Association of diet and outdoor time with inflammatory bowel disease: a multicenter case-control study using propensity matching analysis in China.

Objective: To investigate the association between dietary and some other environmental factors and the risk of inflammatory bowel diseases (IBD) in Chinese population. Materials and methods: A multicenter case-control study was conducted involving 11 hospitals across China. A total of 1,230 subjects were enrolled consecutively, and diet and environmental factor questionnaires were collected. IBD patients were matched with healthy controls (HC) using propensity-score matching (PSM) at a 1:1 ratio with a caliper value of 0.02. Multivariate conditional logistic regression analyses were performed to evaluate the associations between diet, environmental factors, and IBD. Results: Moderate alcohol and milk consumption, as well as daily intake of fresh fruit, were protective factors for both Crohn's disease (CD) and ulcerative colitis (UC). Conversely, the consumption of eggs and chocolate increased the risk of IBD. Outdoor time for more than 25% of the day was a protective factor only for CD. In eastern regions of China, CD patients had higher egg consumption and less outdoor time, while UC patients consumed more chocolate. IBD patients from urban areas or with higher per capita monthly income consumed more fruit, eggs, and chocolate. Conclusions: This study reveals an association between specific foods, outdoor time, and the emergence of IBD in the Chinese population. The findings emphasize the importance of a balanced diet, sufficient outdoor time and activities, and tailored prevention strategies considering regional variations.

Clinical features of inflammatory bowel disease unclassified: a case-control study.

BACKGROUND: Approximately 10-15% of inflammatory bowel disease (IBD) patients with overlapping features of ulcerative colitis (UC) and Crohn's disease (CD) are termed as inflammatory bowel disease unclassified (IBDU). This study aimed to describe the clinical features of IBDU and evaluate the potential associated factors of reclassification. METHODS: The clinical data of 37 IBDU patients were retrospectively analyzed from November 2012 to November 2020. 74 UC and 74 CD patients were randomly selected and age- and sex-matched with the 37 IBDU patients. Clinical characteristics were compared between the three patient groups. Potential factors associated with the IBDU reclassification were evaluated. RESULTS: 60% of IBDU patients displayed rectal-sparing disease, and 70% of them displayed segmental disease. In comparison to UC and CD, the IBDU group demonstrated higher rates of gastrointestinal bleeding (32.4%), intestinal perforation (13.5%), spontaneous blood on endoscopy (51.4%), and progression (56.8%). The inflammation proceeded relatively slowly, manifesting as chronic alterations like pseudopolyps (78.4%) and haustra blunt or disappearance (56.8%). 60% of IBDU patients exhibited crypt abscess, and 16.7% of them exhibited fissuring ulcers or transmural lymphoid inflammation. The proportions of IBDU patients receiving immunosuppressants, surgery, and infliximab were basically the same as those of CD patients. During the 79 (66, 91) months of follow-up, 24.3% of IBDU patients were reclassified as UC, while 21.6% were reclassified as CD. The presence of intestinal hemorrhaging was associated with CD reclassification, while hypoalbuminemia was associated with UC reclassification. CONCLUSIONS: IBDU may evolve into UC or CD during follow-up, and hemorrhage was associated with CD reclassification. Different from the other two groups, IBDU exhibited a more acute onset and a gradual progression. When an IBD patient presents with transmural inflammation or crypt abscess but lacks transmural lymphoid aggregates or fissuring ulcers, the diagnosis of IBDU should be considered.

Psychological symptoms and quality of life in patients with inflammatory bowel disease in China: A multicenter study.

