Clinical studies demonstrated a correlation between sleep dysfunction and intestinal diseases. However, the detailed interactions and underlying mechanisms linking sleep disruption to intestinal microenvironment remain poorly understood. We employed the Curling Prevention by Water (CPW) paradigm to establish a mouse model of sleep deprivation (SD) for durations ranging from 0 to 96 h. The dynamic changes in the intestinal microenvironment were systematically profiled using multi-omics approaches, including metagenomic sequencing, untargeted metabolomics and RNA sequencing. The causal role of microbial dysbiosis and the underlying mechanisms were further investigated using germ-free mice, fecal microbiota transplantation (FMT), flow cytometry, and targeted intervention. The intestinal microenvironment was highly sensitive to SD. Distinct microbial communities and metabolite profiles were observed among brief SD (< 24 h of SD), prolonged SD (24–96 h of SD) and control. Brief SD triggered a self-regulatory response of the gut microbiota, characterized by an increase in certain beneficial bacteria (e.g., Parabacteroides goldsteinii). In contrast, prolonged SD shaped a pro-inflammatory microbial structure, characterized by reduced Akkermansia muciniphila and enriched Pseudomonadota. Multi-omics analysis revealed that SD significantly inhibited microbial bile acid metabolism, particularly taurodeoxycholic acid (TDCA), and impaired intestinal barrier function while suppressing the intestinal immune response to bacteria antigens. Mechanistically, SD exacerbated intestinal barrier damage by inhibiting the TDCA/group 3 innate lymphoid cells (ILC3)/IL-22 axis. Supplementation with TDCA effectively restored ILC3 function, IL-22 production, and barrier integrity in SD mice. Furthermore, FMT from patients with sleep dysfunction significantly disturbed intestinal microenvironment and increased serum cortisol by regulating gut microbiota and inhibiting TDCA/ILC3/IL-22 axis. This study dynamically delineates how SD disrupts intestinal homeostasis by reshaping the gut microbiota and suppressing the TDCA/ILC3/IL-22 axis. These findings provide novel mechanistic insights and identify potential therapeutic targets for sleep dysfunction-associated intestinal complications.

BACKGROUND Perineal small bowel fistula (PSF) is a highly debilitating complication of radical pelvic malignancy resections. It is typically driven by empty pelvis syndrome (EPS) and chronic adhesive disease. Current therapeutic guidelines lack standardization. AIM To evaluate an etiology-driven surgical algorithm, where procedures are chosen based on the underlying mechanism, aiming to improve closure rates. METHODS Retrospective cohort analysis was performed on 28 consecutive patients who underwent definitive repair for complex PSF. Patients were stratified into two surgical groups based on etiology: Group 1 (n = 15) underwent modified pelvic floor reconstruction for structural defects or EPS; group 2 (n = 13) underwent internal intestinal plication for extensive adhesions or tumor recurrence. Overall survival was calculated from the date of definitive surgery to the last follow-up or death. RESULTS The study cohort (mean age 56.6 years) included patients with rectal (35.7%), gynecological (35.7%), and various other pelvic malignancies. There were no significant baseline demographic differences between the groups. A significant correlation was observed between fistula etiology and surgical strategy (P = 0.02). While reconstruction was the exclusive surgical approach for patients with EPS (100%), plication was predominantly utilized for cases of tumor recurrence (66.7%). The overall fistula closure rate was 89.3% (25/28), showing no significant difference between group 1 (86.7%) and group 2 (92.3%; P = 1.0). However, group 2 experienced a significantly longer mean time to postoperative flatus (6.8 days vs 4.2 days; P = 0.002). The median follow-up time for the entire cohort was 34.5 months (range: 9.0-107.0 months). Overall survival was comparable across the two surgical groups (32.0 months vs 37.0 months; P = 0.66). CONCLUSION Managing complex PSFs requires a tailored approach. Employing an etiology-driven strategy, specifically pelvic floor reconstruction for structural voids (EPS) and internal intestinal plication for “frozen” adhesive conditions, achieves > 89% closure rates with acceptable morbidity.

