Pathogenesis Of Inflammatory Bowel Disease Research Articles

Bidirectional communication of the gut-brain axis: new findings in Parkinson’s disease and inflammatory bowel disease

Parkinson’s disease (PD) and inflammatory bowel disease (IBD) are the two chronic inflammatory diseases that are increasingly affecting millions of people worldwide, posing a major challenge to public health. PD and IBD show similarities in epidemiology, genetics, immune response, and gut microbiota. Here, we review the pathophysiology of these two diseases, including genetic factors, immune system imbalance, changes in gut microbial composition, and the effects of microbial metabolites (especially short-chain fatty acids). We elaborate on the gut–brain axis, focusing on role of gut microbiota in the pathogenesis of PD and IBD. In addition, we discuss several therapeutic strategies, including drug therapy, fecal microbiota transplantation, and probiotic supplementation, and their potential benefits in regulating intestinal microecology and relieving disease symptoms. Our analysis will provide a new understanding and scientific basis for the development of more effective therapeutic strategies for these diseases.

Outer Membrane Vesicles Derived from Adherent-Invasive Escherichia coli Induce Inflammatory Response and Alter the Gene Expression of Junction-Associated Proteins in Human Intestinal Epithelial Cells

Adherent-invasive Escherichia coli (AIEC) pathobionts, which are characterized by their ability to adhere to and invade intestinal epithelial cells, are associated with the etiopathogenesis of inflammatory bowel diseases (IBDs). Outer membrane vesicles (OMVs) released by AIEC strains can facilitate the interaction of these bacteria with host cells through delivering bacterial effectors. The aim of this study was to determine the ability of OMVs derived from AIEC strain LF82 to induce the host immune response, leading to production of proinflammatory cytokines and also altering the gene expression of junction-associated proteins in the human epithelial colorectal adenocarcinoma Caco-2 cell line. OMVs were extracted from AIEC strain LF82, and the cell viability of Caco-2 cells treated with these vesicles was assessed by MTT assay. The morphology and size distribution of vesicles were analyzed using transmission electron microscopy and dynamic light scattering, respectively. Gene expression of occludin, ZO-1, claudin-2, E-cadherin, TLR-2, and TLR-4 in response to OMVs was assessed in Caco-2 cells by RT-qPCR. Moreover, the secretion of IL-8 and TNF-α into the supernatant of Caco-2 cells upon treatment with OMVs was measured using ELISA. Our results demonstrated that OMVs upregulated the gene expression level of TLRs and also altered the gene expression level of junction-associated proteins. OMVs derived from AIEC may play a major role in the promotion of intestinal inflammation and epithelial barrier dysfunction. However, further investigations are needed to elucidate the putative role of OMVs in the pathogenesis of AIEC and IBD.

Ace Deficiency Induces Intestinal Inflammation in Zebrafish

Inflammatory bowel disease (IBD) is a nonspecific chronic inflammatory disease resulting from an immune disorder in the intestine that is prone to relapse and incurable. The understanding of the pathogenesis of IBD remains unclear. In this study, we found that ace (angiotensin-converting enzyme), expressed abundantly in the intestine, plays an important role in IBD. The deletion of ace in zebrafish caused intestinal inflammation with increased expression of the inflammatory marker genes interleukin 1 beta (il1b), matrix metallopeptidase 9 (mmp9), myeloid-specific peroxidase (mpx), leukocyte cell-derived chemotaxin-2-like (lect2l), and chemokine (C-X-C motif) ligand 8b (cxcl8b). Moreover, the secretion of mucus in the ace−/− mutants was significantly higher than that in the wild-type zebrafish, validating the phenotype of intestinal inflammation. This was further confirmed by the IBD model constructed using dextran sodium sulfate (DSS), in which the mutant zebrafish had a higher susceptibility to enteritis. Our study reveals the role of ace in intestinal homeostasis, providing a new target for potential therapeutic interventions.