AIMS: To investigate the current situation of mental psychology and quality of life (QoL) in patients with inflammatory bowel disease (IBD) in China, and analyze the influencing factors. METHODS: A unified questionnaire was developed to collect clinical data on IBD patients from 42 hospitals in 22 provinces from September 2021 to May 2022. Multivariate Logistic regression analysis was conducted, and independent influencing factors were screened out to construct nomogram. The consistency index (C-index), receiver operating characteristic (ROC) curve, area under the ROC curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the discrimination, accuracy, and clinical utility of the nomogram model. RESULTS: A total of 2478 IBD patients were surveyed, including 1371 patients with ulcerative colitis (UC) and 1107 patients with Crohn's disease (CD). Among them, 25.5%, 29.7%, 60.2%, and 37.7% of IBD patients had anxiety, depression, sleep disturbance and poor QoL, respectively. The proportion of anxiety, depression, and poor QoL in UC patients was significantly higher than that in CD patients (all p < 0.05), but there was no difference in sleep disturbance between them (p = 0.737). Female, higher disease activity and the first visit were independent risk factors for anxiety, depression and sleep disturbance in IBD patients (all p < 0.05). The first visit, higher disease activity, abdominal pain and diarrhea symptoms, anxiety, depression and sleep disturbance were independent risk factors for the poor QoL of patients (all p < 0.05). The AUC value of the nomogram prediction model for predicting poor QoL was 0.773 (95% CI: 0.754-0.792). The calibration diagram of the model showed that the calibration curve fit well with the ideal curve, and DCA showed that the nomogram model could bring clinical benefits. CONCLUSION: IBD patients have higher anxiety, depression, and sleep disturbance, which affect their QoL. The nomogram prediction model we constructed has high accuracy and performance when predicting QoL.

A case report of refractory amebic colitis and literature review.

RATIONALE: Amebic colitis has been less prevalent in recent times in China, and the similarity of its symptoms to those of inflammatory bowel disease (IBD) results in the difficulty of early identification and diagnosis. PATIENT CONCERNS: A 31-year-old male who exhibited intermittent diarrhea and hematochezia was highly suspected as IBD initially. Despite the partial relief of symptoms following the administration of mesalamine, the endoscopic ulcers remained largely unchanged. DIAGNOSES: Two years after the onset of mesalamine therapy, amebic cysts were detected in stool microscopy and trophozoites were found on the surface of cecal ulcers. The patient was then diagnosed with amebic colitis. INTERVENTIONS: After 2 rounds of standardized metronidazole treatment, amebic colitis remained refractory until diloxanide was administered. OUTCOMES: The patient remained asymptomatic, and the mucosa of colon was normal during the annual follow-up. LESSONS: Individuals newly diagnosed with IBD should undergo essential screening for amebiasis. And the use of steroids should be taken with caution, especially in cases where the effect of mesalamine is limited. For symptomatic intestinal amebiasis, even after the administration of tissue amebicides, the continued use of luminal amebicides is necessary to prevent recurrence.

Pyroptosis burden is associated with anti-TNF treatment outcome in inflammatory bowel disease: new insights from bioinformatics analysis.

Biological agents known as anti-tumor necrosis factor (TNF) drugs are frequently utilized in the treatment of inflammatory bowel disease (IBD). In this study, we analyzed the shared processes of pyroptosis in Ulcerative colitis (UC) and Crohn's disease (CD), as well as explored the correlation between the burden of pyroptosis and the results of anti-TNF treatment based on bioinformatics analyses. We identified CAPS1, CASP5, GSDMD, AIM2, and NLRP3 as the hub genes, with AIM2 being the most effective indicator for predicting the response to anti-TNF therapy. We also noticed that non-responders received anti-TNF therapy exhibited elevated AIM2 protein expression. Subsequently, we conducted a cluster analysis based on AIM2-inflammasome-related genes and discovered that patients with a higher burden of AIM2 inflammasome displayed stronger immune function and a poor response to anti-TNF therapy. Overall, our study elucidates the pathway of pyroptosis in IBD and reveals AIM2 expression level as a potential biomarker for predicting the effectiveness of anti-TNF therapy.

Human umbilical cord mesenchymal stem cells ameliorate colon inflammation via modulation of gut microbiota-SCFAs-immune axis.