Objective: Hypertrophied mesenteric adipose tissue (MAT) wrapped around the inflamed intestine, also known as creeping fat (CrF), is a classic pathological characteristic of Crohn’s disease (CD). Recent studies revealed that the abnormal mesentery in CD exhibits a white-to-beige transformation (known as white adipose browning), which may be a compensatory mechanism for disease attenuation. However, its underlying causes and mechanisms remain unknown. Methods: The beige MAT samples from patients with CD and normal white MAT samples from patients without CD were collected, and targeted metabolome analysis was performed. Interleukin-10 gene knockout (IL-10−/−) and 2,4,6-trinitrobenzenesulphonic acid solution (TNBS)-induced colitis mice were used to evaluate the effects of kynurenic acid (KYNA) on mesenteritis and colitis. Mesenteric explants and adipocytes were collected and cultured to assess the effects of KYNA on adipose tissue browning and macrophage inflammation. Results: Targeted metabolomic sequencing revealed that KYNA exhibited the highest level of upregulation in the beige MAT of CD, which was tightly correlated with the browning marker UCP-1, inflammatory factors, and adipokines. In vivo experiments demonstrated that KYNA triggered the white-to-beige transformation of MAT in IL-10−/− and TNBS-induced colitis mice, which further alleviated mesenteritis and colitis. Additionally, mesenteric explants and adipocytes displayed a browning phenotype with KYNA co-incubation, and their supernatants significantly induced M2 macrophage polarization and inhibited inflammation. Mechanistically, KYNA induced MAT browning and regulated disease procession of CD via GPR35-ERK1/2-PGC-1α signaling pathway. Conclusions: This study provides novel insights into the browning transformation of the mesentery in CD and suggests a potential approach for clinical therapy.

Crohn’s disease (CD) is a chronic non-specific inflammatory bowel disease with an increasing incidence worldwide. Patients with CD are facing elevated risk for mental disorders (MD) than healthy people, and chronic psychological stress is considered to trigger deterioration and relapse of CD. The microbiome-gut-brain axis (MGBA) is recognized as a crucial factor in unraveling this connection. Whereas, so far, few studies have revealed the relationship of the microbiota communities and tryptophan catabolites of the terminal ileum mucosa on gut-brain communication. A total of 52 patients with CD, along with 11 patients with colorectal cancers recruited as controls, were enrolled in this study. The participants completed Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 Questionnaire. The terminal ileal mucosa was collected during surgery. We profiled the microbiota composition of 37 patients and quantified the tryptophan catabolites of 28 patients utilizing 16 S rRNA gene sequencing and liquid chromatography-tandem mass spectrometry, respectively. In addition, bioinformatics methods were used to elucidate the interrelationships between psychological states, microbial communities, and tryptophan catabolites. CD patients with MD showed a significant reduction in microbial diversity within the ileal mucosa. Regarding microbial composition, Prevotella was relatively enriched in CD patients with MD, along with lower relative abundances of Akkermansia and Faecalibacterium. Furthermore, significant disparities in the levels of Picolinic acid (PA), Kynurenic acid (KYNA), Nicotinic acid (N-Acid), and Indole-3-carbaldehyde (ICAld) were detected within the ileal mucosa of CD patients comorbid with MD. A pronounced correlation was observed between PA levels and anxiety scale scores. The heightened abundance of Prevotella may be closely associated with altered levels of PA, N-Acid, and KYNA. Alterations in the microbial composition of the terminal ileum may interact with changes in tryptophan metabolism and are associated with MD in patients with CD undergoing surgery.

Crohn’s disease (CD) often necessitates surgical intervention, with temporary stoma creation after intestinal resection (IR) being a crucial decision. This study aimed to construct novel models based on machine learning (ML) to predict temporary stoma formation after IR for CD. Patient data who underwent IR for CD at our center between July 2017 and March 2023 were collected for inclusion in this retrospective study. Eligible CD patients were randomly divided into training and validation cohorts. Feature selection was executed using the least absolute shrinkage and selection operator. We employed three ML algorithms including traditional logistic regression, novel random forest and XG-Boost to create prediction models. The area under the curve (AUC), accuracy, sensitivity, specificity, precision, recall, and F1 score were used to evaluate these models. SHapley Additive exPlanation (SHAP) approach was used to assess feature importance. A total of 252 patients with CD were included in the study, 150 of whom underwent temporary stoma creation after IR. Eight independent predictors emerged as the most valuable features. An AUC between 0.886 and 0.998 was noted among the three ML algorithms. The random forest (RF) algorithms demonstrated the most optimal performance (0.998 in the training cohort and 0.780 in the validation cohort). By employing the SHAP method, we identified the variables that contributed to the model and their correlation with temporary stoma formation after IR for CD. The proposed RF model showed a good predictive ability for identifying patients at high risk for temporary stoma formation after IR for CD, which can assist in surgical decision-making in CD management, provide personalized guidance for temporary stoma formation, and improve patient outcomes.

