Abnormal intestinal mucosal immunity plays a crucial role in ulcerative colitis (UC). Autotaxin (ATX) can promote T cell migration and was reported to have a regulatory effect on Th17 cells, while sphingosine-1-phosphate (S1P) and its receptors (S1PRs) modulate Th17/Treg balance and inflammation, with S1PR modulators approved for UC. ATX can catalyze sphingosylphosphorylcholine (SPC) to produce S1P; however, the relationship between ATX and S1P/S1PRs in UC is unclear. Understanding the role of ATX-S1P/S1PRs in intestinal immunity can provide new treatment strategies for intestinal inflammatory diseases. Both UC patients and DSS-induced colitic mice showed significantly increased levels of ATX and S1P compared with healthy controls. ATX inhibitor PF8380 treatment led to reduced levels of S1P/S1PRs in colitic mice. Consistent with this, the S1PR antagonist etrasimod was able to alleviate ATX-induced intestinal inflammation, as well as partially restore ATX-induced Th17/Treg imbalance in MLNs and the spleen. In HT-29 and Raw246.7 cells, ATX treatment led to enhanced expression of S1P/S1PRs, with S1PR1 being the most significant. Furthermore, S1PR1 mediates the effect of ATX on Th17/Treg cell differentiation and function in vivo. Therefore, ATX affects the differentiation and function of Th17/Treg cells through S1P/S1PR1 signaling, increased ATX expression leading to Th17/Treg cell imbalance, intestinal mucosal immune dysfunction, and exacerbating intestinal inflammation.

Camellia nitidissima Chi (CNC), whose main composition was gallic acid, catechin, procyanidin-gallate, apigenin-pentosyl-glucoside, vitexin, cyanidin-3-o-glucoside, myricitrin-glucoside, gallocatechin-gallate, epicatechin and rutin, posses sound anti-inflammatory and antioxidant effects. This study aimed to explore the protective effects and mechanisms of the alcoholic extract of CNC on dextran sulfate sodium-induced ulcerative colitis. CNC effectively maintained weight and colon length, and significantly ameliorated colonic histopathological damage. Furthermore, CNC mitigated colitis-induced oxidative stress and exhibited anti-inflammatory properties in UC mice by reducing levels of myeloperoxidase (MPO) and malondialdehyde (MDA), decreasing the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In addition, CNC downregulated the protein expression levels of TLR4, p-NF-κBP65, and p-IκBα of the inflammation-related TLR4/NF-κB signaling pathways. Validation of the molecular docking results also revealed that rutin, the most abundant compound in CNC, interacts with TLR4 and NF-κB protein mainly through hydrogen bonds. CNC also promoted the proliferation of Lactobacillus and Bifidobacterium while reducing the number of Enterococcus, E. coli, Bacteroides, and Peptococcus in mice to improve the intestinal environment and alleviate colitis. CNC inhibited TLR4/NF-κB signaling pathways to relieve inflammation and oxidative damage on UC, is a potential development of natural medicine for UC.

Succinate levels are increased in inflammatory bowel disease (IBD), but its role in disease pathogenicity remains unknown. Here we showed that succinate promoted colitis in mice by reducing the expression of FOXP3 and increasing the expression of interleukin-17 in regulatory T (Treg) cells. Succinate selectively reduced the expression of 2-oxoglutarate dehydrogenase complex (OGDHc), the enzyme for succinyl-CoA synthesis, which in turn reduced FOXP3 succinylation and made FOXP3 lysine residues available for ubiquitination and FOXP3 protein degradation. Genetic deletion of Dlst, a member of OGDHc, in Treg cells led to reduced expression of FOXP3, impaired Treg cells function and severe gut inflammation. Restoring FOXP3 expression fully rescued the immune suppressive functions of Dlst-deficient Treg cells. In individuals with IBD, FOXP3 and OGDHc levels were reduced in Treg cells and negatively correlated with succinate levels and inflammation severity. This study identifies succinate as a pathogenic factor in IBD, uncovering a succinate-driven molecular switch that regulates FOXP3 stability and Treg cells function during inflammation. Fang and colleagues show that the metabolite succinate can inhibit succinylation, and consequently protection from ubiquitin-mediated degradation, of the transcription factor FOXP3, with consequences on Treg cell-suppressive function and IBD pathology.