BACKGROUND: Inflammatory bowel disease (IBD) is a global health problem in which gut microbiota dysbiosis plays a pivotal pathogenic role. Mesenchymal stem cells (MSCs) therapy has emerged as a prospective novel tool for managing IBD, and which can also regulate the composition of gut microbiota. However, the functional significance of MSCs-induced changes in gut microbiome is poorly understood. METHODS: Here, we investigated for the first time the role of gut microbiota in mediating the protective effect of human umbilical cord MSCs (HUMSCs) on DSS-induced colitis. Gut microbiota alteration and short-chain fatty acids (SCFAs) production were analyzed through 16S rRNA sequencing and targeted metabolomics. Spectrum antibiotic cocktail (ABX), fecal microbiota transplantation (FMT) and sterile fecal filtrate (SFF) were employed to evaluate the protective effect of intestinal flora and its metabolites. Cytokine microarray, Enzyme-linked immunosorbent assay (ELISA), and flow cytometry were conducted to assess the effect on CD4+T homeostasis. RESULTS: Here, we investigated for the first time the role of gut microbiota in mediating the protective effect of MSCs on DSS-induced colitis. By performing gut microbiota depletion and fecal microbiota transplantation (FMT) experiments, we revealed that MSCs derived from human umbilical cord ameliorated colon inflammation and reshaped T-cells immune homeostasis via remodeling the composition and diversity of gut flora, especially up-regulated SCFAs-producing bacterial abundance, such as Akkermansia, Faecalibaculum, and Clostridia_UCG_014. Consistently, targeted metabolomics manifested the increased SCFAs production with MSCs administration, and there was also a significant positive correlation between differential bacteria and SCFAs. Meanwhile, combined with sterile fecal filtrate (SFF) gavage experiments, the underlying protective mechanism was further associated with the improved Treg/Th2/Th17 balance in intestinal mucosa mediated via the increased microbiota-derived SCFAs production. CONCLUSION: The present study advances understanding of MSCs in the protective effects on colitis, providing evidence for the new role of the microbiome-metabolite-immune axis in the recovery of colitis by MSCs.

New score models for assessing disease activity in Crohn's disease based on bowel ultrasound and biomarkers: Ideal surrogates for endoscopy or imaging.

Disease activity evaluation is important in Crohn's disease (CD). We aimed to establish new disease activity indices for CD based on noninvasive parameters. The data of 110 patients with CD were retrospectively analyzed. Parameters from bowel ultrasound and biomarkers were measured to select the variables included in the models by univariate analysis. Logistic regression analysis was performed to predict mucosal and transmural activities defined by ileocolonoscopy or computed tomography enterography, respectively. The models' performance was measured by the area under the receiver operating characteristic (ROC) curve (AUC). Leave-one-out cross validation (LOOCV) was applied to adjust for overconfidence in the newly established score models. To predict mucosal activity, erythrocyte sedimentation rate (ESR) and (LimG × BWT)-SUM (the sum of the product of Limberg grade [LimG] and bowel wall thickness [BWT] of each bowel segment) were selected for model A, and the equation was A = 2 × ESR + 9.3 × (LimG × BWT)-SUM. The AUC of ROC, sensitivity, and specificity were 0.927%, 89.8%, and 86.4%, respectively. The AUC of the ROC curve verified by LOOCV was 0.913. To predict transmural activity, albumin (ALB) and LimG-SUM (the sum of the LimG of all the bowel segments) were selected for model B, which was established as B = -1.3 × ALB +1.7 × LimG-SUM. The AUC of ROC, sensitivity, and specificity were 0.851%, 78.0%, and 84.2%, respectively. The AUC of the ROC curve verified by LOOCV was 0.833. Nomograms were developed for two score models. New score models based on noninvasive parameters established in this study showed good abilities in detecting active disease and performed well in the validation phase.

HucMSC-Exo Promote Mucosal Healing in Experimental Colitis by Accelerating Intestinal Stem Cells and Epithelium Regeneration via Wnt Signaling Pathway.

Background: Mucosal healing has emerged as a crucial therapeutic goal for inflammatory bowel diseases (IBD). Exosomes (Exo) as a potential acellular candidate for stem cell therapy might be competent to promote mucosal healing, while its mechanism remains unexplored. Methods: Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) were subjected to experimental colitis mice intraperitoneally to estimate the role in mucosal healing and the regeneration of intestinal stem cells (ISCs) and epithelium. The intestinal organoid model of IBD was constructed utilizing tumor necrosis factor (TNF)-α for subsequent function analysis in vitro. Transcriptome sequencing was performed to decipher the underlying mechanism and Wnt-C59, an oral Wnt inhibitor, was used to confirm that further. Finally, the potential specific components of hucMSC­exo were investigated based on several existing miRNA expression datasets. Results: HucMSC-exo showed striking potential for mucosal healing in colitis mice, characterized by decreased histopathological injuries and neutrophil infiltration as well as improved epithelial integrity. HucMSC-exo up-regulated the expression of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), a specific marker for ISCs and accelerated the proliferation of intestinal epithelium. HucMSC-exo endowed intestinal organoids with more excellent capacity to grow and bud under TNF-α stimulation. More than that, the fact that hucMSC-exo activated the canonical Wnt signaling pathway to promote mucosal healing was uncovered by not only RNA-sequencing but also relevant experimental data. Finally, bioinformatics analysis of the existing miRNA expression datasets indicated that several miRNAs abundant in hucMSC-exo involved widely in regeneration or repair related biological processes and Wnt signaling pathway might be one of the most important signal transduction pathways. Conclusion: Our results suggested that hucMSC-exo could facilitate mucosal healing in experimental colitis by accelerating ISCs and intestinal epithelium regeneration via transferring key miRNAs, which was dependent on the activation of Wnt/ß-catenin signaling pathway.