Crohn's disease (CD), a type of inflammatory bowel disease (IBD), is a chronic disorder involving any part of the gastrointestinal tract. Ileocecal resection may serve as a more effective treatment option for early CD. However, the potential relationship and mechanisms between the ileocecum and remission induction of CD are still elusive. In this study, we conducted 16S rRNA sequencing and liquid chromatography-tandem mass spectrometry (LC-MS/MS) on 68 terminal ileal mucosa and mesentery samples from 34 patients with CD. The results showed an improvement in the microbial health of the ileal mucosa and mesentery in patients with CD after ileocecal resection. In addition, specific spatial alterations in microbiota and metabolites were observed before and after surgery. Furthermore, differentially expressed metabolites in the ileal mucosa and mesentery were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The findings of this study support the therapeutic value of ileocecal resection in CD from a multi-omics perspective and may guide the clinical translation of microbiome-based strategies for precise treatment of CD.

AbstractBackgroundCrohn's disease (CD) is a chronic inflammatory disease in the intestinal tract. Mesenteric fat wrapping and thickening, or creeping fat (CrF), is a typical characteristic of CD and it involves lymphangiogenesis and altered lymphatic function. By releasing extracellular vesicles (EVs), adipose tissue‐derived stem cells (ADSCs) can regulate their adjacent cells. However, the regulating roles of ADSC‐EVs in CrF (CrF‐EVs) in CD, especially in modulating lymphatic function and mitigating the progression of mesenteritis and colitis, remains elusive.MethodsTo evaluate the regulative roles of CrF‐EVs on lymphatic functions, in vitro assays were performed using human lymphatic endothelial cells (HLECs). Next, Interleukin 10 knock‐out (Il‐10−/−) mice were used to assess the biological functions of CrF‐EVs in spontaneous mesenteritis and colitis. Moreover, tissue and serum from various cohorts of CD patients were used to determine the prognostic value of miR‐132‐3p.ResultsCrF‐EVs significantly attenuated spontaneous mesenteritis and colitis in Il‐10−/− mice via promoting lymphangiogenesis and lymphatic drainage. Using high‐throughput sequencing, we demonstrated that CrF‐EVs significantly increased HLEC proliferation, migration, tube formation and CCL‐21 production in a miR‐132‐3p/RASA1/ERK1/2 axis‐dependent manner. Accordingly, upregulated miR‐132‐3p was observed in patient CrF, positively correlated with lymphangiogenesis while negatively correlated with inflammatory factors (tumour necrosis factor‐α and IL‐6) level. Moreover, serum miR‐132‐3p demonstrated a positive correlation with disease activity.ConclusionsEVs derived from CrF ADSCs, containing elevated levels of miR‐132‐3p, could promote lymphatic function and restrain inflammation of CD. Our results provide a novel insight into the role of mesenteric lymphatics in CD progression and reveal a new potential therapeutic.Key points Extracellular vesicles (EVs) of creeping fat (CrF) derived adipose stem cells effectively attenuate chronic mesenteritis and colitis in Crohn's disease (CD). The lymphatic vessels play an important role in disease development of CD and their functions are improved by CrF‐EV‐miR‐132‐3p through RASA1/ERK1/2 signaling. MiR‐132‐3p expression is upregulated in CrF and serum of CD patients, and tightly linked with inflammation and disease activity.

BACKGROUND Due to the complexity and numerous comorbidities associated with Crohn’s disease (CD), the incidence of postoperative complications is high, significantly impacting the recovery and prognosis of patients. Consequently, additional studies are required to precisely predict short-term major complications following intestinal resection (IR), aiding surgical decision-making and optimizing patient care. AIM To construct novel models based on machine learning (ML) to predict short-term major postoperative complications in patients with CD following IR. METHODS A retrospective analysis was performed on clinical data derived from a patient cohort that underwent IR for CD from January 2017 to December 2022. The study participants were randomly allocated to either a training cohort or a validation cohort. The logistic regression and random forest (RF) were applied to construct models in the training cohort, with model discrimination evaluated using the area under the curves (AUC). The validation cohort assessed the performance of the constructed models. RESULTS Out of the 259 patients encompassed in the study, 5.0% encountered major postoperative complications (Clavien-Dindo ≥ III) within 30 d following IR for CD. The AUC for the logistic model was 0.916, significantly lower than the AUC of 0.965 for the RF model. The logistic model incorporated a preoperative CD activity index (CDAI) of ≥ 220, a diminished preoperative serum albumin level, conversion to laparotomy surgery, and an extended operation time. A nomogram for the logistic model was plotted. Except for the surgical approach, the other three variables ranked among the top four important variables in the novel ML model. CONCLUSION Both the nomogram and RF exhibited good performance in predicting short-term major postoperative complications in patients with CD, with the RF model showing more superiority. A preoperative CDAI of ≥ 220, a diminished preoperative serum albumin level, and an extended operation time might be the most crucial variables. The findings of this study can assist clinicians in identifying patients at a higher risk for complications and offering personalized perioperative management to enhance patient outcomes.

