Intestinal strictures in Crohn's disease: An update from 2023.

Crohn's disease (CD) is a chronic inflammatory disease that leads to intestinal stricture in nearly 35% of cases within 10 years of initial diagnosis. The unknown pathogenesis, lack of universally accepted criteria, and absence of an effective management approach remain unconquered challenges in structuring CD. The pathogenesis of stricturing CD involves intricate interactions between factors such as immune cell dysbiosis, fibroblast activation, and microecology imbalance. New techniques such as single-cell sequencing provide a fresh perspective. Non-invasive diagnostic tools such as serum biomarkers and novel cross-sectional imaging techniques offer a precise understanding of intestinal fibrostenosis. Here, we provide a timely and comprehensive review of the worthy advancements in intestinal strictures in 2023, aiming to dispense cutting-edge information regarding fibrosis and to build a cornerstone for researchers and clinicians to make greater progress in the field of intestinal strictures.

Expression of the HIF-1α/VEGF pathway is upregulated to protect alveolar bone density reduction in nasal-obstructed rats.

BACKGROUND: Hypoxia and mouth breathing are closely related to maxillofacial bone metabolism and are characteristic of obstructive sleep apnea-hypopnea syndrome (OSAHS). Being key factors in the hypoxia response, hypoxia-inducible factor 1α (HIF-1α) and HIF-responsive gene vascular endothelial growth factor (VEGF) are essential for bone remodeling. This study focuses on the role of the HIF-1α/VEGF pathway in alveolar bone metabolism during OSAHS. MATERIALS AND METHODS: 36 three-week-old male Wistar rats were divided into three groups: twelve control rats, twelve bilateral nasal obstructed (BNO) rats, twelve BNO rats treated with intraperitoneal injection of Dimethyloxalylglycine (DMOG). After two weeks, the microstructure and bone mineral density (BMD) of alveolar bone were evaluated using micro-computed tomography (micro-CT). The expressions of HIF-1α and VEGF in the alveolar bone were then assessed via immunohistochemistry staining, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Alkaline phosphatase (ALP) staining and Alizarin red S staining were performed to evaluate osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs). RESULTS: Significant reductions in alveolar bone density were noted in BNO rats. Bilateral nasal obstruction increased the expressions of HIF-1α and VEGF in alveolar bone. With upregulation of HIF-1α/VEGF via DMOG, alveolar bone density of BNO rats increased. Furthermore, DMOG promoted the osteogenic differentiation of BMSCs by stabilizing the HIF-1α protein and increasing the expression of VEGF. CONCLUSION: Bilateral nasal obstruction changes alveolar bone structure and leads to a reduction in alveolar bone density. Moreover, the expression of the HIF-1α/VEGF signaling pathway increases to protect alveolar bone density reduction in BNO rats.

Cardiovascular effects of weight loss in old adults with overweight/obesity according to change in skeletal muscle mass.

BACKGROUND: Patients with overweight/obesity and type 2 diabetes are encouraged to lose weight, but not all losing weight gain better cardiovascular health, especially old adults. The change in skeletal muscle mass (SMM) could be the key that explains the heterogenous cardiovascular effects of weight loss. This study aims to assess whether the cardiovascular effects of weight loss vary for those gaining skeletal muscle along with weight loss. METHODS: The old adults with overweight/obesity and type 2 diabetes in the Look AHEAD study having muscle measurement from dual-energy X-ray absorptiometry were included. Based on the weight change (WC) and SMM change (SMMC) between baseline and the 4-year follow-up, participants were allocated into three groups-weight gain (WG) group, weight loss with muscle loss (WL-ML) group and weight loss with muscle gain (WL-MG) group. Cox proportional hazards regression was performed to evaluate the cardiovascular risk of those gaining or losing SMM with weight loss compared with those gaining weight. Among the participants with weight loss, the ratio of SMMC/WC was calculated, and the association of SMMC/WC with primary cardiovascular outcome was assessed. RESULTS: A total of 491 participants were included in the study with an average age of 64.56 ± 3.81 years old. A total of 47.0% were male and 49.9% were from the intensive lifestyle intervention arm. Based on their WC and SMMC, 43 were assigned to the WG group, 373 to the WL-ML group and 75 to the WL-MG group. Over a follow-up of almost 10 years, 97 participants encountered the primary endpoint. The WG group had the highest incidence of 25.59%, the WL-MG group had the lowest incidence of 9.33% and the WL-ML group had 21.18% (P = 0.040). In the fourth adjusted Cox model, the WL-MG group achieved significantly decreased odds of the primary endpoint compared with the WG group (hazard ratio [HR] 0.33, 95% confidence interval [CI] [0.12, 0.87], P = 0.026), whilst the WL-ML group did not (HR 0.91, 95% CI [0.47, 1.78], P = 0.670). Among the participants with weight loss, when SMMC/WC reached around 50%, this HR soared to approximately two-fold. CONCLUSIONS: The participants gaining SMM along with weight loss achieved the lowest odds of adverse cardiovascular events, whilst those who lost SMM along with weight loss had comparable cardiovascular risk with those gaining weight. The more muscle lost during weight loss, the greater the harm. The cardiovascular effects of weight loss were modulated by whether the participants gained SMM meanwhile losing weight.