Vitamin D Status Is Associated With Immune Checkpoint Inhibitor Efficacy and Immune-related Adverse Event Severity in Lung Cancer Patients: A Prospective Cohort Study.

Vitamin D (VitD) is potentially immunomodulatory, so here we aimed to explore the relationships between serum VitD levels, immune checkpoint inhibitor (ICI) efficacy, and immune-related adverse events (irAEs). Serum 25-hydroxyvitamin D [25(OH)D] levels were quantified before and after ICI treatment in prospectively enrolled patients with advanced lung cancers. Of 77 enrolled patients, 29 developed 42 irAEs. Baseline 25(OH)D levels of partial response (PRs) patients were significantly higher than non-PR patients (19.39±7.16 vs. 16.28±5.99 ng/mL, P =0.04). The area under the curve of 25(OH)D >15.73 ng/mL to identify PR was 0.63 (95% CI, 0.51-0.76, P =0.047), and baseline 25(OH)D levels >15.73 ng/mL (odds ratio: 2.93, 95% CI, 1.10-7.79, P =0.03) and prior targeted therapy (odds ratio: 0.30, 95% CI, 0.10-0.92, P =0.04) were independent predictors of PR as best efficacy by multivariable logistic regression. With respect to irAEs, baseline 25(OH)D levels were higher in grade 1 irAE patients than in grade 2/3/4 irAE patients (20.07±8.64 vs. 15.22±2.30 ng/mL, P =0.02). However, the area under the curve was only 0.56 (95% CI, 0.42-0.70, P =0.39) for a baseline 25(OH)D of 20.99 ng/mL for predicting irAE occurrence. There was a direct monotonic relationship and U-shaped relationship between baseline 25(OH)D levels and ICI efficacy and irAE occurrence, respectively. Overall survival was significantly different between VitD sufficient, insufficient, and deficient patients (log-rank P =0.01), which remained after adjustment in Cox proportional hazards regression models. Baseline 25(OH)D levels seem to be associated with ICI efficacy and prognosis, it might be helpful to assess the baseline VitD status, and supplementation with VitD might bring some benefit to enhance ICI efficacy and reduce moderate-severe irAEs.

Dynamic gut microbiota changes in patients with advanced malignancies experiencing secondary resistance to immune checkpoint inhibitors and immune-related adverse events.

Background: Immune checkpoint inhibitors (ICIs) have been a breakthrough in cancer immunotherapy, but secondary resistance (SR) and immune-related adverse events (irAEs) are significant clinical dilemmas. Although the gut microbiota is associated with ICI efficacy and irAEs, the knowledge of longitudinal gut microbiota dynamics during SR and irAE development is still quite limited. Methods: This was a prospective observational cohort study of cancer patients initially receiving anti-programmed cell death-1 (PD-1) treatment between May 2020 and October 2022. Clinical information was collected to evaluate therapy response and AEs. Patients were divided into a secondary resistance (SR) group, a non-secondary resistance (NSR) group, and an irAE group. Fecal samples were longitudinally obtained from baseline across multiple timepoints and analyzed with 16S rRNA sequencing. Results: Thirty-five patients were enrolled, and 29 were evaluable. After a median follow-up of 13.3 months, NSR patients had a favorable progression-free survival (PFS) compared with SR (457.9 IQR 241.0-674.0 days vs. 141.2 IQR 116.9-165.4 days, P=0.003) and irAE patients (457.9 IQR 241.0-674.0 days vs. 269.9, IQR 103.2-436.5 days, P=0.053). There were no significant differences in the microbiota between groups at baseline. Several previously reported beneficial microbiomes for ICI efficacy including Lachnospiraceae, Ruminococcaceae, Agathobacter, and Faecalibacterium showed decreasing trends as secondary resistance developed, yet not achieved significance (P>0.05). Significant changes in butyrate-producing bacteria were also presented in the SR cohort (P=0.043) with a decreasing trend upon secondary resistance occurrence (P=0.078). While the abundance of IgA-coated bacteria was stable in the SR cohort, there was a temporary decrease upon ICI treatment initiation and reestablishment after continuation of ICI treatment in the NSR cohort (primary ICI response: 0.06, IQR 0.04-0.10; durable ICI response: 0.11, IQR 0.07-0.14; P=0.042). Bacteroides contributed most to the difference between baseline and irAE occurrence, which decreased after irAE occurrence (Baseline: 0.10 IQR 0.07-0.36; irAE occurrence: 0.08 IQR 0.06-0.12) and was restored upon irAE remission to a comparable level as baseline (irAE remission: 0.10 IQR 0.09-0.18). Conclusions: The development of SR and irAEs is related to the longitudinal dynamics of the intestinal microbiota. The investigation into the preventative and protective effects of enteric microbe manipulation strategies is further required.

