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Abstract Lipid metabolism disorder is a critical feature of Crohn’s disease (CD). Phosphatidylinositol (PI) and its derivative, phosphatidylinositol bisphosphate (PIP2), are associated with CD. The mechanisms underlying such association remain unknown. In this study, we explored the role played by the major PI derivative, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], in CD pathogenesis. The relationship between CD activity and PI or PIP2 was analyzed via lipidomics. The mucosal expression of PI(4,5)P2 in patients with CD was measured using immunofluorescence. The function and mechanism of PI(4,5)P2 were examined in dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-induced Caco-2 cell models, along with MeRIP and mRNA sequencing. The results suggested lipid PI and PIP2 were substantially negatively associated with disease activity and high-sensitivity C-reactive protein. PI(4,5)P2 was substantially downregulated in the inflamed mucosa of patients with CD. PI(4,5)P2 alleviated mouse colitis, with improvements in survival rate, colon length, weight, and disease activity index. PI(4,5)P2 also alleviated DSS-induced tissue damage, tight junction loss, and intestinal epithelial cell (IEC) pyroptosis. In the in vitro LPS-induced cell model, PI(4,5)P2 inhibited pyroptosis, as well as NLRP3, and caspase-1 expression, in addition to reducing interleukin (IL)-18, IL-1β, and lactate dehydrogenase (LDH) secretion. PI(4,5)P2 mediated NNMT upregulation in mice and Caco-2 cells and suppressed pyroptosis in IECs. NNMT knockdown restricted the inhibitory effect of PI(4,5)P2 on IEC pyroptosis. NNMT inhibited the stability of RBP4 mRNA via m6A modification, thereby preventing pyroptosis following PI(4,5)P2 treatment. Significant correlations were also observed between PI(4,5)P2 and NNMT, NNMT and RBP4, and RBP4 and GSDMD expression in the intestinal tissues from patients with CD. Our results indicated that PI(4,5)P2 ameliorates colitis by inhibiting IEC pyroptosis via NNMT-mediated RBP4 m6A modification. Thus, PI(4,5)P2 shows potential as a therapeutic target in CD.

Background: Vedolizumab (VDZ), a humanized monoclonal antibody that selectively inhibits the binding of the α4β7 integrin, has been approved for treating inflammatory bowel disease (IBD). Long-term safety studies of VDZ in clinical trials identified Clostridium difficile infection (CDI) as the major opportunistic infection. Objectives: We aimed to address the incidence and risk factors of C. difficile colonization (CDC) and CDI in a real-world setting among IBD patients treated with VDZ. Design: Retrospective multicenter study. Methods: We retrospectively included IBD patients who tested negative for C. difficile before initiating standard VDZ therapy at four tertiary hospitals from November 1, 2021, to November 31, 2023. The primary outcome was the occurrence of CDC after VDZ initiation, and the secondary outcome was the occurrence of CDI and severe CDI. Results: A total of 454 patients were included in the final analysis. The median follow-up time was 12.9 (8.2–16.3) months, and the study was followed for 2488.6 person-months. The CDC occurred in 28 patients (6.2%), including 23 (11.4%) patients with ulcerative colitis (UC; 18 asymptomatic carriers and 5 with symptomatic CDI) and 5 (2.0%) patients with Crohn’s disease (asymptomatic carriers). Multivariate analysis showed that age >40 years old and UC were independent risk factors for the occurrence of the CDC after VDZ initiation. The incidence of CDI was 1.1%, and all patients were able to continue VDZ therapy after receiving antibiotic treatment. No risk factors were found to be significantly associated with CDI. There were no cases of severe CDI or deaths within 30 days. Conclusion: The incidence of CDC after VDZ treatment was 6.2% and the majority of patients identified as asymptomatic carriers and were able to continue VDZ treatment. Age (>40 years old) and UC were the risk factors for CDC.

Background/Aims Data on the natural course of Chinese patients with ulcerative colitis (UC) was lacking. This study aimed to evaluate the natural history and prognosis of patients with UC in the past 15 years in China. Methods This cohort study included patients with UC in a tertiary hospital in southern China from 2007 to 2021 (cohort I: 2007–2011, cohort II: 2012–2016, cohort III: 2017–2021). Patients’ clinical characteristics and natural history were analyzed retrospectively. Results Of 1,139 included patients, 683 patients presented with proctitis or left-sided colitis at diagnosis and 38.5% of them (263/683) developed proximal disease extension. Fifty-eight percent of patients experienced relapse, chronic continuous and intermittent active course. Five patients (0.4%) developed colorectal tumors/dysplasia. The overall surgery rate was 8.6%, and the rates were 14.2%, 7.8%, and 8.0% in the 3 cohorts, respectively (P=0.059). Average time from diagnosis to surgery decreased from cohorts I to III (144 months vs. 36 months, P