The Impact of Microbiome Interventions on the Progression and Severity of Inflammatory Bowel Disease: A Systematic Review.

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic intestinal inflammation. The dysbiotic gut microbiome likely contributes to IBD pathogenesis. Microbiome-directed therapies such as fecal microbiota transplantation (FMT), probiotics, and synbiotics may help induce and maintain remission. This systematic review aimed to determine the efficacy of microbiome interventions compared to standard therapy or placebo for IBD treatment. PubMed, EMBASE, Cochrane CENTRAL, and Web of Science were searched for randomized controlled trials on microbiome interventions in IBD from inception to October 2023. The risk of bias was assessed using Cochrane tools. Outcomes included disease activity, endoscopy, histology, quality of life, and adverse events. A total of 18 randomized controlled trials were included. Three trials found intensive (i.e., high frequency of administration and/or large volumes of fecal material) multi-donor FMT superior to autologous FMT or glucocorticoids for UC remission induction. Seven placebo-controlled trials demonstrated higher remission rates with FMT, especially intensive protocols, versus control for mild-to-moderate UC. However, a single FMT did not prevent relapses. Seven probiotic trials showed the potential to improve UC activity and maintain remission. One synbiotic trial reported reduced inflammation and symptoms versus placebo. Serious adverse events were rare. Small sample sizes and protocol heterogeneity limited the conclusions. Current evidence indicates the potential benefits of microbiome interventions, particularly intensivemulti-donor FMT, for inducing and maintaining remission in UC. Probiotics may also improve outcomes. Adequately powered trials using standardized protocols are still needed to firmly establish efficacy and safety. Microbiome-directed therapies represent a promising approach for improving IBD outcomes.

The role of enhanced expression of Cx43 in patients with ulcerative colitis.

The pathogenesis of ulcerative colitis (UC) involves chronic inflammation of the submucosal layer and disruption of epithelial barrier function within the gastrointestinal tract. Connexin 43 (Cx43) has been implicated in the pathogenesis of intestinal inflammation and its associated carcinogenic effects. However, a comprehensive analysis of Cx43's role in mucosal and peripheral immunity in patients with UC is lacking. In this study, the colon tissues of patients with UC exhibited severe damage to the intestinal mucosal barrier, resulting in a significant impairment of junctional communication as observed by transmission electron microscopy. The mRNA expression of Cx43 was found to be significantly elevated in the UC group compared to the control group, as determined using the Affymetrix expression profile chip and subsequently validated using qRT-PCR. The immunofluorescence analysis revealed a significantly higher mean fluorescence intensity of Cx43 in the UC group compared to the control group. Additionally, Cx43 was observed in both the cell membrane and nucleus, providing clear evidence of nuclear translocation. The proportion of Cx43 in the UC group for CD4+ and CD8+ T lymphocytes was increased in the control group, but only the proportion of Cx43 for CD8+ T lymphocytes showed significant difference by flow cytometry. The involvement of Cx43 in the pathogenesis of UC and its potential role in mucosal immunity warrants further investigation, as it holds promise as a prospective biomarker and therapeutic target for this condition. The proportion of Cx43 in the UC group for CD4+ and CD8+ T lymphocytes was increased in the control group, but only the proportion of Cx43 for CD8+ T lymphocytes showed a significant difference.

Readily Available Oral Prebiotic Protein Reactive Oxygen Species Nanoscavengers for Synergistic Therapy of Inflammation and Fibrosis in Inflammatory Bowel Disease.