Prognostic factors for the efficacy of infliximab in patients with luminal fistulizing Crohn's disease.

BACKGROUND: Enteric fistula is one of the penetrating features in Crohn's disease (CD). This study aimed to clarify the prognostic factors for the efficacy of infliximab (IFX) treatment in luminal fistulizing CD patients. METHODS: We retrospectively included 26 cases diagnosed with luminal fistulizing CD hospitalized in our medical center from 2013 to 2021. The primary outcome of our research was defined as death from all causes and undergoing of any relevant abdominal surgery. Kaplan-Meier survival curves were used to describe overall survival. Univariate and multivariate analyses were used to identify prognostic factors. A predictive model was constructed using Cox proportional hazard model. RESULTS: The median follow-up time was 17.5 months (range 6-124 months). The 1- and 2-year surgery-free survival rates were 68.1% and 63.2%, respectively. In the univariate analysis, the efficacy of IFX treatment at 6 months after initiation (P < 0.001, HR 0.23, 95% CI 0.01-0.72) and the existence of complex fistula (P = 0.047, HR 4.11, 95% CI 1.01-16.71) was found significantly related to the overall surgery-free survival, while disease activity at baseline (P = 0.099) also showed predictive potential. The multivariate analysis showed that efficacy at 6 months (P = 0.010) was an independent prognostic factor. The C-index of the model for surgery-free survival was 0.923 (P < 0.001), indicating an acceptable predictive effect. CONCLUSION: Prognostic model including the existence of complex fistula, disease activity at baseline and efficacy of IFX at 6 months may be useful to predict long-term outcome of luminal fistulizing CD patients.

Gut microbiota composition in patients with advanced malignancies experiencing immune-related adverse events.

Introduction: The gut microbiota is implicated in the occurrence and severity of immune-related adverse events (irAEs), but the role it plays as well as its causal relationship with irAEs has yet to be established. Methods: From May 2020 to August 2021, 93 fecal samples were prospectively collected from 37 patients with advanced thoracic cancers treated with anti-PD-1 therapy, and 61 samples were collected from 33 patients with various cancers developing different irAEs. 16S rDNA amplicon sequencing was performed. Antibiotic-treated mice underwent fecal microbiota transplantation (FMT) with samples from patients with and without colitic irAEs. Results: Microbiota composition was significantly different in patients with and without irAEs (P=0.001) and with and without colitic-type irAEs (P=0.003). Bifidobacterium, Faecalibacterium, and Agathobacter were less abundant and Erysipelatoclostridium more abundant in irAE patients, while Bacteroides and Bifidobacterium were less abundant and Enterococcus more abundant in colitis-type irAE patients. Major butyrate-producing bacteria were also less abundant in patients with irAEs than those without (P=0.007) and in colitic vs. non-colitic irAE patients (P=0.018). An irAE prediction model had an AUC of 86.4% in training and 91.7% in testing. Immune-related colitis was more common in colitic-irAE-FMT (3/9) than non-irAE-FMT mice (0/9). Conclusions: The gut microbiota is important in dictating irAE occurrence and type, especially for immune-related colitis, possibly by modulating metabolic pathways.

