The metabolic determinants that distinguish Crohn's disease (CD) from ulcerative colitis (UC) and their roles in driving immune dysregulation remain elusive. We aimed to identify systemic metabolic signatures of inflammatory bowel disease (IBD) and elucidate the mechanistic link between metabolite availability and regulatory T cell (Treg) homeostasis. We performed untargeted LC-MS-based metabolomics on plasma from patients with CD (n = 17), UC (n = 13), and healthy controls (n = 15). Pathway enrichment and topology analysis were used to identify perturbed biological processes. The functional role of identified metabolites was validated using primary murine naive CD4+ T cell differentiation assays, Seahorse XF metabolic flux analysis, and siRNA-mediated knockdown. The therapeutic relevance was assessed in a DSS-induced murine model of colitis. Metabolomic profiling identified 175 significant differential metabolites, revealing a profound systemic depletion of fatty acids and a specific deficit in the fatty acid oxidation (FAO) pathway in CD patients. Palmitic acid and butyrate emerged as robust diagnostic biomarkers (AUC = 0.877-0.975). In vitro, butyrate dose-dependently promoted iTreg differentiation by increasing the oxygen consumption rate and maximal respiratory capacity. This effect was dependent on carnitine palmitoyltransferase 1A (CPT1A), as pharmacological or genetic inhibition of CPT1A-mediated FAO abolished butyrate's pro-differentiation capacity. In vivo, the ability of butyrate to attenuate colitis and promote colonic iTreg accumulation was significantly reversed by the CPT1 inhibitor etomoxir. CPT1A-mediated fatty acid oxidation is a critical metabolic pivot through which butyrate signals to maintain immune tolerance. The systemic loss of FAO intermediates in CD patients directly contributes to impaired iTreg development, identifying the butyrate-CPT1A axis as a potential target for precision metabolic intervention.

Adverse drug events (ADEs) are a major source of preventable harm. Inflammatory bowel disease (IBD) requires long-term multidrug management, making ADEs frequent and clinically significant. Extracting ADEs from electronic health records (EHRs) is central to pharmacovigilance but challenging due to overlapping disease activity and drug toxicity, complex polypharmacy, and heterogeneous Chinese clinical narratives. Conventional named entity recognition (NER)–relation extraction (RE) pipelines and fixed vocabularies often miss evolving expressions. Large language models (LLMs) show promise for ADE detection[1], yet most current approaches are not end-to-end and rely on constrained annotation schemas, limiting scalability and real-world generalizability in IBD. We developed an end-to-end LLM pipeline for open-vocabulary detection of ADEs following treatment with corticosteroids, immunomodulators, biologics, and small-molecule inhibitors in IBD. A total of 8406 IBD notes (Peking Union Medical College Hospital = 7936; Zunyi Medical University = 216; Guizhou Provincial People’s Hospital = 254) were annotated. The system directly reads clinical text, expands candidate events through knowledge-augmented retrieval, and normalizes outputs to MedDRA to ensure reliable and scalable pharmacovigilance. It integrates (i) a high-recall pre-screening module to retain plausible ADE signals while minimizing unnecessary LLM calls, (ii) graph-based retrieval over a drug–event bipartite network to broaden candidate scope, (iii) ensemble LLM inference guided by a self-learned instruction set, and (iv) ontology-aware normalization aligning terms with MedDRA and ensuring cross-center consistency. In the binary classification task of detecting the presence of any AE within a patient’s record, we ultimately select HYBRID + LR model for subsequent analyses which achieved Area Under the Curve (AUC) of 0.809 in CD test set(Figure1A), and 0.828 in UC test set(Figure1B). Our model then achieved the good performance on identifying drug-AE pairs: CD test set an F1-score of 0.577, a recall of 0.706, and a precision of 0.488 for the CD cohort; For the UC cohort, the model achieved an overall F1-score of 0.545, recall of 0.624, and precision of 0.484. We identified the top five ADEs in the IBD cohort: bone marrow suppression (n = 137), liver function abnormality (n = 134), C.difficile infection (n = 73), rash (n = 71), and paresthesia (n = 70). The pipeline enables near real-time ADE detection and supports risk prediction in IBD. Embedding LLM-based pharmacovigilance in EHRs may deliver continuous safety surveillance and bridge clinical practice with regulatory science for data-driven, real-time monitoring. Reference: 1. Syrowatka A, Song W, Amato MG, et al. Key use cases for artificial intelligence to reduce the frequency of adverse drug events: a scoping review. Lancet Digit Health. Feb 2022;4(2):e137-e148. doi:10.1016/s2589-7500(21)00229-6 Conflict of interest: Ms. Wei, Yuge: None Ronghao, Li: None Gechong, Ruan: None Bai, Xiaoyin: None Yinghao, Sun: None Dejun, Cui: None Fang, Yan: None Huijun, Shu: None Xuemin, Yan: None Honglei, Liu: None Yang, Hong: None