Constipation is a prevalent gastrointestinal disorder associated with alterations in the gut microbiota. However, the potential microbial targets and their underlying mechanisms remain to be explored. Our analysis found the genus Ruminococcus was depleted in constipated patients. We then tested four species, R. bromii, R. torques, R. obeum, and R. gnavus, in constipated mice, finding all alleviated symptoms. R. bromii was most effective, with its pullulanase enzyme being key to degrading resistant starch. This degradation boosted short-chain fatty acid production and fostered beneficial bacteria like Akkermansia and Bifidobacterium. A subsequent clinical trial confirmed that the constipation-relieving effect of dietary resistant starch was dependent on the presence and abundance of R. bromii in the gut. This study identifies R. bromii as a key microbial mediator for constipation relief through resistant starch metabolism, positioning it as a promising candidate for targeted probiotic or synbiotic therapies.

Ethnopharmacological relevance: Currently, the clinical treatment is limited and difficult to achieve satisfactory results for ulcerative colitis (UC). The role of traditional Chinese medicine (TCM) in the treatment of UC is very complex. Kuijie decoction (KJD) as a classic TCM, is widely used in the clinical treatment of UC, but the mechanism of its action is still unclear.Aim of the study: This study is to investigate the protective effects of KJD on UC and the underlying mechanisms. Materials and methods: The experimental model of UC was induced by DSS, and KJD was introduced into the model at the same time. Clinical symptoms, including the body weight, colon length and colon histopathological, were used to measure the severity of colitis. The expression of inflammatory cytokines and tight junction proteins was quantified. The effect of KJD on intestinal flora and intestinal metabolism was determined by 16S rRNA and untargeted metabolomics analysis, respectively. The proportion of Th17 cells and Tregs in the spleen was examined by flow cytometry.Results: Mice treated with KJD showed significantly alleviated clinical symptoms and histological damage, such as more body weight gain, lower disease activity index (DAI) score, and longer colon length. The administration of KJD also led to the down-regulation of inflammatory mediators, upregulation of the expression of ZO-1, occludin and decreased claudin-2, as well as altered microbiota composition against DSS challenges (especially an increase of Lachnospiraceae). KJD enhanced the percentage of Treg cells but decreased the proportion of Th17 cells to maintain intestinal homeostasis by improving gut microbiota metabolism. Conclusions: In summary, KJD maintained intestinal epithelial homeostasis by regulating epithelial barrier function, intestinal flora, and restoring Th17/Treg balance. KJD has the potential to be a Chinese medicine treatment for UC.