A significant gap exists in the demand for safe and effective drugs for inflammatory bowel disease (IBD), and its associated intestinal fibrosis. As oxidative stress plays a central role in the pathogenesis of IBD, astaxanthin (AST), a good antioxidant with high safety, holds promise for treating IBD. However, the application of AST is restricted by its poor solubility and easy oxidation. Herein, different protein-based nanoparticles (NPs) are fabricated for AST loading to identify an oral nanovehicle with potential clinical applicability. Through systematic validation via molecular dynamics simulation and in vitro characterization of properties, whey protein isolate (WPI)-driven NPs using a simple preparation method without the need for cross-linking agents or emulsifiers were identified as the optimal carrier for oral AST delivery. Upon oral administration, the WPI-driven NPs, benefiting from the intrinsic pH sensitivity and mucoadhesive properties, effectively shielded AST from degradation by gastric juices and targeted release of AST at intestinal lesion sites. Additionally, the AST NPs displayed potent therapeutic efficacy in both dextran sulfate sodium (DSS)-induced acute colitis and chronic colitis-associated intestinal fibrosis by ameliorating inflammation, oxidative damage, and intestinal microecology. In conclusion, the AST WPI NPs hold a potential therapeutic value in treating inflammation and fibrosis in IBD.

Сучасні уявлення про патогенетичні механізми розвитку запальних захворювань кишківника

The high frequency of prevalence and the decrease in the quality of life of patients determine the urgency of studying the peculiarities of the etiology and pathogenesis of inflammatory bowel diseases. The difficulty of finding new non-invasive markers lies in the lack of a clear understanding of the molecular mechanisms of the pathogenesis of these diseases. One of the promising directions in the diagnosis of chronic inflammatory diseases is the identification of specific miRNA molecules in blood serum, which act as powerful negative regulators of gene expression.

A prediction of the CRNDE role by modulating NF-κB pathway in inflammatory bowel disease (IBD)

Long non-coding RNAs (lncRNAs) regulate multiple pathways and cellular mechanisms. Recent research has emphasized their involvement in the pathogenesis of complex diseases, such as Inflammatory Bowel Disease (IBD) which is characterized by chronic inflammation of the intestines. The two most common types of IBD are ulcerative colitis and Crohn's disease. CRNDE lncRNA was initially detected in colorectal cancer (CRC) and found to be involved in the tumorigenesis pathways. Further studies revealed the role of CRNDE in activating inflammation and promoting the release of inflammatory cytokines. This study utilizes the RNA-seq data analysis and bioinformatics tools to clarify the role of CRNDE in the IBD pathogenesis and confirms its expression in inflamed HT-29 and Caco-2 cell lines and also colonic and blood samples of UC patients and controls ex vivo. Based on our results, CRNDE was significantly upregulated in IBD samples compared to controls in RNA-seq data analysis and Real-time PCR of inflamed HT-29 cell line and colonic biopsies from UC patients. Additionally, predicted that its expression is positively correlated with the pro-inflammatory cytokines production. CRNDE interactions was investigated with several inflammation-related miRNAs and regulatory proteins computationally. Thus, CRNDE upregulation in the colon of IBD patients could be involved in IBD pathogenesis by promoting inflammatory pathways and targeting anti-inflammatory miRNAs.

Exploring the Gut Microbiome's Role in Inflammatory Bowel Disease: Insights and Interventions.

Inflammatory Bowel Disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and relapsing inflammatory condition of the intestine that significantly impairs quality of life and imposes a heavy burden on healthcare systems globally. While the exact etiology of IBD is unclear, it is influenced by genetic, environmental, immunological, and microbial factors. Recent advances highlight the gut microbiome's pivotal role in IBD pathogenesis. The microbial dysbiosis characteristic of IBD, marked by a decline in beneficial bacteria and an increase in pathogenic microbes, suggests a profound connection between microbial imbalance and disease mechanisms. This review explores diagnostic approaches to IBD that integrate clinical assessment with advanced microbiological analyses, highlighting the potential of microbiome profiling as a non-invasive diagnostic tool. In addition, it evaluates conventional and emerging treatments and discusses microbiome-targeted intervention prospects, such as probiotics, symbiotics, and faecal microbiota transplantation. The necessity for future research to establish their efficacy and safety is emphasised.