Background: Patients with pancreatitis may be at increased risk of cardiovascular disease (CVD), but the biochemical mechanisms underlying this risk are not fully defined. Inflammatory biomarkers may provide valuable prognostic information. Methods: We retrospectively analyzed 180 patients with pancreatitis (Jan 2021-Dec 2023). Serum levels of interleukin-8 (IL-8), procalcitonin (PCT), tumor necrosis factor-a (TNF-a), and C-reactive protein (CRP) were quantified using enzyme-linked immunosorbent assay (ELISA) and routine laboratory tests. Logistic regression was applied to identify independent biochemical predictors of CVD, and a risk prediction model was developed and validated using ROC curve analysis. Results: IL-8, PCT, CRP and age emerged as independent predictors of CVD occurrence in pancreatitis patients (all P< 0.05). The biochemical prediction model demonstrated high accuracy, with an AUC of 0.893 in the training set and 0.978 in the validation set. Sensitivity and specificity exceeded 85% across datasets. Conclusions: This study highlights the clinical and laboratory significance of inflammatory biomarkers in pancreatitis. The proposed biochemical model provides a reliable tool for predicting cardiovascular risk and may contribute to improved laboratory-guided risk assessment and patient management.

Intestinal inflammation and barrier disruption induced by high-altitude exposure are recognized contributors to colitis. Although artificial-enzyme-engineered Bifidobacterium longum (AE-BL) has demonstrated therapeutic potential against inflammatory bowel disease, the precise mechanisms remain elusive. The present study aimed to assess the efficacy of AE-BL against high-altitude colitis and to elucidate its underlying mechanisms. AE-BL was generated through the assembly of single-atom enzymes (SAzymes) with Bifidobacterium longum (BL). In vivo investigations involved housing mice in a hypobaric hypoxic chamber to replicate high-altitude conditions, followed by AE-BL administration. After seven days, colon specimens were collected for histopathological evaluation, inflammatory and ferroptosis-related parameter analyses, and the expression of glycerol-3-phosphate dehydrogenase 2 (GPD2), tight junction proteins, and ferroptosis markers. An in vitro colitis model was also established using Caco-2 cells subjected to lipopolysaccharide (LPS) and hypoxia, followed by AE-BL treatment. Administration of AE-BL markedly ameliorated high-altitude-induced colitis in mice, as reflected by attenuated weight loss, increased colon length, reduced disease activity index (DAI), and diminished histopathological injury. Pro-inflammatory cytokine production was suppressed, and intestinal barrier integrity was preserved. Mechanistic investigations indicated that the protective actions of AE-BL were potentially mediated through suppression of GPD2-driven ferroptosis. Under hypoxic conditions, AE-BL significantly reduced ferroptosis in colon tissue and colonic epithelial cells both in vivo and in vitro, thereby alleviating inflammation and restoring intestinal barrier function.

