagy-associated protein expression in colon tissue and CCD841 cells. Cell apoptosis and reactive oxygen species (ROS) were measured via flow cytometry. RESULTS: We observed reduced NR1D1 expression in the IECs of UC patients, accentuated under jet lag and DSS exposure in mice. NR1D1 ablation led to disrupted immune homeostasis and declined mitophagy in IECs. NR1D1, usually a transcriptional repressor, was a positive regulator of BNIP3 expression, leading to impaired mitophagy, cellular inflammation, and apoptosis. Administering the NR1D1 agonist SR9009 ameliorated colitis symptoms, primarily by rectifying defective mitophagy. CONCLUSIONS: Our results suggest that NR1D1 bridges the circadian clock and UC, controlling BNIP3-mediated mitophagy and representing a potential therapeutic target. Its agonist, SR9009, shows promise in UC symptom alleviation.

An updated review of gastrointestinal toxicity induced by PD-1 inhibitors: from mechanisms to management.

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.

Oat beta-glucan reduces colitis by promoting autophagy flux in intestinal epithelial cells via EPHB6-TFEB axis.

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.

Clinical value of fecal calprotectin for evaluating disease activity in patients with Crohn's disease.

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.

Differential diagnosis of adrenal adenomas and metastases using spectral parameters in dual-layer detector spectral CT.

OBJECTIVE: To assess the diagnostic value of spectral parameters in differentiating adrenal adenomas from metastases based on dual-layer detector spectral CT (DLSCT). MATERIALS AND METHODS: Patients with adenomas or metastases who underwent enhanced DLSCT of the adrenals were enrolled. The CT values of virtual non-contrast images (CTVNC), iodine density (ID) values, and Z-effective (Z-eff) values, the normalized iodine density (NID) values, slopes of spectral HU curves (s-SHC), and iodine-to-CTVNC ratios of the tumors were measured in each phase. Receiver operating characteristic (ROC) curves were used to compare the diagnostic values. RESULTS: Ninety-nine patients with 106 adrenal lesions (63 adenomas, 43 metastases) were included. In the venous phase, all spectral parameters were significantly different between adenomas and metastases (all p < 0.05). The combined spectral parameters showed a better diagnostic performance in the venous phase than in other phase (p < 0.05). The iodine-to-CTVNC value had a larger area under the ROC curve (AUC) than the other spectral parameters in the differential diagnosis of adenomas and metastases, with a diagnostic sensitivity and specificity of 74.4% and 91.9%, respectively. In the differential diagnosis of lipid-rich adenomas, lipid-poor adenomas and metastases, the CTVNC value and s-SHC value also had a larger AUC than the other spectral parameters, with a diagnostic sensitivity of 97.7%, 79.1% and specificity of 91.2%, 93.1%, respectively. CONCLUSION: On DLSCT, the combined spectral parameters in the venous phase could help better distinguish adrenal adenomas from metastases. The iodine-to-CTVNC, CTVNC and s-SHC values had the highest AUC values in differentiating adenomas, lipid-rich adenomas and lipid-poor adenomas from metastases, respectively.

Secreted glucose regulated protein78 ameliorates DSS-induced mouse colitis.

The secreted form of 78-kDa glucose-regulated protein (sGRP78) has been widely reported for its property in aiding resolution of inflammatory. However, little is known on its potential in the treatment of colitis. To investigate the expression pattern and functional outcome of GRP78 in ulcerative colitis, its expression was measured in human and murine colitis samples. It was found that GRP78 was spontaneously secreted to a high level in gut, which is a physiological site of immune tolerance. During the active phase of DSS-induced colitis, the sGRP78 level was significantly reduced but rebounded quickly during resolving phase, making it a potential candidate for the treatment of colitis. In the following experiments, the administration of sGRP78 was proved to decrease susceptibility to experimental colitis, as indicated by an overall improvement of intestinal symptoms, restoration of TJ integrity, decreased infiltration of immune cells and impaired production of inflammatory cytokines. And specific cleavage of endogenous sGRP78 could aggravate DSS colitis. Adoptive transfer of sGRP78-conditioned BMDMs reduced inflammation in the gut. We linked sGRP78 treatment with altered macrophage biology and skewed macrophage polarization by inhibiting the TLR4-dependent MAP-kinases and NF-κB pathways. Based on these studies, as a naturally occurring immunomodulatory molecule, sGRP78 might be an attractive novel therapeutic agent for acute intestinal inflammation.

Gastrointestinal Talaromyces marneffei infection in a patient with AIDS: A case report and systematic review.

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.

The efficacy of mesalazine on nonspecific terminal ileal ulcers: A randomized controlled trial.