The metabolic syndrome and its components as prognostic factors in colorectal cancer: A meta-analysis and systematic review.

BACKGROUND AND AIM: Metabolic syndrome (MetS) increases the risk of colorectal cancer (CRC), and the impact of MetS on CRC prognosis remains controversial after the diagnosis of CRC has been established. This study aimed to explore the impact of the individual components and synergies of MetS on the prognosis of patients with CRC. METHODS: We searched articles published before August 3, 2022, in four databases, including PubMed, Embase, Cochrane Library, and ScienceDirect. The random-effects model inverse variance method was used to estimate the summarized effect size. RESULTS: Patients with CRC with MetS were 1.342 times more likely to experience all-cause mortality than those without MetS, and the 95% confidence interval (CI) of hazard ratio (HR) was 1.107-1.627 (P = 0.003). CRC-specific mortality in patients with CRC with MetS was 2.122 times higher than in those without MetS, and the 95% CI of HR was 1.080-4.173 (P = 0.029). CRC-specific mortality exhibited an increasing trend of risk with increased metabolic risk factors. The HR of CRC-specific mortality for one, two, and three metabolic risk factors was 1.206 (95% CI, 1.034-1.407; P = 0.017), 1.881 (95% CI, 1.253-2.824; P = 0.002), and 2.327 (95% CI, 1.262-4.291; P = 0.007), respectively. CONCLUSIONS: Metabolic syndrome increased all-cause and CRC-specific mortality in patients with CRC. As a single component of MetS, diabetes mellitus increased overall mortality in patients with CRC, while obesity increased CRC-specific mortality in patients with CRC, with a significant difference from non-MetS. Moreover, the risk of CRC-specific mortality increased with increasing number of metabolic risk factors.

Sex-specific comparison of clinical characteristics and prognosis in Crohn's disease: A retrospective cohort study of 611 patients in China.

Background: Real-world data on the impact of sex on the disease progression and prognosis of Crohn's disease (CD) from large-scale Chinese cohorts are lacking. Aims: This study aimed to evaluate sex disparities in the clinical characteristics of, disease progression behaviours of and surgery-related risk factors for CD. Methods: A retrospective cohort study comprising 611 patients consecutively diagnosed with CD at Peking Union Medical College Hospital from January 2000 to December 2020 was conducted. Multivariate Cox regression and survival analyses was performed to assess the risk factors for disease progression and CD-related surgery in sex subgroups. Results: Male sex was an independent protective factor against multisystemic extraintestinal manifestations [EIMs] (HR: 0.52, p = 0.03) and a risk factor for intestinal perforation (HR: 1.85, p = 0.01). Male patients had longer EIM-free survival (p = 0.024) and shorter intestinal perforation-free survival (PFS) than females (p = 0.012). Of the 397 patients with the A2 classification, male patients had a higher risk of CD-related surgery (HR: 1.80, p = 0.028) and shorter surgery-free survival (SFS) than female patients (p = 0.04). Conclusion: Sex disparities in disease progression and outcomes of CD were revealed in a single Chinese centre. Male sex was independently associated with worse disease progression and prognosis including multisystemic EIMs and perforation, which suggests the need for individualized management according to risk classification.

The diagnosis of immune-related pancreatitis disguised as multifocal lesions on MRI by endoscopic ultrasound-guided fine-needle biopsy: A case report.

Immune checkpoint inhibitor (ICI)-related acute pancreatitis (irAP) is a rare, potentially life-threatening immune-related adverse event. Whereas CT and MRI remain first-line diagnostic imaging modalities, more patients are presenting with atypical irAP as ICI use increases. To appropriately manage these events, it is important to catalog these presentations and provide comprehensive clinical, radiological, and pathological descriptions to guide evidence-based practice. Here, we present the case of a 66-year-old man with advanced lung adenocarcinoma who, after the fifth course of toripalimab, developed epigastric discomfort and elevated serum amylase and lipase. irAP was suspected, but MRI revealed atypical, multifocal pancreatic lesions. To exclude metastases, an endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) was performed. EUS revealed a slightly swollen pancreas with heterogeneous echoic signals and scattered hyperechoic areas in the parenchyma without an obvious mass. Histopathological examination of the FNB revealed retention of the normal lobular pancreatic architecture with focal acinar atrophy associated with a CD8+ T lymphocyte-predominant infiltrate, further confirming the diagnosis of irAP. After starting glucocorticoids, his symptoms resolved, serum amylase and lipase rapidly decreased to normal, and the abnormal MRI features diminished. irAP can, therefore, present as multifocal lesions on MRI, and, when metastatic disease requires exclusion, EUS-FNB is an effective way to establish a definitive diagnosis. Refining the histopathological and immunopathological criteria for the diagnosis of irAP is now warranted.