Background Liver fibrosis, a key feature of chronic liver diseases, involves dysregulated extracellular matrix accumulation, and whether quercetin alleviates fibrosis by targeting 5-lipoxygenase (ALOX5) in Kupffer cells to modulate macrophage polarization remains unclear. Methods Using a dimethylnitrosamine (DMN)-induced liver fibrosis mouse model, mice were treated with quercetin (20, 50, 80 mg/kg/day) or controls. Hepatic fibrosis was evaluated via histopathology (HE/Masson staining), serum liver function markers (ALT, AST, TBIL), and Suzuki scoring. Kupffer cells and macrophages were isolated for flow cytometry, co-culture assays, and molecular analyses (RT-qPCR, Western blot). ALOX5 expression was manipulated using shRNA lentivirus or overexpression vectors to validate its role in quercetin’s mechanism. Results Quercetin dose-dependently reduced hepatic inflammatory cell infiltration, collagen deposition, and liver function injury (p < 0.01 or p < 0.001). Mechanistically, quercetin suppressed ALOX5 expression predominantly in Kupffer cells, promoting macrophage polarization from pro-inflammatory M1 (iNOS+) to anti-inflammatory M2 (CD206+) phenotypes (p < 0.01 or p < 0.001). Co-culture experiments showed ALOX5 knockdown in Kupffer cells mimicked the polarization effects of quercetin (p < 0.001), while ALOX5 overexpression promoted M1 polarization (p < 0.001). In vivo, quercetin did not show further antifibrotic benefit when ALOX5 was silenced (p > 0.05), suggesting that ALOX5 is involved in its antifibrotic mechanism. Conclusions Quercetin alleviates liver fibrosis by targeting ALOX5 in Kupffer cells to promote M2 macrophage polarization. These findings suggest that ALOX5 may represent a potential therapeutic target and supports the clinical application of quercetin.

Background: Crohn’s disease (CD) has an evolving course and may progress to stricturing or penetrating complications, intestinal surgery, and treatment escalation. Existing models often rely on baseline or time-agnostic data, limiting risk assessment during routine follow-up. We developed and externally validated a time-updated model CD-ProFormer for prediction of CD progression using longitudinal electronic health records (EHRs). Methods: We assembled multicenter EHR cohorts: a development cohort from Peking Union Medical College Hospital (PUMCH) (761 patients; 11,984 visits) and external validation cohorts from Guizhou (74 patients; 510 visits) and Nanjing (271 patients; 3934 visits). Using each visit as index, CD-ProFormer, a time-aware Transformer that used EHR trajectories to predict 1-, 3-, and 5-year risks of behavior progression, CD-related intestinal surgery, and major medication initiation. Global SHAP, temporal SHAP, decision curve analysis, and representative cases assessed interpretability and clinical utility. Findings: CD-ProFormer showed strong internal discrimination for behavior progression, with AUROCs of 0.979, 0.951, and 0.910 at 1, 3, and 5 years; macro-area under the curve for first-progression time-window classification was 0.811. External validation remained acceptable, with AUROCs of 0.725–0.879 in Guizhou and 0.856–0.913 in Nanjing, consistently exceeding recurrent baselines. Performance for surgery and medication initiation was comparable to recurrent models and better than conventional models. Interpretation: In this prognostic study, CD-ProFormer enabled time-updated, horizon-specific prediction of CD behavior progression, with surgery and medication initiation assessed in parallel. These findings suggest that prognosis in CD can be updated at follow-up visits using routinely collected longitudinal data and may support risk stratification, monitoring intensity, and timely treatment planning.

Chinese herbal compound prescriptions have demonstrated efficacy in preventing and treating liver fibrosis (LF), though their mechanisms remained unclear. This study is aimed at identifying diagnostic biomarkers and elucidating the molecular mechanism underlying the effects of the TCM prescription on LF. LF-related datasets (GSE162694, GSE84044, and GSE136103) were obtained from a public database. Active ingredient-related target genes (AIRTGs) and LF-related target genes (LFRTGs) were intersected with differentially expressed genes (DEGs) between the LF and normal control (NC) group to select candidate genes. Subsequently, biomarkers for LF diagnosis were determined using Boruta and LASSO algorithms, receiver operating characteristic (ROC), and expression analyses. A nomogram was constructed to evaluate the capability of these biomarkers for predicting LF risk. Furthermore, GSEA and immunoinfiltration analysis were conducted, along with single-cell analysis to identify relevant cell types in LF. COL3A1 and ALOX5 were identified as diagnostic biomarkers for LF, and the nomogram was proven effective in predicting LF risk. GSEA showed that COL3A1 might play vital roles in cell growth and differentiation, extracellular matrix organization, and cell-matrix interactions. The functions of ALOX5 might be associated with cell-cell interaction, cytoskeletal regulation, and so forth. Immunoinfiltration analysis revealed that activated dendritic cells (DCs) were highly infiltrated, whereas monocytes were less infiltrated in LF. COL3A1 expression was positively correlated with monocytes, but both COL3A1 and ALOX5 showed negative correlations with activated DCs. Single-cell analysis identified nine cell types, with macrophages, B cells, and mesenchyme cells emerging as key cell types. Cell communication analysis demonstrated stronger interactions between macrophages and mesenchymal cells in the LF group. Pseudotime analysis unveiled that the expression of ALOX5 was upregulated and then downregulated, whereas that of COL3A1 was gradually downregulated during the midstage and stabilized thereafter. COL3A1 and ALOX5 may serve as biomarkers for the diagnosis and treatment of LF with Chinese herbal compound prescriptions, contributing to more accurate diagnosis and improved LF therapy.