Role of IL-33/ST2 Pathway in Inflammatory Bowel Disease: An Overview and Future Perspectives

Inflammatory bowel disease (IBD) represents a heterogenous and complex group of idiopathic chronic inflammatory conditions affecting the gastrointestinal tract and other extraintestinal systems with rising global incidences. The interplay of genetic predisposition and environmental factors contributes to its pathogenesis. Among the key cytokines implicated in IBD molecular alterations, IL-33 stands out for its multifaceted roles in both pathogenesis and repair mechanisms. IL-33, known for its action in initiating immune responses, is closely associated with Th2 immunity and is considered a potent inflammatory factor with dual functions, acting both as a pro-inflammatory cytokine and a transcriptional regulator. Primarily expressed by non-hematopoietic cells in the gastrointestinal tract, IL-33 interacts with its receptor, ST2, to modulate immune responses. In IBD, dysregulated IL-33 expression exacerbates mucosal inflammation, compromising barrier integrity and promoting tissue damage and fibrosis. Additionally, IL-33 plays a complex role in IBD-related colorectal cancer (CRC), affecting tumor progression and angiogenesis. This review summarizes the multifaceted roles of IL-33 in gastrointestinal health and disease, emphasizing its significance in the pathogenesis of IBD and CRC. Moreover, we thought it of interest to provide new insights into potential therapeutic avenues targeting IL-33 signaling for the management of these debilitating conditions.

Quercetin ameliorates ulcerative colitis by restoring the balance of M2/M1 and repairing the intestinal barrier via downregulating cGAS‒STING pathway.

Macrophage polarization is closely associated with the pathogenesis of ulcerative colitis (UC). Quercetin, a flavonoid, has shown promise as a treatment for inflammatory diseases, but its specific mechanism of action remains unclear. This study investigates whether quercetin can regulate intestinal macrophage polarization and promote intestinal tissue repair via the cGAS-STING pathway for the treatment of UC. In vivo, mice with 3% DSS-induced UC were intraperitoneally injected with quercetin and RU.521 for 7days, following which their general conditions and corresponding therapeutic effects were assessed. The impact of interferon-stimulated DNA (ISD) and quercetin on macrophage polarization and the cGAS-STING pathway was investigated using RAW264.7 cells and bone marrow-derived macrophages (BMDMs) in vitro. The results demonstrated that ISD induced M1 macrophage polarization and activated the cGAS-STING pathway in vitro, while quercetin reversed ISD's inflammatory effects. In vivo, quercetin suppressed the cGAS-STING pathway in the intestinal macrophages of DSS-induced UC mice, which reduced M1 macrophage polarization, increased M2 polarization, and facilitated intestinal barrier repair in UC. Taken together, these findings provide new insights into the mechanisms via which quercetin could be used to treat UC.

MTOR promotes an inflammatory response through the HIF1 signaling pathway in ulcerative colitis

The imbalance between T helper cell 17 （Th17）and regulatory T cells (Treg) cells leading to inflammation has an important role in the pathogenesis of ulcerative colitis (UC). Mammalian target of rapamycin (mTOR) can regulate the differentiation of T cells, but the specific pathway leading mTOR to regulate Th17/Treg cells in UC remains unclear. Our aim with this study was to investigate the effects of mTOR overexpression and silencing on the hypoxia inducible factor-1α (HIF-1α) − Th17/Treg signaling pathway. To mimic a human study, we established a colon cancer epithelial cell line (HT-29) co-culture system with human CD4+ T cells, and we treated the cells with TNF-α. We observed the effects of mTOR on the HIF-Th17/Treg signaling pathway to determine whether mTOR is involved in the regulatory mechanism.Under the stimulation of TNF-α, the levels of HIF-1α in CD4+T cells were increased in the HT-29 co-culture with CD4+ T cells, promoting glycolysis, increasing the Th17 proportion, decreasing the Treg proportion, increasing the pro-inflammatory factors levels, and decreasing the anti-inflammatory factors levels. Moreover, after mTOR silencing, the HIF-1α level and cell glycolysis levels decreased, Th17 cell differentiation decreased, the pro-inflammatory factor levels decreased, and the anti-inflammatory factor levels increased. In contrast, mTOR overexpression lead to the opposite results.mTOR promotes inflammation by regulating the HIF signaling pathway during UC, and silencing mTOR may alleviate inflammation. An mTOR inhibitor is a potential therapeutic target for UC treatment.