Early transmural healing and its predictors assessed by magnetic resonance enterography in patients with Crohn's disease receiving ustekinumab.

Background: Transmural healing (TH) is a potential therapeutic goal of Crohn's disease (CD) and is associated with better clinical outcomes. However, few studies have described early TH and its predictors. Objectives: We aimed to evaluate early TH and its predictors using magnetic resonance enterography (MRE) in patients with CD receiving ustekinumab (UST). Design: This was a retrospective observational study. Methods: Patients with active CD treated with UST and their intestinal segments with bowel wall thickness (BWT) ⩽ 3 mm at baseline were included. Clinical characteristics, laboratory indicators, endoscopic manifestations, and MRE indices were evaluated at baseline and week 26 (W26) of the therapy. The following MRE parameters were assessed: BWT, edema, apparent diffusion coefficient (ADC), Clermont score, Magnetic Resonance Index of Activity score, fat stranding, comb sign, and stricture. TH was defined as BWT ⩽ 3 mm without any signs of inflammation (i.e., ulceration, edema, diffusion-weighted hyperintensity, and increased contrast enhancement) at W26. Results: The study included 37 patients with 106 intestinal segments (including 15 proximal small intestines, 33 terminal ilea, and 58 colons). Clinical features, laboratory indicators, endoscopic results, and MRE parameters at W26 were significantly improved after UST treatment in both patient-based and intestinal segment-based analysis. Seven (18.9%) patients and 26 (24.5%) intestinal segments achieved TH at W26. Baseline BWT [odds ratio (OR) = 0.287, 95% confidence interval (CI), 0.090-0.918, p = 0.035] and ADC (OR = 2.997, 95% CI, 1.009-8.908, p = 0.048) predict TH of patients at W26. Baseline ADC (OR = 2.857, 95% CI, 1.285-6.349, p = 0.010) and presence of stenosis (OR = 0.196, 95% CI, 0.052-0.735, p = 0.016) were associated with TH of segments at W26. Conclusion: Early TH assessed by MRE was observed in nearly one-fifth of patients with CD and intestinal segments after UST treatment for 26 weeks. Baseline MRE indices such as BWT and presence of stenosis might negatively predict TH, while ADC might positively predict early TH.

Cellular and Molecular Mechanisms of Intestinal Fibrosis.

Intestinal fibrosis associated stricture is a common complication of inflammatory bowel disease usually requiring endoscopic or surgical intervention. Effective anti-fibrotic agents aiming to control or reverse intestinal fibrosis are still unavailable. Thus, clarifying the mechanism underpinning intestinal fibrosis is imperative. Fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins at the injured sites. Multiple cellular types are implicated in fibrosis development. Among these cells, mesenchymal cells are major compartments that are activated and then enhance the production of ECM. Additionally, immune cells contribute to the persistent activation of mesenchymal cells and perpetuation of inflammation. Molecules are messengers of crosstalk between these cellular compartments. Although inflammation is necessary for fibrosis development, purely controlling intestinal inflammation cannot halt the development of fibrosis, suggesting that chronic inflammation is not the unique contributor to fibrogenesis. Several inflammation-independent mechanisms including gut microbiota, creeping fat, ECM interaction, and metabolic reprogramming are involved in the pathogenesis of fibrosis. In the past decades, substantial progress has been made in elucidating the cellular and molecular mechanisms of intestinal fibrosis. Here, we summarized new discoveries and advances of cellular components and major molecular mediators that are associated with intestinal fibrosis, aiming to provide a basis for exploring effective anti-fibrotic therapies in this field.

Comprehensive investigation on volatile and non-volatile metabolites in low-salt doubanjiang with different fermentation methods.