BACKGROUND:Portulacae Herba and Granati Pericarpium pair (PGP) is a traditional Chinese herbal medicine treatment for colitis, clinically demonstrating a relatively favorable effect on relieving diarrhea and abnormal stools. However, the underlying mechanism remain uncertain.PURPOSE:The present study intends to evaluate the efficacy of PGP in treating colitis in mice and investigate its underlying mechanism.METHODS:The protective effect of PGP against colitis was determined by monitoring body weight, colon length, colon weight, and survival rate in mice. Colonic inflammation was assessed by serum cytokine levels, colonic H&E staining, and local neutrophil infiltration. The reversal of intestinal epithelial barrier damage by PGP was subsequently analyzed with Western blot and histological staining. Furthermore, RNA-seq analysis and molecular docking were performed to identify potential pathways recruited by PGP. Following the hints of the transcriptomic results, the role of PGP through the IL-6/STAT3/SOCS3 pathway in DSS-induced colitis mice was verified by Western blot.RESULTS:DSS-induced colitis in mice was significantly curbed by PGP treatment. PGP treatment significantly mitigated DSS-induced colitis in mice, as evidenced by improvements in body weight, DAI severity, survival rate, and inflammatory cytokines levels in serum and colon. Moreover, PGP treatment up-regulated the level of Slc26a3, thereby increasing the expressions of the tight junction/adherens junction proteins ZO-1, occludin and E-cadherin in the colon. RNA-seq analysis revealed that PGP inhibits the IL-6/STAT3/SOCS3 pathway at the transcriptional level. Molecular docking indicated that the major components of PGP could bind tightly to the proteins of IL-6 and SOCS3. Meanwhile, the result of Western blot revealed that the IL-6/STAT3/SOCS3 pathway was inhibited at the protein level after PGP administration.CONCLUSION:PGP could alleviate colonic inflammation and reverse damage to the intestinal epithelial barrier in DSS-induced colitis mice. The underlying mechanism involves the inhibition of the IL-6/STAT3/SOCS3 pathway.

Exposure to bisphenol A (BPA) during gestation leads to fetal growth restriction (FGR), whereby the underlying mechanisms remain unknown. Here, we found that FGR patients showed higher levels of BPA in the urine, serum, and placenta; meanwhile, trophoblast ferroptosis was observed in FGR placentas, as indicated by accumulated intracellular iron, impaired antioxidant molecules, and increased lipid peroxidation products. To investigate the role of ferroptosis in placental and fetal growth, BPA stimulation was performed both in vivo and in vitro. BPA exposure during gestation was associated with FGR in mice; also, it induces ferroptosis in mouse placentas and human placental trophoblast. Pretreatment with ferroptosis inhibitor ferritin-1 (Fer-1) alleviated BPA-induced oxidative damage and cell death. Notably, BPA reduced the trophoblastic expression of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which regulated tissue growth and organ size. YAP or TAZ siRNA enhanced BPA-induced ferroptosis, suggesting that trophoblast ferroptosis is dependent on YAP/TAZ downregulation after BPA stimulation. Consistently, the protein levels of YAP/TAZ were also reduced in FGR placentas. Further results revealed that silencing YAP/TAZ promoted BPA-induced ferroptosis through autophagy. Pretreatment with autophagy inhibitor chloroquine (CQ) attenuated BPA-induced trophoblast ferroptosis. Ferritinophagy, an autophagic degradation of ferritin (FTH1), was observed in FGR placentas. Similarly, BPA reduced the protein level of FTH1 in placental trophoblast. Pretreatment with iron chelator desferrioxamine (DFO) and NCOA4 (an autophagy cargo receptor) siRNA weakened the ferroptosis of trophoblast after exposure to BPA, indicating that autophagy mediates ferroptosis in BPA-stimulated trophoblast by degrading ferritin. In summary, ferroptosis was featured in BPA-associated FGR and trophoblast injury; the regulation of ferroptosis involved the YAP/TAZ-autophagy-ferritin axis.

Dietary fiber is known to promote the production of short-chain fatty acids (SCFAs) by gut bacteria, which can enhance intestinal epithelial barrier function and ameliorate intestinal inflammation in patients with inflammatory bowel disease (IBD). Interestingly, some IBD patients show reduced expression of solute carrier family member 3 (Slc26a3) in intestinal epithelial cells. The objective of this research was to investigate the interaction between SCFAs and Slc26a3 during colitis and assess how this interaction affects intestinal epithelial barrier function. We showed that butyrate alleviated colonic inflammation in a dose-dependent manner in a dextran sulfate sodium salt (DSS)-induced colitis model. Consistent with this, butyrate increased Slc26a3 and tight junction protein levels. In addition, butyrate inhibited histone deacetylase (HDAC) levels and significantly increased the expression of Slc26a3 by the acetylation of histones in Caco-2BBe cells. The utilization of a pan-HDAC inhibitor or inhibitors specific to certain classes of HDACs revealed that butyrate primarily suppressed HDAC8 to blunt the NF-kappa B pathways and enhance the expression of Slc26a3. Notably, we demonstrated that HDAC8 activation counteracted the beneficial effect of butyrate in DSS-induced colitis. Therefore, we concluded that butyrate improves the expression of Slc26a3 via inhibition of the HDAC8/NF-kappa B pathway, leading to increased intestinal epithelial barrier function.