BackgroundCrohn’s disease (CD) is an immune-mediated disorder characterized by immune cell infiltration that induces persistent chronic inflammation of the gastrointestinal tract. Programmed cell death (PCD) plays a critical role in the pathogenesis of CD. This study identified vital PCD-related genes in CD based on immune infiltration using bioinformatic analysis.MethodsWe obtained two CD datasets from the Gene Expression Omnibus (GEO) database and examined immune cell infiltration to investigate immune cell dysregulation in CD. PCD-related genes were retrieved from the GeneCards database. Based on the differentially expressed genes (DEGs) and PCD gene sets, PCD-related DEGs were identified. Candidate hub genes were identified using a protein-protein interaction (PPI) network, and their diagnostic effectiveness was predicted using receiver operating characteristic (ROC) curve analysis. Functional enrichment and immune infiltration analyses were used to assess the distinct roles of the hub genes. Finally, the miRWalk and ENCORI databases were used to predict which microRNAs (miRNAs) regulated the hub genes and to verify gene expression in CD colonic tissues via transcriptome sequencing.ResultsA total of 335 PCD-related DEGs and 3 hub genes (MMP1, SAA1, and PLAU) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses indicated the enrichment of these genes in the immune response. Infiltration analysis of immune cells showed abundant endothelial cells, plasma cells, dendritic cells, and monocytes in the CD samples. Based on the correlation analysis, the three hub genes were positively correlated with monocytes and negatively correlated with CD8 naïve T-cells. MMP1, SAA1, and PLAU correlated with the pathogenicity of CD and had good diagnostic value for CD. The three hub genes were highly expressed in the CD tissues, as confirmed using transcriptome sequencing.ConclusionThis study identified MMP1, SAA1, and PLAU as hub genes involved in PCD in patients with CD. These genes regulate immune cell function and their expression levels are closely related to immune cell infiltration. These findings provide novel insights into the mechanisms underlying CD pathogenesis. The identified PCD genes and regulatory miRNAs are potential biomarkers and therapeutic targets for CD.

Background: No head-to-head trial directly compares the effectiveness of vedolizumab (VDZ) and infliximab (IFX) in patients with ulcerative colitis (UC) who were naïve to biologic therapy. Objectives: We aimed to compare the clinical and endoscopic effectiveness of VDZ and IFX in biologic-naïve patients with UC in real-world settings. Design: It was a multicenter, observational, real-world cohort study conducted at five centers. Methods: Patients diagnosed with UC and treated with either IFX or VDZ as their first-line biologic therapy were retrospectively enrolled. Steroid-free remission, clinical response, clinical remission, and endoscopic healing at week 14 and week 52 were compared between the two groups after propensity score weighting. Results: A total of 199 patients (117 VDZ and 82 IFX) were included in the study. There were no significant differences in steroid-free remission (64.6% vs 56.1%, p = 0.224), clinical response (83.4% vs 73.4%, p = 0.086), or clinical remission (69.4% vs 60.1%, p = 0.174) at week 14. However, VDZ showed better results in steroid-free remission (67.5% vs 44.4%, p = 0.004), clinical response (69.7% vs 47.1%, p = 0.005), and clinical remission (67.5% vs 44.4%, p = 0.004) at week 52. In terms of endoscopic healing, VDZ was similar to IFX at week 14 (25.7% vs 17.4%, p = 0.185), but VDZ had a significantly higher rate at week 52 (29.5% vs 11.8%, p = 0.027). VDZ was found to be superior to IFX in therapeutic continuation (hazard ratio = 0.339, 95% CI: 0.187–0.614, p

Abstract Background Variations exist in the response of patients with Crohn’s disease (CD) to ustekinumab (UST) treatment, but the underlying cause remains unknown. Our objective was to investigate the involvement of immune cells and identify potential biomarkers that could predict the response to interleukin (IL) 12/23 inhibitors in patients with CD. Methods The GSE207022 dataset, which consisted of 54 non-responders and 9 responders to UST in a CD cohort, was analyzed. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the most powerful hub genes. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performances of these genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to estimate the proportions of immune cell types. These significantly altered genes were subjected to cluster analysis into immune cell-related infiltration. To validate the reliability of the candidates, patients prescribed UST as a first-line biologic in a prospective cohort were included as an independent validation dataset. Results A total of 99 DEGs were identified in the integrated dataset. GO and KEGG analyses revealed significant enrichment of immune response pathways in patients with CD. Thirteen genes (SOCS3, CD55, KDM5D, IGFBP5, LCN2, SLC15A1, XPNPEP2, HLA-DQA2, HMGCS2, DDX3Y, ITGB2, CDKN2B and HLA-DQA1), which were primarily associated with the response versus nonresponse patients, were identified and included in the LASSO analysis. These genes accurately predicted treatment response, with an area under the curve (AUC) of 0.938. T helper cell type 1 (Th1) cell polarization was comparatively strong in nonresponse individuals. Positive connections were observed between Th1 cells and the LCN2 and KDM5D genes. Furthermore, we employed an independent validation dataset and early experimental verification to validate the LCN2 and KDM5D genes as effective predictive markers. Conclusions Th1 cell polarization is an important cause of nonresponse to UST therapy in patients with CD. LCN2 and KDM5D can be used as predictive markers to effectively identify nonresponse patients. Trial registration: Trial registration number: NCT05542459; Date of registration: 2022-09-14; URL: https://www.clinicaltrials.gov .