SIRT1 plays a crucial role in the production of reactive oxygen species (ROS) and ischemia/reperfusion (I/R), yet the upstream mechanisms that directly regulate SIRT1 expression during intestinal I/R remain unclear. Recent studies have shown that noncoding RNAs, such as circular RNAs (circRNAs), are important players in physiological and pathological processes based on their multiple regulatory roles in gene expression. This study aimed to elucidate the role of SIRT1 in intestinal mucosa barrier damage and to investigate the regulation of SIRT1 by circRNA sponges. Third-degree burn mouse model was used. Before third-degree burn, mice were injected with miR-624-5pagomir or Circ_Slc7a11 siRNA intravenously. In addition, hypoxia reoxidation (H/R) was performed in vitro on Caco-2 cells to mimic an in vivo model of intestinal mucosa barrier damage. In vitro, SIRT1 deficiency significantly reduced H/R-induced ROS overproduction and acetylation levels by decreasing mitochondrial superoxide anion (O2-) levels, inhibiting NADPH oxidase activity, and enhancing antioxidant enzyme expression. miR-624-5p was pinpointed as a direct regulator of SIRT1 expression. The circRNA transcribed from the Slc7a11 gene, called Circ_Slc7a11, regulated SIRT1 expression as a sponge of miR-624-5p. Circ_Slc7a11 silencing or miR-624-5p overexpression downregulated SIRT1 expression, and reduced oxidative stress and acetylation levels to alleviate intestinal mucosa barrier damage. Elevated Circ_Slc7a11 and decreased miR-624-5p levels were observed in mice with intestinal I/R. Our results reveal the key role of Circ_Slc7a11/miR-624-5p/SIRT1 signaling pathway in regulating oxidative stress and acetylation in intestinal mucosa barrier damage.

Objective To evaluate the relationship between essential hypertension and the risk of colorectal tumor through a meta-analysis.Methods Chinese and English literatures about the relationship between essential hypertension and colorectal tumor published so far were searched in China National Knowledge Infrastructure(CNKI),Wanfang Database,VIP Database,Chinese Medical Journal Database,PubMed,Web of Science,The Cochrane Library and Embase Database.Information extraction and quality evaluation were carried out on the included documents,statistical analysis was carried out by using RevMan 5.3 software,forest map was drawn,and sensitivity and publication bias were detected.Results Six articles including 5 530 369 participants were finally included.Meta-analysis showed that the risk of colorectal tumor in patients with essential hypertension increased(OR=1.71,95％CI 1.65-1.77,P＜0.001).The results of sensitivity analysis showed that the results were stable,and the publication bias analysis showed that there was no significant publication bias.Conclusion There is a correlation between essential hypertension and colorectal tumor.