CXC chemokine receptor 6 (CXCR6), a seven-transmembrane domain G-protein-coupled receptor, plays a pivotal regulatory role in inflammation and tissue damage through its interaction with CXC chemokine ligand 16 (CXCL16). This axis is implicated in the pathogenesis of various fibrotic diseases and correlates with clinical parameters that indicate disease severity, activity, and prognosis in organ fibrosis, including afflictions of the liver, kidney, lung, cardiovascular system, skin, and intestines. Soluble CXCL16 (sCXCL16) serves as a chemokine, facilitating the migration and recruitment of CXCR6-expressing cells, while membrane-bound CXCL16 (mCXCL16) functions as a transmembrane protein with adhesion properties, facilitating intercellular interactions by binding to CXCR6. The CXCR6/CXCL16 axis is established to regulate the cycle of damage and repair during chronic inflammation, either through modulating immune cell-mediated intercellular communication or by independently influencing fibroblast homing, proliferation, and activation, with each pathway potentially culminating in the onset and progression of fibrotic diseases. However, clinically exploiting the targeting of the CXCR6/CXCL16 axis requires further elucidation of the intricate chemokine interactions within fibrosis pathogenesis. This review explores the biology of CXCR6/CXCL16, its multifaceted effects contributing to fibrosis in various organs, and the prospective clinical implications of these insights.

Re-expression of an embryonic morphogen, Nodal, has been seen in several types of malignant tumours. By far, studies about Nodal's role in colorectal cancer (CRC) remain limited. Ferroptosis is essential for CRC progression, which is caused by cellular redox imbalance and characterized by lipid peroxidation. Herein, we observed that Nodal enhanced CRC cell's proliferative rate, motility, invasiveness, and epithelial-mesenchymal transition (EMT) in vivo and in vitro. Notably, Nodal overexpression induced monounsaturated fatty acids synthesis and increased the lipid unsaturation level. Nodal knockdown resulted in increased CRC cell lipid peroxidation. Stearoyl-coenzyme A desaturase 1 (SCD1) inhibition at least partially abolished the resistance of Nodal-overexpressing cells to RSL3-induced ferroptosis. Mechanistically, SCD1 was transcriptionally up-regulated by Smad2/3 pathway activation in response to Nodal overexpression. Significant Nodal and SCD1 up-regulation were observed in CRC tissues and were associated with CRC metastasis and poor clinical outcomes. Furthermore, bovine serum albumin nanoparticles/si-Nodal nanocomplexes targeting Nodal had anti-tumour effects on CRC progression and metastasis. This research elucidated the role of Nodal in CRC development and revealed a potential gene-based therapeutic strategy targeting Nodal for improving CRC treatment.

慢性肠道和肺部疾病的发生与进展已被证明与微生态的紊乱和失调相关.肠道微生物改变可能促进肺部感染,肺部疾病也可能影响肠道菌群的组成.而微生物群可通过"肺-肠"轴介导慢性肠道疾病如炎症性肠病与肺部慢性疾病之间的相互作用.本文对微生态在肺和肠相关疾病的"肺-肠"轴相互影响过程中所起的作用,以及相关机制研究进展进行综述.

本研究回顾性分析1例经自然腔道取标本全腹腔镜胰十二指肠切除术联合全结肠切除术治疗Turcot综合征患者的临床资料，该患者为39岁女性，因上腹痛伴排便习惯改变2个月余入院，既往有脑部恶性肿瘤手术史，入院完善检查发现十二指肠肿瘤、家族性息肉病，结合患者对微创治疗及远期疗效的综合要求行经自然腔道取标本全腹腔镜胰十二指肠切除术联合全结肠切除术。患者术后随访4年余，生存良好，无明显肿瘤复发迹象，本研究提示行经自然腔道取标本全腹腔镜胰十二指肠切除术联合全结肠切除术治疗此类患者安全可行，远期疗效较好。

Intestinal obstruction is one of the most common complications of Crohn’s disease (CD), jeopardizing the quality of life of patients. Numerous factors may contribute to intestinal obstruction in CD. Thus far, the primary reason has been identified as intestinal fibrosis caused by repeated chronic inflammation during the active phase of CD. Herein, we report two rare complicated CD cases and provide a reference for the clinical diagnosis and treatment of similar patients. Case one involves capsule endoscope retention in the small intestine of one CD patient concurrent with intestinal obstruction. Case two is a CD patient with intestinal obstruction caused by a mesangial hernia and ileal stenosis. Individualized and minimally invasive surgical intervention ultimately resulted in the successful management of these two patients. The two cases serve as an excellent guide for diagnosing and treating CD patients who present with similar symptoms.