Inflammatory Bowel Disease (IBD), a chronic nonspecific intestinal inflammatory disease, is comprised of Ulcerative Colitis (UC) and Crohn's Disease (CD). IBD is closely related to a systemic inflammatory reaction and affects the progression of many intestinal and extraintestinal diseases. As one of the representative bacteria for probiotic-assisted therapy in IBD, multiple strains of Lactobacillus have been proven to alleviate intestinal damage and strengthen the intestinal immunological barrier, epithelial cell barrier, and mucus barrier. Lactobacillus also spares no effort in the alleviation of IBD-related diseases such as Colitis-associated Colorectal cancer (CAC), Alzheimer's Disease (AD), Depression, Anxiety, Autoimmune Hepatitis (AIH), and so on via gut-brain axis and gut-liver axis. This article aims to discuss the role of Lactobacillus in IBD and IBD-related diseases, including its underlying mechanisms and related curative strategies from the present to the future.

S1P, also referred to as sphingosine-1-phosphate, is a lipid molecule with bioactive properties involved in numerous cellular processes such as cell growth, movement, programmed cell death, self-degradation, cell specialization, aging, and immune system reactions. Autophagy is a meticulously controlled mechanism in which cells repurpose their elements to maintain cellular balance. There are five stages in autophagy: initiation, nucleation, elongation and maturation, fusion, and degradation. New research has provided insight into the complex connection between S1P and autophagy, uncovering their interaction in both normal and abnormal circumstances. Gaining knowledge about the regulatory mechanism of S1P signaling on autophagy can offer a valuable understanding of its function in well-being and illness, potentially leading to innovative therapeutic concepts for diverse ailments. Hence, this review analyzes the essential stages in mammalian autophagy, with a specific emphasis on recent research exploring the control of each stage by S1P. Additionally, it sheds light on the roles of S1P-induced autophagy in various disorders.

INTRODUCTION:Endothelial dysfunction is one of the basic pathological changes in pre-eclampsia. Extracellular vesicles (EVs) can transport miRNAs expressed by placental trophoblast cells into endothelial cells. The aim of this study was to explore the differential effects of EVs induced by hypoxic trophoblasts (1%HTR-8-EV) and those derived from normoxic trophoblasts (20%HTR-8-EV) on the regulation of endothelial cell functions.METHODS:Normoxia and hypoxia were preconditioned to induce trophoblast cells-derived EVs. The effect of EVs, miRNA, target gene, and their interactions on endothelial cell proliferation, migration, and angiogenesis were determined. Quantitative analysis of miR-150-3p and CHPF were verified by qRT-PCR and western blotting. The binding relationship among EVs pathway was demonstrated by luciferase reporter assay.RESULTS:Compared with 20%HTR-8-EV, 1%HTR-8-EV had a suppressive effect on proliferation, migration, and angiogenesis of endothelial cells. The results of miRNA sequencing showed the vital role of miR-150-3p in trophoblast-to-endothelium communication. 1%HTR-8-EV carrying miR-150-3p could move into endothelial cells and target chondroitin polymerizing factor (CHPF) gene. MiR-150-3p inhibited endothelial cell functions by regulating CHPF. In patient-derived placental vascular tissues, there was a similar negative correlating between miR-150-3p and CHPF.DISCUSSION:Our findings indicate that extracellular vesicles miR-150-3p derived from hypoxic trophoblasts inhibits endothelial cells proliferation, migration, and angiogenesis by modulating CHPF, illuminating a novel mechanism of hypoxic trophoblasts regulation of endothelial cells and their potential role in PE pathogenesis.