Doubanjiang is a well-known fermented condiment in China, but the high-salt concentration in its traditional manufacture process greatly lengthens the fermentation time, and leads to potential health risks. Here, the effects of salt reduction and co-inoculated starters (Tetragenococcus halophilus and Zygosaccharomyces rouxii) on the volatile metabolites (VMs) and non-volatile metabolites (NVMs) of doubanjiang were investigated using metabolomics technology and chemometrics analysis. Results showed that 75 VMs were identified, and 12 of them had significant aroma contribution (ROVAs ≥ 1). In addition, 106 NVMs were defined as significantly different metabolites (p < 0.05; VIP ≥ 1). Salt reduction could significantly increase the concentrations of VMs, but this strategy also promoted some undesirable odors like 2-phetylfuran and hexanoic acid, which could be totally suppressed by inoculation of starter. Moreover, the two starters improved amino acid, ester, and acid metabolites. This study provides a deeper insight into the development of low-salt fermented foods.

Ulcerative colitis increases risk of hypertension in a UK biobank cohort study.

OBJECTIVE: Inflammatory bowel disease (IBD) is not only a chronic inflammatory disorder of the gastrointestinal tract but also accompanied by systemic inflammation. The onset of hypertension is closely related to systemic inflammation. However, the relationship between IBD and hypertension has not been investigated. We aimed to investigate the potential association between IBD and the incidence of hypertension. METHOD: We retrieved IBD onset and the incidence of hypertension from a public database UK Biobank. The association between the onset of IBD and subsequent incidence of hypertension was analyzed using a multivariate Cox regression analysis, and propensity score matching was performed for sensitivity analysis. RESULT: Of a total of 281,064 participants included in the study, 2376 (0.8%) were diagnosed with IBD at baseline, and 20,129 (7.2%) in the whole cohort developed hypertension with a median follow-up duration of 8.1 years (interquartile range [IQR] 7.3-8.8 years). Patients with IBD had a higher cumulative risk of hypertension compared with general population (10.9% in ulcerative colitis [UC], 7.7% in Crohn's disease [CD], and 9.3% in IBD unclassified [IBD-U] vs. 7.1% in non-IBD, p < 0.001). Multivariate Cox regression analysis identified that UC, rather than CD or IBD-U, was independently associated with subsequent occurrence of hypertension (HR 1.30, 95% CI: 1.11-1.52, p = 0.001). In propensity matching analysis, UC also showed its robustness as a risk factor for the prediction of hypertension (HR 1.56, 95% CI: 1.21-2.03, p = 0.001). CONCLUSION: In IBD patients, UC rather than CD is associated with a higher risk for the incidence of hypertension compared with general population. Close monitoring of hypertension might be required in clinical practice.

Regulation of osteogenic differentiation under hypoxia by EphrinB2/EphB4 in MC3T3-E1 cells / 口腔疾病防治

Objective @# To investigate the effect of erythropoietin producing hepatocyte kinase receptor ligand B2-erythropoietin producing hepatocyte kinase receptor B4 (EphrinB2/EphB4) on the osteogenic differentiation of MC3T3-E1 cells in a hypoxic environment to provide experimental evidence for hypoxia regulation of osteoblast differentiation.@*Methods @# Control groups and cobalt chloride (CoCl2)-induced hypoxia groups were set up first. qRT-PCR was used to detect the mRNA expression of the osteogenic markers alkaline phosphatase (ALP), collogen1 (COL I), runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN). ALP staining was used to detect the activity of cell alkaline phosphatase after osteogenic induction. The mRNA and protein expression levels of hypoxia inducible factor-1α (HIF-1α), EphrinB2 and EphB4 in the two groups were detected via qRT-PCR and Western blot. Then, the CoCl2 + inhibitor group was established. NVP-BHG712, an EphB4 phosphorylation inhibitor, was added to this group to prevent EphrinB2 from binding to EphB4 and producing signals. qRT-PCR and Western blot were used to detect the mRNA and protein expression of osteogenic markers, including ALP, RUNX2, COL I, and OCN. ALP staining and Alizarin red S staining were used to measure osteoblast differentiation and mineralization. @*Results @# Compared with the control group, the mRNA expression of the osteogenic differentiation markers ALP, RUNX2, COL-1, and OCN in MC3T3-E1 cells increased, and ALP activity and mineralization were enhanced under CoCl2-induced hypoxia in vitro (P<0.05). Additionally, the expression of HIF-1α, EphrinB2 and EphB4 was upregulated at the mRNA and protein levels under hypoxia (P<0.05). When NVP-BHG712 was used to block the connection between EphrinB2 and EphB4, the expression of osteogenic markers and ALP activity and mineralization were decreased (P<0.05).@*Conclusion@#EphrinB2/EphB4 can promote osteogenic differentiation of MC3T3-E1 cells and increase the expression of osteogenic markers and tissue mineralization in a hypoxic environment.