Assessment of the content of short-chain fatty acids in ulcerative colitis as an indicator of the patient's metabolic health

Numerous studies show that in the pathogenesis of ulcerative colitis (UC), a significant role is played by a change in the diversity of the intestinal microflora, which is associated with fewer bacteria producing short-chain fatty acids (SCFAs). SCFCS affect the differentiation and activation of cells of the immune system, play a protective role in maintaining the integrity of the epithelial barrier, participate in the regulation of intestinal peristalsis and blood supply to its wall, muscle anabolism, bioavailability of amino acids.The aim of the study. To evaluate the content of SCLC in the feces of UC patients with varying degrees of severity of the current attack, as well as to investigate the relationship between the content of SCLC with dietary characteristics, body mass index (BMI), and dyspenia.Materials and methods. The study involved 80 UC patients, conducted a survey, objective examination, filling out medical history and outpatient records, blood and stool sampling. The content of SCLC was determined in feces. The study of nutritional characteristics in patients with UC was conducted using a standardized questionnaire of the WHO CINDI program. Statistical methods: median (Me), upper and lower quartiles (P25, P75) were calculated; Mann-Whitney criterion; Kolmogorov-Smirnov criterion; nonparametric correlation analysis was performed.Results. The absolute content of SCFCS in the feces of patients with UC is lower than the reference values. The relative content of propionic acid in the subgroup with severe attack was significantly lower than in the remission subgroup, in the subgroup with mild and moderate attack of the disease. In patients with body weight deficiency, the relative content of propionic acid is lower than in UC patients with normal or overweight. A positive relationship was found between the total content of SCFCS in feces and the amount of dietary fiber consumed in the form of fruits and vegetables. In patients with dinapenia, the relative content of butyric acid in feces is significantly lower than in patients without dinapenia.

Mesenteric Lymphatic B Cells Migrate to the Intestine and Aggravate DSS-Induced Colitis via the CXCR5-CXCL13 Axis.

The pathogenesis of inflammatory bowel disease (IBD) is still unknown. Mesenteric lymphatics (MLs), which are closely related to the intestine in both anatomy and physiology, have been suggested to be involved in IBD. In the present study, we aim to investigate the effects of ML immune cells on IBD and explore the potential associated mechanisms. Acute colitis was induced in rats using dextran sulfate sodium salt (DSS). Mesenteric lymphangiogenesis, ML stenosis, and dilation were observed, with an increased proportion of MLB cells in DSS-induced colitis rats. The adoptive transfer of B cells isolated from ML (MLB) was employed to investigate their effects on colitis. MLB cells derived from DSS-induced colitis rats exhibited a higher propensity to migrate to the intestine. The proportion of colonic T cells was altered, along with the aggravated colitis induced by the adoptive transfer of MLB cells derived from DSS-induced colitis rats. RNA sequencing revealed increased Cxcr5 expression in MLB cells from colitis rats, while real-time PCR indicated an upregulation of its ligand Cxcl13 in the colon of colitis rats. These findings suggest that MLB cells may migrate to the intestine and aggravate colitis. In summary, colonic T cells respond to MLB cells from colitis rats, and MLB cells aggravate DSS-induced colitis via the CXCR5-CXCL13 axis.

Bacterial dysbiosis in newly diagnosed treatment naïve pediatric ulcerative colitis in Saudi Arabia.