BACKGROUND AND AIM:High-altitude environments are characterized by low oxygen and reduced low pressure, which impose significant physiological challenges on organisms. Among various adaptive systems, the intestinal flora plays a crucial role in maintaining gut health and barrier integrity function under such conditions. This study aimed to elucidate the regulatory mechanisms of intestinal flora in high-altitude environments, focusing on downregulating intracellular Bone Morphogenetic Protein 4 (BMP4) to influence glycolysis metabolism, thereby affecting intercellular communication of the intestinal mucosal barrier and matrix remodeling. METHODS:High-altitude mouse intestinal flora composition and function were analyzed using 16S rRNA and metagenomic sequencing. Additionally, single-cell sequencing was employed to examine cell population communication and gene expression differences between normal and high-altitude mouse intestinal tissues. RESULTS:Single-cell sequencing showed significantly reduced interactions between intestinal fibroblasts and epithelial cells in high-altitude mice, accompanied by a marked increase in BMP4 expression. Overexpression of BMP4 was found to activate the glycolysis pathway. Gut microbiota metabolites, including secondary bile acids, lactic acid, and butyrate, exhibited protective effects on hypoxia-induced intestinal mucosal barrier injury, with butyrate showing the most prominent effect. Under hypoxic conditions, butyrate suppressed the BMP4/glycolysis pathway, thereby alleviating hypoxia-induced intestinal mucosal barrier damage. CONCLUSION:This study uncovered a novel mechanism by which the gut microbiota in high-altitude environments modulate glycolysis metabolism through BMP4 downregulation, thereby affecting intercellular communication and matrix remodeling within the intestinal mucosal barrier.

BACKGROUND:This study investigated a circRNA (Circ_Atp8a1) in regulating intestinal epithelial repair in intestinal mucosal barrier damage. METHODS:A mouse model of intestinal mucosal barrier damage caused by burn injury was constructed. Skin and intestinal histopathologic changes in injured and control mice were compared. Glycolytic enzyme protein expression, lactate production, and glucose consumption in intestinal tissues were detected. Microarray analysis was used to screen differentially expressed circRNAs in mucosal tissues, and RT-qPCR, Sanger sequencing, RNAse R test, nucleoplasmic isolation experiments, and fluorescence in situ hybridization (FISH) were used to characterize the circular structure and localization of Circ_Atp8a1. In Caco-2 cells, adenoviral overexpression vector and small interfering RNA (siRNA) were constructed to regulate Circ_Atp8a1 expression. Cell proliferation and migration were detected by combining with the experiments of CCK-8, EdU, wound healing, and Transwell. The interaction between Circ_Atp8a1 and miR-200b-3p was investigated by dual luciferase reporter assay, RNA pull-down assay, and FISH assay. The target gene of miR-200b-3p was predicted and validated. Finally, the effects of intraperitoneal injection of KD-Circ_Atp8a1 and OE-Circ_Atp8a1 on intestinal mucosal damage in burned mice were observed by in vivo experiments. RESULTS:Mice with burn-induced intestinal mucosal damage had higher CMDI scores, increased expression of glycolytic enzymes in intestinal tissues, and altered glycolytic processes. A total of 308 aberrantly expressed circRNAs were screened, among which Circ_Atp8a1 was significantly down-regulated and mainly distributed in cytoplasm and jejunal crypts. In Caco-2 cells, overexpression of Circ_Atp8a1 inhibited cell proliferation, migration, and glycolysis, and knockdown of Circ_Atp8a1 did the opposite. Circ_Atp8a1 acted as a sponge for miR-200b-3p, which targeted and inhibited IGF2, which affected glycolysis-related metrics. Circ_Atp8a1 regulated IGF2 indirectly through miR-200b-3p, which in turn regulated intestinal mucosal damage. in vivo experiments showed that overexpression of Circ_Atp8a1 could inhibit miR-200b-3p expression, promote IGF2 expression, reduce intestinal mucosal damage and decrease mucosal permeability. CONCLUSION:Circ_Atp8a1 plays a key regulatory role in the process of intestinal mucosal damage and affects the process of glycolysis through adsorption of miR-200b-3p to regulate IGF2. It is expected to be a new target for the treatment of intestinal mucosal damage.