Computed tomography enterography increases the ability of endoscopy to differentiate Crohn's disease from intestinal Behçet's disease.

Background: Distinguishing Crohn's disease (CD) and intestinal Behçet's disease (BD) is difficult in clinical practice. Aim: To evaluate the ability of CT enterography (CTE) to enhance the diagnostic value of endoscopy in differentiating CD from intestinal BD and to establish differential diagnosis models. Methods: A total of 113 patients with CD and 70 patients with intestinal BD from seven tertiary inflammatory bowel disease centers were enrolled. The univariate and multivariate analyses were used by SAS software version 9.2. Three differential scoring models based on the multivariate analysis of endoscopic features alone (model 1), endoscopic features combined with clinical symptoms (model 2), and endoscopic features combined with clinical symptoms and CTE (model 3) were established. Results: The results showed that model 2 increased the efficacy of model 1 in differential diagnosis and model 3 had the highest accuracy of 84.15% at a cutoff value of two points. The scoring of model 3 was as follows: genital ulcer (-3 points), skin lesions (-3 points), oval ulcer (-2 points), longitudinal ulcer (1 point), number of ulcers > 5 (3 points), inflammatory polyps (2 points), mucosal severe enhancement (2 points), and fibrofatty proliferation (1 point). Conclusion: Clinical symptoms and CTE increased the ability of endoscopy to differentiate CD from intestinal BD.

Human umbilical cord mesenchymal stem cells regulate immunoglobulin a secretion and remodel the diversification of intestinal microbiota to improve colitis.

Background: Mesenchymal stem cell (MSC) therapy has emerged as a promising novel therapeutic strategy for managing inflammatory bowel disease (IBD) mainly via dampening inflammation, regulating immune disorders, and promoting mucosal tissue repair. However, in the process, the associated changes in the gut microbiota and the underlying mechanism are not yet clear. Methods: In the present study, dextran sulfate sodium (DSS) was used to induce colitis in mice. Mice with colitis were treated with intraperitoneal infusions of MSCs from human umbilical cord mesenchymal stem cells (HUMSCs) and evaluated for severity of inflammation including weight reduction, diarrhea, bloody stools, histopathology, and mortality. The proportion of regulatory T cells (Tregs) and immunoglobulin A-positive (IgA+) plasmacytes in gut-associated lymphoid tissue were determined. The intestinal and fecal levels of IgA were tested, and the proportion of IgA-coated bacteria was also determined. Fecal microbiome was analyzed using 16S rRNA gene sequencing analyses. Results: Treatment with HUMSCs ameliorated the clinical abnormalities and histopathologic severity of acute colitis in mice. Furthermore, the proportion of Tregs in both Peyer's patches and lamina propria of the small intestine was significantly increased. Meanwhile, the proportion of IgA+ plasmacytes was also substantially higher in the MSCs group than that of the DSS group, resulting in elevated intestinal and fecal levels of IgA. The proportion of IgA-coated bacteria was also upregulated in the MSCs group. In addition, the microbiome alterations in mice with colitis were partially restored to resemble those of healthy mice following treatment with HUMSCs. Conclusions: Therapeutically administered HUMSCs ameliorate DSS-induced colitis partially via regulating the Tregs-IgA response, promoting the secretion of IgA, and facilitating further the restoration of intestinal microbiota, which provides a potential therapeutic mechanism for HUMSCs in the treatment of IBD.

Gut microbiota shed new light on the management of immune-related adverse events.