The role of microbiota in the pathogenesis of ulcerative colitis (UC) has been increasingly recognized. However, most of the reports are from Western populations. In Middle Eastern countries, including Saudi Arabia, little is known about the role of microbiota. Therefore, our aim was to describe the bacterial microbiota profile and signature in pediatric UC in Saudi Arabia. Twenty children with UC and 20 healthy controls enrolled in the study gave stool samples. Twenty rectal mucosal samples were taken from UC and 20 from non-UC controls. Inclusion criteria included newly diagnosed and untreated children and lack of antibiotic exposure for at least 6 months before stool collection was required for children with UC and controls. Bacterial deoxyribonucleic acid was extracted and sequenced using shotgun metagenomic analysis. Statistical analysis included Shannon alpha diversity metrics, Bray-Curtis dissimilarity, DESeq2, and biomarker discovery. The demographic characteristics were similar in children with UC and controls. There was a significant reduction in alpha diversity (P = 0.037) and beta diversity in samples from children with UC (P = 0.001). Many taxa were identified with log2 abundance analysis, revealing 110 and 102 species significantly depleted and enriched in UC, respectively. Eleven bacterial species' signatures were identified. In Saudi Arabian children with UC, we demonstrate a dysbiosis similar to reports from Western populations, possibly related to changes of lifestyle. Microbial signature discovery in this report is an important contribution to research, leading to the development of adjunctive non-invasive diagnostic options in unusual cases of UC.

Role of Vitamin D in the Pathogenesis of Inflammatory Bowel Diseases: Literature Review

The pathogenesis of inflammatory bowel diseases still remains unclear nowadays. Genetic disposition, impaired immune regulation, disturbance in intestinal microbiota composition, exposure to environmental factors are associated with the development of inflammation in intestinal mucosa and increased epithelial penetrance that define disease's development and progression. There is a theory in scientific literature that vitamin D deficiency (among other environmental factors) increases the risk of inflammatory bowel disease. However, the role of vitamin D in the development of gastrointestinal tract diseases remains poorly studied. This article presents current data on the vitamin D effect on the intestinal mucosa barrier function, on the immune system and on the intestinal microbiota in the context of inflammatory bowel diseases pathogenesis.

Targeting programmed cell death in inflammatory bowel disease through natural products: New insights from molecular mechanisms to targeted therapies.

Inflammatory bowel disease (IBD) is an autoimmune disorder primarily characterized by intestinal inflammation and recurrent ulceration, leading to a compromised intestinal barrier and inflammatory infiltration. This disorder's pathogenesis is mainly attributed to extensive damage or death of intestinal epithelial cells, along with abnormal activation or impaired death regulation of immune cells and the release of various inflammatory factors, which contribute to the inflammatory environment in the intestines. Thus, maintaining intestinal homeostasis hinges on balancing the survival and functionality of various cell types. Programmed cell death (PCD) pathways, including apoptosis, pyroptosis, autophagy, ferroptosis, necroptosis, and neutrophil extracellular traps, are integral in the pathogenesis of IBD by mediating the death of intestinal epithelial and immune cells. Natural products derived from plants, fruits, and vegetables have shown potential in regulating PCD, offering preventive and therapeutic avenues for IBD. This article reviews the role of natural products in IBD treatment by focusing on targeting PCD pathways, opening new avenues for clinical IBD management.