BackgroundNUP62, a key component of the nuclear pore complex, is closely associated with cellular functions and cancer progression. However, its expression patterns, prognostic value, and relationship with tumour immunity and drug sensitivity across multiple cancers have not been systematically studied. This study used multi-omics analyses combined with experimental validation in gastric cancer to investigate the expression, functional characteristics, and clinical relevance of NUP62 in cancer.MethodsData from TCGA, GTEx, and CPTAC databases were used to analyse the expression, mutation characteristics, and clinical associations of NUP62. Tools such as SangerBox, TIMER 2.0, and GSEA were employed to evaluate the relationship between NUP62 and the tumour immune microenvironment, as well as its involvement in signalling pathways. Immunohistochemistry and RT-PCR were used to validate the expression of NUP62 in gastric cancer tissues. PRISM and CTRP databases were utilised to assess the correlation between NUP62 expression and drug sensitivity.ResultsNUP62 was significantly upregulated in multiple cancers and was associated with poor prognosis in cancers such as clear cell renal carcinoma (KIRC), lower-grade glioma (LGG), and adrenocortical carcinoma (ACC), while playing a protective role in others, such as bladder cancer (BLCA) and stomach cancer (STAD). Functional analyses showed that NUP62 is involved in cell cycle regulation, DNA damage repair, and tumour immunity. High NUP62 expression was significantly correlated with increased infiltration of immune cells, such as macrophages and T cells, and a higher response rate to immunotherapy. Drug sensitivity analysis identified NUP62 as a marker of sensitivity to various chemotherapeutic agents. Validation experiments demonstrated that NUP62 mRNA and protein levels were significantly higher in gastric cancer tissues than in adjacent normal tissues.ConclusionsNUP62 plays a critical role in multiple cancers and shows potential as a biomarker for cancer diagnosis, prognosis, and therapeutic response prediction. Its role in tumour immunity and signalling pathways highlights its potential as a target for immunotherapy and precision medicine.

Worldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC. A DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H2O2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance. DSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P < 0.05). In the DSS-induced mouse model, the expression of miR-125a-5p rebounded and ferroptosis was inhibited after Rh2 treatment (all P < 0.05). Inhibition of miR-125a-5p or upregulation of SP1 expression counteracted the protective effects of Rh2 on UC mice and ferroptosis cell models (all P < 0.05). Rh2 mitigated DSS-induced colitis in mice and restrained ferroptosis by targeting miR-125a-5p. Downregulating miR-125a-5p or elevating SP1 could counteract the protective impacts of Rh2 on ferroptotic cells. The findings convey that Rh2 has a latent application value in the treatment of UC.

Hypobaric hypoxia, commonly experienced at elevated altitudes, presents significant physiological challenges. Our investigation is centered on the impact of the bromodomain protein 4 (BRD4) under these conditions, especially its interaction with the Wnt/β-Catenin pathway and resultant effects on glycolytic inflammation and intestinal barrier stability. By combining transcriptome sequencing with bioinformatics, we identified BRD4's key role in hypoxia-related intestinal anomalies. Clinical parameters of altitude sickness patients, including serum BRD4 levels, inflammatory markers, and barrier integrity metrics, were scrutinized. In vitro studies using CCD 841 CoN cells depicted expression changes in BRD4, Interleukin (IL)-1β, IL-6, and β-Catenin. Transepithelial electrical resistance (TEER) and FD4 analyses assessed barrier resilience. Hypoxia-induced mouse models, analyzed via H&E staining and Western blot, provided insights into barrier and protein alterations. Under hypoxic conditions, marked BRD4 expression variations emerged. Elevated serum BRD4 in patients coincided with intensified Wnt signaling, inflammation, and barrier deterioration. In vitro, findings showed hypoxia-induced upregulation of BRD4 and inflammatory markers but a decline in Occludin and ZO1, affecting barrier strength—effects mitigated by BRD4 inhibition. Mouse models echoed these patterns, linking BRD4 upregulation in hypoxia to barrier perturbations. Hypobaric hypoxia-induced BRD4 upregulation disrupts the Wnt/β-Catenin signaling, sparking glycolysis-fueled inflammation and weakening intestinal tight junctions and barrier degradation.