Fibrosis in fat: From other diseases to Crohn's disease.

Creeping fat is a specific feature of Crohn's disease (CD) and is characterized by mesenteric fat wrapping around the intestine. It highly correlates with intestinal transmural inflammation, muscular hypertrophy, fibrosis, and stricture formation. However, the pathogenesis of creeping fat remains unclear. Molecular crosstalk exists between mesenteric fat and the intestine. Indeed, creeping fat contains different types of cells, including adipocytes and immune cells. These cell types can produce various cytokines, fatty acids, and growth factors, which affect the mesenteric fat function and modulate intestinal inflammation and immunity. Moreover, adipocyte progenitors can produce extracellular matrix to adapt to fat expansion. Previous studies have shown that fat fibrosis is an important feature of adipose tissue malfunction and exists in other diseases, including metabolic disorders, cancer, atrial fibrillation, and osteoarthritis. Furthermore, histological sections of CD showed fibrosis in the creeping fat. However, the role of fibrosis in the mesenteric fat of CD is not well understood. In this review, we summarized the possible mechanisms of fat fibrosis and its impact on other diseases. More specifically, we illustrated the role of various cells (adipocyte progenitors, macrophages, mast cells, and group 1 innate lymphoid cells) and molecules (including hypoxia-inducible factor 1-alpha, transforming growth factor-beta, platelet-derived growth factor, and peroxisome proliferator-activated receptor-gamma) in the pathogenesis of fat fibrosis in other diseases to understand the role of creeping fat fibrosis in CD pathogenesis. Future research will provide key information to decipher the role of fat fibrosis in creeping fat formation and intestinal damage, thereby helping us identify novel targets for the diagnosis and treatment of CD.

Intestinal strictures in Crohn's disease: a 2021 update.

Intestinal strictures remain one of the most intractable and common complications of Crohn's disease (CD). Approximately 70% of CD patients will develop fibrotic strictures after 10 years of CD diagnosis. Since specific antifibrotic therapies are unavailable, endoscopic balloon dilation and surgery remain the mainstay treatments despite a high recurrence rate. Besides, there are no reliable methods for accurately evaluating intestinal fibrosis. This is largely due to the fact that the mechanisms of initiation and propagation of intestinal fibrosis are poorly understood. There is growing evidence implying that the pathogenesis of stricturing CD involves the intricate interplay of factors including aberrant immune and nonimmune responses, host-microbiome dysbiosis, and genetic susceptibility. Currently, the progress on intestinal strictures has been fueled by the advent of novel techniques, such as single-cell sequencing, multi-omics, and artificial intelligence. Here, we perform a timely and comprehensive review of the substantial advances in intestinal strictures in 2021, aiming to provide prompt information regarding fibrosis and set the stage for the improvement of diagnosis, treatment, and prognosis of intestinal strictures.

Prognosis of patients with hepatocellular carcinoma and portal vein tumor thrombus treated with combination of transarterial chemoembolization and palliative thermal ablation.

PURPOSE: Transarterial chemoembolization (TACE) was obtained acceptable benefit for advanced hepatocellular carcinoma (HCC). Here in this study, we compared the benefit of TACE combined palliative thermal ablation with TACE alone for HCC with portal vein tumor thrombus (PVTT). METHODS: Patients with HCC and PVTT were retrospectively analyzed from January 2012 to December 2017, who accepted treatment of TACE alone (TACE group) or TACE plus palliative thermal ablation (TACE + P-ablation group). Propensity score matching (PSM) was applied to balance differences between the two groups. Overall survival (OS) and progression-free survival (PFS) rates were compared between groups. RESULTS: Median follow-up time was 7.4 (3.0-60.0) months. In the cohort, 142 patients were enrolled in TACE group and 86 patients were enrolled in TACE + P-ablation group. The pre-PSM estimated 6-, 12-, and 18-month OS rates for the TACE + P-ablation group were 70.9, 46.5, and 31%, respectively, whereas rates for the TACE group were 57, 23.1, and 10%, respectively. After PSM, OS and PFS rates remained coincident with the pre-PSM. Risk factors for poor OS included PVTT type III and type II relative to type I (HR = 1.76; 95% CI, 1.13-2.74; p = .01) and (HR = 1.86; 95% CI, 1.2-2.88; p = .006), TACE alone (HR = 1.40; 95% CI, 1.01-1.96; p = .04), a single TACE treatment (HR = 2.69; 95% CI, 1.79-4.03; p < .001), 2 or 3 TACE treatments (HR = 2.02; 95% CI, 1.32-3.09; p = .001). CONCLUSIONS: The combination of TACE and palliative thermal ablation for HCC with PVTT could obtain delayed progression and longer survival.