Epigenetic Memory of Intestinal Epithelial Cells in Inflammatory Bowel Disease

Background: The pathogenesis of human Inflammatory Bowel Disease (IBD) is a multifactorial process including interaction between immune, epithelial, and environmental factors. Growing evidence suggests that epithelial cell defects play major role in the pathogenesis of IBD. Epigenetic memory involves lasting, cell-type specific modifications to chromatin at multiple scales, which impacts transcriptional programs required for normal cell functions. A major gap in knowledge are the mechanisms involved in establishing and maintaining memory in cell types and diseases of the intestine. The objective of this study was to determine if intestinal epithelial cells (IECs) retain a memory of altered chromatin architectures and resultant regulation following inflammation. The hypothesis was that the IECs would show lasting altered chromatin structure landscapes (epigenetic memory) in response to inflammation. Methods: We have developed a multicellular model system of IBD using adult stem cell derived organoids from humans with IBD, from regions of the colon with and without active inflammation. We performed ATAC-seq, bulk RNA-seq and single cell RNA-seq on these organoids derived from the uninflamed and inflamed tissues of IBD patients, specifically Ulcerative Colitis (UC). Results: Regions of increased chromatin accessibility are enriched in organoids derived from areas of inflammation in UC patients compared to organoids from patient-matched, uninflamed regions. These open chromatin regions are associated with proinflammatory genes, with modest transcriptional alterations, pointing to an epigenetic inflammatory memory. Motif analysis for accessibly peaks in UC showed an enrichment of the AP-1 family of transcription factors and chromatin remodelers (SMARCA4). This data is consistent with other studies of inflammatory memory from other epithelial cell types, but we show this for the first time in IECs in the context of IBD. Conclusions: This study presents a novel line of investigation and development of model systems to examine epigenetic memory of IECs in human IBD. We expect that our studies will identify new chromatin-based mechanisms of IEC function that are impacted by inflammation. This research was funded by American Gastroenterological Association Research Scholar Award and KL2 Scholar Career Development Award (KL2 TR002379, National Center for Advancing Translational Science). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Physiologically-based pharmacokinetic modeling to predict the exposure and provide dosage regimens of ustekinumab in pediatric patients with inflammatory bowel disease

Ustekinumab (UST), a fully human immunoglobulin G1 κ monoclonal antibody, exhibiting high affinity for the p40 subunit shared by IL-12 and IL-23, which play key roles in the pathogenesis of inflammatory bowel disease (IBD). By scaling the physiologically-based pharmacokinetic modeling (PBPK) model of UST in adult patients with IBD, we aim to predict effective dosages for UST in pediatric patients, thereby offering a more practical dosing regimen for real-world applications. In this work, a PBPK model for UST in adult patients with IBD has been developed using PK-Sim and Mobi. Advanced ontogeny model has been incorporated to extrapolate the model to pediatric patients. The simulation results showed that the fold errors of the predicted and observed values of the area under the curve (AUC) and peak plasma concentration (Cmax) were between 0.79 and 1.73. For children aged 6-18, it is recommended to administer the drug per kilogram of body weight, at the model-recommended dose, to achieve a median AUC similar to that of the adult reference population post-administration. This comprehensive model construction enables us to comprehensively and extensively explore the pharmacokinetic characteristics of UST in pediatric patients of different age groups, providing robust support for clinical applications and personalized drug therapy.

17β-estradiol promotes myeloid-derived suppressor cells functions and alleviates inflammatory bowel disease by activation of Stat3 and NF-κB signalings

Inflammatory bowel disease (IBD) describes a group of clinically common autoimmune diseases characterized by chronic intestinal inflammation, with gender differences in prevalence. Estrogen has been previously shown to exert anti-inflammatory action in IBD development, however, the mechanisms remain obscure. Recent research has revealed that myeloid-derived suppressor cells (MDSCs) play a protective role in IBD pathogenesis. To investigate the molecular mechanisms of estrogen steroid 17β-estradiol (E2) in IBD progression, we established IBD mouse models (DNB-induced) with or without prior ovariectomy (OVX) and E2 implantation. We found that OVX led to worse IBD symptoms and reduced MDSCs frequency, whereas E2 significantly alleviated these effects in vivo. Moreover, in vitro experiments showed that E2 promoted the proliferation and immunosuppressive function of MDSCs through phosphorylation of Stat3 and p65. Mechanistically, E2-mediated Stat3/p65 phosphorylation depends on the interaction between HOTAIR, a long non-coding RNA that are well-known in MDSCs proliferation, and Stat3/p65 respectively. In conclusion, our study revealed that E2 promotes the expansion and immunosuppressive function of MDSCs, and thus diminished the occurrence and development of IBD.