In this study, we investigated the role of hypoxia in the development of chronic inflammatory bowel disease (IBD), focusing on its impact on the HIF-1α signaling pathway through the upregulation of lipocalin 2 (LCN2). Using a murine model of colitis induced by sodium dextran sulfate (DSS) under hypoxic conditions, transcriptome sequencing revealed LCN2 as a key gene involved in hypoxia-mediated exacerbation of colitis. Bioinformatics analysis highlighted the involvement of crucial pathways, including HIF-1α and glycolysis, in the inflammatory process. Immune infiltration analysis demonstrated the polarization of M1 macrophages in response to hypoxic stimulation. In vitro studies using RAW264.7 cells further elucidated the exacerbation of inflammation and its impact on M1 macrophage polarization under hypoxic conditions. LCN2 knockout cells reversed hypoxia-induced inflammatory responses, and the HIF-1α pathway activator dimethyloxaloylglycine (DMOG) confirmed LCN2's role in mediating inflammation via the HIF-1α-induced glycolysis pathway. In a DSS-induced colitis mouse model, oral administration of LCN2-silencing lentivirus and DMOG under hypoxic conditions validated the exacerbation of colitis. Evaluation of colonic tissues revealed altered macrophage polarization, increased levels of inflammatory factors, and activation of the HIF-1α and glycolysis pathways. In conclusion, our findings suggest that hypoxia exacerbates colitis by modulating the HIF-1α pathway through LCN2, influencing M1 macrophage polarization in glycolysis. This study contributes to a better understanding of the mechanisms underlying IBD, providing potential therapeutic targets for intervention.

Background This study investigates the molecular mechanisms behind firmicutes-mediated macrophage (Mψ) polarization and glycolytic metabolic reprogramming through HIF-1α in response to intrinsic mucosal barrier injury induced by high-altitude hypoxia. Methods Establishing a hypoxia mouse model of high altitude, we utilized single-cell transcriptome sequencing to identify key cell types involved in regulating intestinal mucosal barrier damage caused by high-altitude hypoxia. Through proteomic analysis of colonic tissue Mψ and metabolomic analysis of Mψ metabolites, we determined crucial proteins and metabolic pathways influencing intestinal mucosal barrier damage induced by high-altitude hypoxia. Mechanistic validation was conducted using RAW264.7 Mψ in vitro by assessing cell viability with CCK-8 assay following treatment with different metabolites. The hypoxia mouse model was further validated in vivo by transplanting gut microbiota of Firmicutes. Histological examinations through H&E staining assessed colonic cell morphology and structure, while the FITC-dextran assay evaluated intestinal tissue permeability. Hypoxia probe signal intensity in mouse colonic tissue was assessed via metronidazole staining. Various experimental techniques, including flow cytometry, immunofluorescence, ELISA, Western blot, and RT-qPCR, were employed to study the impact of HIF-1α/glycolysis pathway and different gut microbiota metabolites on Mψ polarization. Results Bioinformatics analysis revealed that single-cell transcriptomics identified Mψ as a key cell type, with their polarization pattern playing a crucial role in the intestinal mucosal barrier damage induced by high-altitude hypoxia. Proteomics combined with metabolomics analysis indicated that HIF-1α and the glycolytic pathway are pivotal proteins and signaling pathways in the intestinal mucosal barrier damage caused by high-altitude hypoxia. In vitro cell experiments demonstrated that activation of the glycolytic pathway by HIF-1α led to a significant upregulation of mRNA levels of IL-1β, IL-6, and TNFα while downregulating mRNA levels of IL-10 and TGFβ, thereby promoting M1 Mψ activation and inhibiting M2 Mψ polarization. Further mechanistic validation experiments revealed that the metabolite butyric acid from Firmicutes bacteria significantly downregulated the protein expression of HIF-1α, GCK, PFK, PKM, and LDH, thus inhibiting the HIF-1α/glycolytic pathway that suppresses M1 Mψ and activates M2 Mψ, consequently alleviating the hypoxic symptoms in RAW264.7 cells. Subsequent animal experiments confirmed that Firmicutes bacteria inhibited the HIF-1α/glycolytic pathway to modulate Mψ polarization, thereby mitigating intestinal mucosal barrier damage in high-altitude hypoxic mice. Conclusion The study reveals that firmicutes, through the inhibition of the HIF-1α/glycolysis pathway, mitigate Mψ polarization, thereby alleviating intrinsic mucosal barrier injury in high-altitude hypoxia.