Inflammatory bowel disease (IBD) is an immune-mediated disease. Autotaxin (ATX) is associated with increased inflammatory molecules, however, its effect on IBD is not well understood. Autophagy plays an important role in IBD, whether ATX and autophagy act in concert in IBD remains unknown. This study is to explore the possible mechanisms of ATX affecting autophagy leading to the disruption of intestinal epithelial barrier, thereby exacerbating colitis. The expression of ATX was upregulated in UC patients and dextran sulfate sodium (DSS)-induced colitis mice. Here, we described that providing an ATX inhibitor during DSS colitis increased autophagy and ameliorated colonic inflammation. Conversely, intrarectal administration with recombinant (r)ATX increased colitis and decreased autophagy. This pro-colitic effect was attenuated in mice treated with rapamycin, resulting in increased autophagy activity and mild colitis. Moreover, the inhibitory effect of rATX on autophagy was confirmed in vitro and was reversed by the addition of rapamycin. The damaging effects of ATX on epithelial barrier function were reversed by ATX inhibitor or rapamycin treatment. In sum, our results show that ATX can inhibit autophagy through the mTOR pathway, resulting in exaggerated damage to the intestinal epithelial barrier during colitis. These findings suggest that ATX may be a key pro-colitic factor, and represent a potential therapeutic target for treating IBD in the future.

Endoscopic evaluation is the key to the management of ulcerative colitis (UC). However, there is interobserver variability in interpreting endoscopic images among gastroenterologists. Furthermore, it is time-consuming. Convolutional neural networks (CNNs) can help overcome these obstacles and has yielded preliminary positive results. We aimed to develop a new CNN-based algorithm to improve the performance for evaluation tasks of endoscopic images in patients with UC. A total of 12,163 endoscopic images from 308 patients with UC were collected from January 2014 to December 2021. The training set and test set images were randomly divided into 37,515 and 3191 after excluding possible interference and data augmentation. Mayo Endoscopic Subscores (MES) were predicted by different CNN-based models with different loss functions. Their performances were evaluated by several metrics. After comparing the results of different CNN-based models with different loss functions, High-Resolution Network with Class-Balanced Loss achieved the best performances in all MES classification subtasks. It was especially great at determining endoscopic remission in UC, which achieved a high accuracy of 95.07% and good performances in other evaluation metrics with sensitivity 92.87%, specificity 95.41%, kappa coefficient 0.8836, positive predictive value 93.44%, negative predictive value 95.00% and area value under the receiver operating characteristic curve 0.9834, respectively. In conclusion, we proposed a new CNN-based algorithm, Class-Balanced High-Resolution Network (CB-HRNet), to evaluate endoscopic activity of UC with excellent performance. Besides, we made an open-source dataset and it can be a new benchmark in the task of MES classification.

Intestinal metabolites are attracting increasing interest, especially more and more studies have found they are closely related to diseases. Microbial fermentation of indigestible dietary fibers in the gut produces short chain fatty acids (SCFAs) as the main product. SCFAs can exert influences on the integrity of the intestinal epithelial and mucosal barrier, immune reactions, and the diversity of microbiota in humans. Thus, alteration in SCFAs may affect inflammatory bowel disease (IBD). In IBD, SCFAs are involved in the main pathogenic process and play an important role in the development of intestinal inflammation. Although many studies have proved that pretreatment with SCFAs can effectively ameliorate inflammation in the gut, the mechanisms are not fully understood. In this review, we describe the relationship between SCFAs and IBD from the aspects of defense barrier, immune effects, and microbial alterations. We also summarize the effects of SCFAs on comorbidities in IBD via the gut-brain, gut-liver, and gut-lung axis, and we give an overview of the prospects of their clinical application. A better understanding of the relevance of SCFAs in IBD may reveal novel targets for future study.