Immunotherapy has dramatically revolutionized the therapeutic landscape for patients with cancer. Although immune checkpoint inhibitors are now accepted as effective anticancer therapies, they introduce a novel class of toxicity, termed immune-related adverse events, which can lead to the temporary or permanent discontinuation of immunotherapy and life-threatening tumor progression. Therefore, the effective prevention and treatment of immune-related adverse events is a clinical imperative to maximize the utility of immunotherapies. Immune-related adverse events are related to the intestinal microbiota, baseline gut microbiota composition is an important determinant of immune checkpoint inhibitor-related colitis, and antibiotics exacerbate these undesirable side-effects. Supplementation with specific probiotics reduces immune checkpoint inhibitor-related colitis in mice, and fecal microbiota transplantation has now been shown to effectively treat refractory immune checkpoint inhibitor-related colitis in the clinic. Hence, modifying the microbiota holds great promise for preventing and treating immune-related adverse events. Microbiomes and their metabolites play important roles in the potential underlying mechanisms through interactions with both innate and adaptive immune cells. Here we review the gut microbiota and immune regulation; the changes occurring in the microbiota during immune checkpoint inhibitor therapy; the relationship between the microbiota and immune-related adverse events, antibiotics, probiotics/prebiotics, and fecal microbiota transplantation in immune checkpoint inhibitor-related colitis; and the protective mechanisms mediated by the microbiome and metabolites in immune-related adverse events.

Identification and Validation of Prognosis-Related Necroptosis Genes for Prognostic Prediction in Hepatocellular Carcinoma.

Background: The prediction of hepatocellular carcinoma (HCC) survival is challenging because of its rapid progression. In recent years, necroptosis was found to be involved in the progression of multiple cancer types. However, the role of necroptosis in HCC remains unclear. Methods: Clinicopathological parameters and transcriptomic data of 370 HCC patients were obtained from TCGA-LIHC dataset. Prognosis-related necroptosis genes (PRNGs) were identified and utilized to construct a LASSO risk model. The GEO cohorts (GSE54236 and GSE14520) were used for external validation. We evaluated the distribution of HCC patients, the difference in prognosis, and the accuracy of the prognostic prediction of the LASSO risk model. The immune microenvironment and functional enrichment of different risk groups were further clarified. Finally, we performed a drug sensitivity analysis on the PRNGs that constructed the LASSO model and verified their mRNA expression levels in vitro. Results: A total of 48 differentially expressed genes were identified, 23 of which were PRNGs. We constructed the LASSO risk model using nine genes: SQSTM1, FLT3, HAT1, PLK1, MYCN, KLF9, HSP90AA1, TARDBP, and TNFRSF21. The outcomes of low-risk patients were considerably better than those of high-risk patients in both the training and validation cohorts. In addition, stronger bile acid metabolism, xenobiotic metabolism, and more active immune cells and immune functions were observed in low-risk patients, and high expressions of TARDBP, PLK1, and FLT3 were associated with greater drug sensitivity. With the exception of FLT3, the mRNA expression of the other eight genes was verified in Huh7 and 97H cells. Conclusions. The PRNG signature provides a novel and effective method for predicting the outcome of HCC as well as potential targets for further research.

Dyslipidaemia Is Associated with Severe Disease Activity and Poor Prognosis in Ulcerative Colitis: A Retrospective Cohort Study in China.

Background: Clinical data on the correlation of dyslipidaemia with the long-term outcomes of ulcerative colitis (UC) are limited. This study aimed to evaluate the impact of lipid levels on disease activity and prognosis in UC. Methods: The retrospective data of UC patients who had detailed lipid profiles were collected from January 2003 to September 2020. All patients were followed-up to 30 September 2021. The long-term outcomes were UC-related surgery and tumorigenesis. Results: In total, 497 patients were included in the analysis. Compared to patients with normal lipid levels, those with dyslipidaemia commonly presented with more serious disease activity. Low high-density lipoprotein cholesterol (p < 0.05) levels were associated with higher risks of severe disease activity in UC. Regarding the long-term outcomes, patients with persistent dyslipidaemia were at higher risks of UC-related surgery (HR: 3.27, 95% CI: 1.86−5.75, p < 0.001) and tumorigenesis (HR: 7.92, 95% CI: 3.97−15.78, p < 0.001) and had shorter surgery- and tumour-free survival (p < 0.001) than patients with transient dyslipidaemia and normal lipid levels. Low levels of high-density lipoprotein cholesterol (p < 0.001) and apolipoprotein A1 (p < 0.05) were associated with higher risks of surgery and tumorigenesis. Conclusion: Persistent dyslipidaemia was associated with a higher risk of serious disease activity and worse long-term outcomes among patients with UC. Lipid patterns should be assessed to improve the management of high-risk patients with UC in the early phase.