This study aimed to elucidate the influence of various culture medium components, including carbon sources, nitrogen sources, inorganic salts, suspension agents, and temperature, on the mycelial growth characteristics of Phallus dongsun. Employing single-factor experiments and response surface methodology within glass Petri dishes, the research identified that carrot powder, soybean powder, and ZnSO4 notably enhanced the proliferation of aerial mycelium, significantly augmenting the growth rate of P. dongsun mycelium. The resultant mycelium was observed to be dense, robust, and fluffy in texture. In particular, ZnSO4 markedly accelerated the mycelium growth rate. Furthermore, xanthan gum was found to effectively modulate the medium’s viscosity, ensuring a stable suspension and facilitating nutrient equilibrium. The optimal cultivation temperature was determined to be 25°C, with mycelial growth ceasing below 5°C and mycelium perishing at temperatures exceeding 35°C. The optimal medium composition was established as follows: wheat starch 5 g/l, carrot powder 5 g/l, soybean powder 7.50 g/l, glucose 10 g/l, ZnSO4 0.71 g/l, NH4Cl 0.68 g/l, xanthan gum 0.5 g/l, and agar 20 g/l. Under these optimized conditions, the mycelium of P. dongsun exhibited a rapid growth rate (1.04 ± 0.14 mm/day), characterized by a thick, dense, and well-developed structure. This investigation provides a theoretical foundation for the conservation, strain selection, and breeding of P. dongsun.

Family farming plays a pivotal role in ensuring household food security and bolstering the resilience of food systems against climate change. Traditional agricultural practices are evolving into context-specific, climate-resilient systems such as family farming, homestead gardening, and urban agriculture. This study examines the ways in which family farming can foster climate-resilient food systems amidst climate vulnerabilities. A systematic literature review spanning the past 22 years was undertaken to develop a conceptual framework. From this review, 37 pertinent documents were identified, leading to the creation of a context-specific, climate-resilient food system framework. The research posits that family farming facilitates easy access to food and nutrition by capitalizing on family-sourced land, labor, and capital, and by securing access to technology and markets. Each facet of family farming is intricately linked with sustainability principles. Local adaptation strategies employed by climate-vulnerable households can diminish their vulnerability and augment their adaptive, absorptive, and transformative capacities, enabling them to establish a climate-resilient food system. The research further reveals that farming families employ a myriad of strategies to fortify their food systems. These include crop diversification, adjusting planting times, cultivating high-value crops and fish, planting fruit trees, rearing poultry and livestock, and leveraging their land, labor, and resources—including their homesteads—to access food and nutrition. This study endorses the climate-resilient family farming framework and offers multiple metrics for assessing the resilience of family farming in developing countries.

Summary: Background: Ustekinumab and vedolizumab are both effective for treating Crohn’s disease (CD). However, no head-to-head trials have been conducted thus far. We aimed to compare the effectiveness of ustekinumab and vedolizumab in CD patients either naïve or exposed to tumor necrosis factor-alpha inhibitors (TNFi). Methods: Patients treated with vedolizumab or ustekinumab for luminal CD were included from six centers in China from May 2020 to July 2023. Steroid-free remission, clinical remission, objective response, and remission at Weeks 26 and 52 were evaluated in a retrospective multicenter propensity score–weighted cohort. Findings: A total of 536 patients were included (386 ustekinumab, and 150 vedolizumab). After adjustment, ustekinumab showed higher rates of clinical remission (56.4% vs. 47.8%, P = 0.005), steroid-free remission (55.4% vs. 46.1%, P = 0.003), and objective response (67.8% vs. 42.7%, P

ABSTRACTThe world is witnessing a global increase in the urban population, particularly in developing Asian and African countries. Concomitantly, the global burden of non-communicable diseases (NCDs) is rising, markedly associated with the changing landscape of lifestyle and environment during urbanization. Accumulating studies have revealed the role of the gut microbiome in regulating the immune and metabolic homeostasis of the host, which potentially bridges external factors to the host (patho-)physiology. In this review, we discuss the rising incidences of NCDs during urbanization and their links to the compositional and functional dysbiosis of the gut microbiome. In particular, we elucidate the effects of urbanization-associated factors (hygiene/pollution, urbanized diet, lifestyles, the use of antibiotics, and early life exposure) on the gut microbiome underlying the pathogenesis of NCDs. We also discuss the potential and feasibility of microbiome-inspired and microbiome-targeted approaches as novel avenues to counteract NCDs, including fecal microbiota transplantation, diet modulation, probiotics, postbiotics, synbiotics, celobiotics, and precision antibiotics.