溃疡性结肠炎(ulcerative colitis,UC)是一种局限于大肠黏膜及黏膜下层的炎症过程.中毒性巨结肠多发生在重症UC患者,其临床特征是严重的中毒症状及节段性或全结肠扩张[1].本文报道1例UC合并中毒性巨结肠患者的临床表现、诊疗经过及转归,以期提高临床医师对早期诊断、及时治疗的认识.

Background: The transport of transepithelial Cl- and HCO3- is crucial for the function of the intestinal epithelium and maintains the acid-based homeostasis. Slc26a3 (DRA), as a key chloride-bicarbonate exchanger protein in the intestinal epithelial luminal membrane, participates in the electroneutral NaCl absorption of intestine, together with Na+/H+ exchangers. Increasing recent evidence supports the essential role of decreased DRA function or expression in infectious diarrhea and inflammatory bowel disease (IBD).Method: In this review, we give an overview of the current knowledge of Slc26a3, including its cloning and expression, function, roles in infectious diarrhea and IBD, and mechanisms of actions. A better understanding of the physiological and pathophysiological relevance of Slc26a3 in infectious diarrhea and IBD may reveal novel targets for future therapy.Conclusion Understanding the physiological function, regulatory interactions, and the potential mechanisms of Slc26a3 in the pathophysiology of infectious diarrhea and IBD will define novel therapeutic approaches in future.

Background:The prompt diagnosis of pulmonary tuberculosis (PTB) remains a challenge in clinical practice. The present study aimed to optimize an algorithm for rapid diagnosis of PTB in a real-world setting.Methods:28,171 adult inpatients suspected of having PTB in China were retrospectively analyzed. Bronchoalveolar lavage fluid (BALF) and/or sputum were used for acid-fast bacilli (AFB) smear, Xpert MTB/RIF (Xpert), and culture. A positive mycobacterial culture was used as the reference standard. Peripheral blood mononuclear cells (PBMC) were used for T-SPOT.TB. We analyzed specimen types' effect on these assays' performance, determined the number of smears for diagnosing PTB, and evaluated the ability of these assays performed alone, or in combination, to diagnose PTB and nontuberculous mycobacteria (NTM) infections.Results:Sputum and BALF showed moderate to substantial consistency when they were used for AFB smear or Xpert, with a higher positive detection rate by BALF. 3-4 smears had a higher sensitivity than 1-2 smears. Moreover, simultaneous combination of AFB and Xpert correctly identified 44/51 of AFB+/Xpert+ and 6/7 of AFB+/Xpert- cases as PTB and NTM, respectively. Lastly, when combined with AFB/Xpert sequentially, T-SPOT showed limited roles in patients that were either AFB+ or Xpert+. However, T-SPOTMDC (manufacturer-defined cut-off) showed a high negative predicative value (99.1%) and suboptimal sensitivity (74.4%), and TBAg/PHA (ratio of Mycobacterium tuberculosis-specific antigens to phytohaemagglutinin spot-forming cells, which is a modified method calculating T-SPOT.TB assay results) ≥0.3 demonstrated a high specificity (95.7%) and a relatively low sensitivity (16.3%) in AFB-/Xpert- patients.Conclusions:Concurrently performing AFB smear (at least 3 smears) and Xpert on sputum and/or BALF could aid in rapid diagnosis of PTB and NTM infections in a real-world high-burden setting. If available, BALF is preferred for both AFB smear and Xpert. Expanding this algorithm, PBMC T-SPOTMDC and TBAg/PHA ratios have a supplementary role for PTB diagnosis in AFB-/Xpert- patients (moderately ruling out PTB and ruling in PTB, respectively). Our findings may also inform policy makers' decisions regarding prevention and control of TB in a high burden setting.