We conducted an investigation to determine the potential of mitochondrial-related genes as diagnostic biomarkers in ulcerative colitis (UC), while also examining their association with immune cell infiltration. To achieve this, we acquired four datasets pertaining to UC, which included gene expression arrays and clinical data, from the GEO database. Subsequently, we selected three signature genes (PDK2, CHDH, and ALDH5A1) to construct a diagnostic model for UC. The nomogram and ROC curves exhibited exceptional diagnostic efficacy. Following this, quantitative real-time polymerase chain reaction and western blotting assays validated the decreased mRNA and protein expression of PDK2, CHDH, and ALDH5A1 in the model of UC cells and dextran sulfate sodium salt (DSS)-induced mice colitis tissues, aligning with the findings in the risk model. This investigation suggested a negative correlation between the expression of ALDH5A1, CHDH, and PDK2 and the infiltration of M1 macrophages. Then, immunofluorescence analysis confirmed the augmented expression of CD86 in the tissue of mice subjected to DSS, while a diminished expression of ALDH5A1, CHDH, and PDK2 was observed. Consequently, it can be inferred that targeting mitochondria-associated genes, namely PDK2, CHDH, and ALDH5A1, holds potential as a viable strategy for prognostic prediction and the implementation of immune therapy for UC.

Various factors, including fatty liver and macrophage alterations, influence colorectal cancer (CRC). This study explores the mechanistic role of fatty liver in CRC progression, focusing on macrophage polarization and lipid metabolism. A murine fatty liver model was created with a high-fat diet (HFD), and CRC was induced using AOM and DSS. Single-cell transcriptome sequencing (scRNA-seq) identified MAPKAP1 as a critical gene promoting CRC via M2 macrophage polarization and lipid metabolism reprogramming. Prognosis analysis on the TCGA-CRC dataset confirmed MAPKAP1′s significance. In vitro and in vivo experiments demonstrated that EVs from fatty liver cells enhanced MAPKAP1 expression, accelerating CRC development and metastasis. HFD exacerbated CRC, but fatty acid inhibitors delayed progression. Fatty liver upregulates MAPKAP1, driving M2 macrophage polarization and lipid metabolism changes, worsening CRC. These findings suggest potential therapeutic strategies for CRC, particularly targeting lipid metabolism and macrophage-mediated tumor promotion.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic gastrointestinal (GI) tract disorder with an uncertain etiology. Several studies have documented the presence of vitamin and mineral deficiencies among individuals with IBD, examining their impact on symptoms, quality of life, and demonstrating considerable variability in clinical significance. Bibliometric software and clinical data were used to explore the current state of research on vitamin D in the development of inflammatory bowel disease (IBD). CiteSpace 6.2.R4 was used for the analysis and visualization of various aspects including publication years, countries, institutions, journals/cited journals, authors/cited authors, references, and keywords. A retrospective analysis was conducted on a cohort of 77 patients with IBD who underwent 25-OH-vitamin D, blood routine, biochemical tests, and colonoscopy. A total of 1,322 records were acquired. The substantial increase was observed between 2017 and 2022. It was determined that the journal NUTRIENTS exhibited the highest level of productivity, while GASTROENTEROLOGY emerged as the most frequently cited journal. In terms of influence, the United States demonstrated the greatest impact, boasting the highest number of publications and centrality. Harvard University emerged as the most prolific institution. Cantorna, Margherita T emerged as the most prominent author in terms of both publication count and citations received. Respectively, the articles authored by Ananthakrishnan AN were found to have the highest frequency and centrality of cited references. The primary subjects of interest pertaining to vitamin D in IBD encompassed "bone mineral density," "vitamin D deficiency," "vitamin D receptor," and "risk factors". The keyword "osteoporosis" exhibited the most significant citation burst, and the most emerging keyword was identified as "gut microbiota." A total of 42 patients (54.5%) exhibiting vitamin D deficiency were categorized as the deficiency group, while the remaining 35 patients (45.5%) were classified as the non-deficient group. Patients in the deficiency group demonstrated significantly decreased levels of serum albumin compared to those in the non-deficient group. Furthermore, a negative correlation was observed between serum vitamin D levels and C-reactive protein (CRP) levels. Additionally, findings from colonoscopy examinations indicated that the administration of vitamin D supplements may potentially alleviate inflammation in the colon. This investigation is to discover new knowledge regarding potential partnerships and collaborative institutions, emerging areas of interest, and cutting-edge research frontiers in the field. Patients with moderate to severe forms of IBD require intensified monitoring to assess the need for vitamin D supplementation. As a result, this study provides valuable guidance for further exploration and implementation of vitamin D in the treatment of IBD.