Multiple examinations indicated associations between abnormal regional homogeneity and cognitive dysfunction in major depressive disorder.

Background: This study aimed to investigate the relationships between regional neural activity and multiple related indicators in patients with major depressive disorder (MDD). Methods: Forty-two patients and 42 healthy controls (HCs) were enrolled. Pearson/Spearman correlation analyses were applied to examine the associations between abnormal regional homogeneity (ReHo) and different indicators in the patients. Results: Compared with HCs, patients with MDD had increased ReHo in the left inferior temporal gyrus (ITG) and decreased ReHo values in the left putamen, anterior cingulate cortex (ACC), and precentral gyrus. The ReHo of the left putamen was positively correlated with the PR interval, Repeatable Battery for the Assessment of Neuropsychological Status 4A, and Discriminant analysis (D), and negatively correlated with Ae (block) and Ae (total) in the patients. The ReHo value of the left ACC was positively correlated with the severity of depression, Stroop Color Word Test of C - 2B + 100 in reaction time, and negatively correlated with Ce (Missay) and Perseverative Responses in the patients. The ReHo of the left ITG was positively correlated with the Neuroticism scores and negatively correlated with the Lie scores in the patients. Conclusion: These results suggested that the decreased ReHo of the salience network might be the underpinning of cognitive impairments in patients with MDD.

Preoperative Versus Postoperative Transarterial Chemoembolization on Prognosis of Large Hepatocellular Carcinoma.

Background: Transarterial chemoembolization (TACE) has proven to be an effective adjuvant therapy with liver resection (LR) to treat patients with hepatocellular carcinoma (HCC). The aim of this study was to evaluate outcomes in patients with HCC larger than 5 cm, comparing those who had TACE before LR to those who had TACE after LR. Materials and methods: A total of 320 consecutive patients who underwent LR in combination with TACE for HCC larger than 5 cm from January 2009 to December 2014 were enrolled in study. Patients were divided into two groups: preoperative TACE group (n=199) and postoperative TACE group (n=121). Overall survival (OS) and recurrence-free survival (RFS) of patients were compared between preoperative TACE and postoperative TACE groups by propensity score-matching (PSM). We determined prognostic factors for recurrence and death using multivariate cox regression analysis. Results: Among the 320 patients, the median age was 48 (range, 18 to 75) years, and 285 (89.1%) patients were male. During the follow- up period, 88 (44.2%) patients in the preoperative TACE group and 69 (57.0%) patients in the postoperative TACE group died. Before PSM, both OS and RFS were significantly longer in the preoperative TACE group than those in the postoperative TACE group (P=0.001 and P<0.001, respectively). After PSM, compared to those received postoperative TACE, patients with preoperative TACE had significantly better OS (Hazard ratio [HR]=1.92; 95% confidence interval [CI], 1.22-3.02; P=0.005) and RFS (HR=1.64; 95% CI, 1.16-2.32; P=0.005). Conclusions: Patients with large HCC undergoing LR appear to derive greater disease control and survival benefit from a single preoperative TACE treatment than from postoperative TACE.

Transcriptome and Gut Microbiota Profiling Revealed the Protective Effect of Tibetan Tea on Ulcerative Colitis in Mice.

Traditionally, Ya'an Tibetan tea is routinely consumed by local people in the Tibet region. It is believed to possess promising anti-inflammatory benefits. This study was conducted to elucidate the protective impact of Tibetan tea extract (TTE) on dextran sodium sulfate (DSS)-induced colitis in mice. Mice were split into four groups: control (C) group, Tibetan tea (T) group, DSS-induced model (CD) group, and Tibetan tea + DSS (TD) group. The intake of TTE significantly reduced the clinical symptoms of ulcerative colitis (UC) by alleviating the impact of cellular damage and reducing glandular hypertrophy and the infiltration of inflammatory cells. UC led to a prominent shift of the microbial communities in the gut. Interestingly, the beneficial microbes, such as Lactobacillus reuteri, Bifidobacterium choerinum, and Lactobacillus intestinalis, were significantly increased in TTE-treated mice when compared to any other experimental group. The transcriptome analysis revealed that the positive effect of TTE on UC could be attributed to changes in the G alpha (i) signaling pathway and the innate immune system. The genes related to inflammation and immune system pathways were differentially expressed in the TTE-treated group. Moreover, the relative expression of genes linked to the inflammatory TLR4/MyD88/NF-κB signaling pathway was significantly downregulated toward the level of normal control samples in the TD group. Overall, this study revealed the modulatory effect by which TTE reversed the development and severity of chronic colon damage.