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.

The association between disruption of the circadian rhythm and aggravation of colitis in mice.

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.

Differential Diagnosis of Crohn's Disease and Ulcerative Primary Intestinal Lymphoma: A Scoring Model Based on a Multicenter Study.

Background: Differential diagnosis of Crohn's disease (CD) and ulcerative primary intestinal lymphoma (UPIL) is a tough problem in clinical practice. Aims: Our study identified key differences between CD and UPIL patients and aimed to further establish a scoring model for differential diagnosis. Methods: A total of 91 CD and 50 UPIL patients from 9 tertiary inflammatory bowel disease centers were included. Univariate and multivariate analyses were used to determine significant markers for differentiating CD and UPIL. A differential scoring model was established by logistic regression analysis. Results: The differential model was based on clinical symptoms, endoscopic and imaging features that were assigned different scores: intestinal bleeding (-2 points), extraintestinal manifestation (2 points), segmental lesions (1 point), cobblestone sign (2 points), homogeneous enhancement (-1 point), mild enhancement (-1 point), engorged vasa recta (1 point). A total score of ≥1 point indicates CD, otherwise UPIL was indicated. This model produced an accuracy of 83.66% and an area under the ROC curve of 0.947. The area under the ROC curve for validation using the 10-fold validation method was 0.901. Conclusion: This study provided a convenient and useful model to differentiate CD from UPIL.

Alterations of Regional Homogeneity in Crohn's Disease With Psychological Disorders: A Resting-State fMRI Study.

Abnormal psychological processing in the central nervous system has been found in Crohn's disease (CD) patients. Resting-state functional magnetic resonance images of 57 inactive and 58 active CD patients, and 92 healthy controls (HC) were obtained. The psychological assessment used a psychological questionnaire that was collected within 1 week before functional MRI examination. We investigated the neural basis of CD patients and the correlation among regional homogeneity (ReHo), clinical features and psychological assessment scores. We found that more severe psychological assessment disorder scores were observed in the active CD group than in the inactive CD group and HC group (P<0.001). Compared with HC, the active CD patients exhibited higher ReHo values in the frontal superior medial, frontal middle and lower values in the postcentral, supplementary motor area, and temporal middle. Meanwhile, inactive CD patients exhibited higher ReHo values in the frontal middle and lower ReHo values in the precentral, postcentral and putamen (all voxel P< 0.001, cluster P<0.01, corrected). The values of the frontal superior medial, postcentral and supplementary motor area were correlation with psychological assessment scores (r = 0.38, -0.41, -0.32, P = 0.001, 0.014, 0.003), and the clinical features of simple endoscopic score for Crohn's disease and erythrocyte sedimentation rate were negatively correlated with psychological assessment scores in active CD patients (r = -0.35, -0.34, P = 0.06, 0.08). These results provide evidence for abnormal resting-state brain activity in CD and suggest that the psychological of CD may play a critical role in brain function.

Resolvin D1 ameliorates hepatic steatosis by remodeling the gut microbiota and restoring the intestinal barrier integrity in DSS-induced chronic colitis.

BACKGROUND AND PURPOSE: The maintenance of intestinalmucosalbarrier function plays an important role in hepatic steatosis. Increasing evidence has shown that resolvin D1 (RVD1) exerts a potential effect on hepatic steatosis. The aims of this study were to explore the mechanisms of RVD1 on hepatic steatosis based on the gut-liver axis and intestinal barrier function. EXPERIMENTAL APPROACH: We established a DSS-induced chronic colitis model to evaluate hepatic steatosis. RVD1 was administered i.p. during the last 4 weeks. The colon and liver samples were stained with hematoxylin and eosin for histopathological analysis. The expression levels of intestinal tight junction genes and inflammatory genes were determined by quantitative PCR. The serum levels of glucose, cholesterol, triglycerides and LPS were measured, and the gut microbiota was analyzed by 16S rRNA gene sequencing. KEY RESULTS: RVD1 prevented weight loss, histopathological changes, and elevated levels of inflammatory cytokines. Moreover, RVD1 administration attenuated DSS-induced hepatic steatosis and inflammatory responses in mice. In addition, RVD1 improved intestinal barrier function by increasing levels of tight junction molecules and decreasing the plasma LPS levels. The RVD1-treated mice also showed a different gut microbiota composition compared with found in the mice belonging to the DSS group but similar to that in normal chow diet-fed mice. CONCLUSIONS AND IMPLICATIONS: RVD1 treatment ameliorates DSS-induced hepatic steatosis by ameliorating gut inflammation, improving intestinal barrier function and modulating intestinal dysbiosis.