Pathogenesis Of Inflammatory Bowel Disease Research Articles

Enteric-coated cerium dioxide nanoparticles for effective inflammatory bowel disease treatment by regulating the redox balance and gut microbiome

Reactive oxygen species (ROS) play crucial roles in the pathogenesis of inflammatory bowel disease (IBD) by disrupting the mucosal barrier and subsequently leading to the dysregulation of the gut microbiome. Therefore, ROS scavengers present a promising and comprehensive strategy for the effective IBD treatment. In the current work, we explored the therapeutic potential of cerium dioxide (CeO2) nano-enzyme, which is well-known for their potent antioxidant properties and capability to mimic natural antioxidant enzymes in the regulation of oxidative stress. We developed a novel enteric-coated nanomedicine (CeO2@S100) aiming at improving the oral delivery efficacy of CeO2 in the complex gastrointestinal environment. CeO2@S100 is composed of a CeO2 nanoparticle core and a protective polyacrylic acid resin shell (Eudragit S100), ensuring targeted delivery of the core specifically at inflamed intestinal sites due to the negative surface charge. In vivo experiments revealed CeO2@S100 significantly alleviates the IBD by balancing oxidative stress and regulating gut microbiota in a dextran sulfate sodium-induced mouse colitis model. The uncomplicated synthesis of CeO2@S100 highlights its promise for clinical use, presenting an effective and safe approach to managing IBD.

Lactic Acid Bacteria–Gut-Microbiota-Mediated Intervention towards Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), arises from intricate interactions involving genetics, environment, and pharmaceuticals with an ambiguous pathogenic mechanism. Recently, there has been an increasing utilization of lactic acid bacteria (LAB) in managing IBD, attributed to their ability to enhance intestinal barrier function, mitigate inflammatory responses, and modulate gut microbiota. This review initiates by elucidating the pathogenesis of IBD and its determinants, followed by an exploration of the mechanisms underlying LAB therapy in UC and CD. Special attention is directed towards their influence on intestinal barrier function and homeostasis regulated by gut microbiota. Furthermore, the review investigates the complex interplay among pivotal gut microbiota, metabolites, and pathways associated with inflammation. Moreover, it underscores the limitations of LAB in treating IBD, particularly in light of their varying roles in UC and CD. This comprehensive analysis endeavors to offer insights for the optimized application of LAB in IBD therapy.

Key Disease-Related Genes and Immune Cell Infiltration Landscape in Inflammatory Bowel Disease: A Bioinformatics Investigation.

Inflammatory Bowel Diseases (IBD), which encompass ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic inflammation and tissue damage of the gastrointestinal tract. This study aimed to uncover novel disease-gene signatures, dysregulated pathways, and the immune cell infiltration landscape of inflamed tissues. Eight publicly available transcriptomic datasets, including inflamed and non-inflamed tissues from CD and UC patients were analyzed. Common differentially expressed genes (DEGs) were identified through meta-analysis, revealing 180 DEGs. DEGs were implicated in leukocyte transendothelial migration, PI3K-Akt, chemokine, NOD-like receptors, TNF signaling pathways, and pathways in cancer. Protein-protein interaction network and cluster analysis identified 14 central IBD players, which were validated using eight external datasets. Disease module construction using the NeDRex platform identified nine out of 14 disease-associated genes (CYBB, RAC2, GNAI2, ITGA4, CYBA, NCF4, CPT1A, NCF2, and PCK1). Immune infiltration profile assessment revealed a significantly higher degree of infiltration of neutrophils, activated dendritic cells, plasma cells, mast cells (resting/activated), B cells (memory/naïve), regulatory T cells, and M0 and M1 macrophages in inflamed IBD tissue. Collectively, this study identified the immune infiltration profile and nine disease-associated genes as potential modulators of IBD pathogenesis, offering insights into disease molecular mechanisms, and highlighting potential disease modulators and immune cell dynamics.

The Role of Host Genetics and Intestinal Microbiota and Metabolome as a New Insight into IBD Pathogenesis.

Inflammatory bowel disease (IBD) is an incurable, chronic disorder of the gastrointestinal tract whose incidence increases every year. Scientific research constantly delivers new information about the disease and its multivariate, complex etiology. Nevertheless, full discovery and understanding of the complete mechanism of IBD pathogenesis still pose a significant challenge to today's science. Recent studies have unanimously confirmed the association of gut microbial dysbiosis with IBD and its contribution to the regulation of the inflammatory process. It transpires that the altered composition of pathogenic and commensal bacteria is not only characteristic of disturbed intestinal homeostasis in IBD, but also of viruses, parasites, and fungi, which are active in the intestine. The crucial function of the microbial metabolome in the human body is altered, which causes a wide range of effects on the host, thus providing a basis for the disease. On the other hand, human genomic and functional research has revealed more loci that play an essential role in gut homeostasis regulation, the immune response, and intestinal epithelial function. This review aims to organize and summarize the currently available knowledge concerning the role and interaction of crucial factors associated with IBD pathogenesis, notably, host genetic composition, intestinal microbiota and metabolome, and immune regulation.

ACSL4 mediates inflammatory bowel disease and contributes to LPS-induced intestinal epithelial cell dysfunction by activating ferroptosis and inflammation.

The pathogenesis of inflammatory bowel disease (IBD) is closely associated with the dysfunction of the intestinal epithelial barrier, leading to increased bacterial translocation, leukocyte infiltration, and mucosal injury, which may act as a pivotal or incipient event in the pathophysiology of the disorder. The primary objective of this study is to examine the key genes implicated in IBD and the perturbation of intestinal epithelial cell function. The genes associated with ferroptosis were identified through the utilization of the Gene Expression Omnibus (GEO) database and the GeneCard database. Additionally, an in vitro model of IBD was established by stimulating Caco-2 cells with lipopolysaccharides (LPSs) to investigate the molecular mechanisms underlying intestinal epithelial cell dysfunction. We discovered evidence that establishes a connection between ferroptosis and the inflammatory responses associated with the development of IBD. This evidence suggests that IBD patients who exhibit an inflammatory response have higher expression of the acyl-CoA synthetase long-chain family member 4 (ACSL4) gene compared to IBD patients without an inflammatory response or healthy individuals. Exposure to LPS at concentrations of 1 or 10 μg/mL resulted in a significant upregulation of ferroptosis-related genes ACSL4, GPX4, and SLC7A11, as well as an increase in ferroptosis biomarkers MDA and a decrease in CAT and GSH-Px levels compared to the control group. Inhibition of ACSL4 using si-ACSL4 or rosiglitazone demonstrated protective effects against LPS-induced ferroptosis and NF-κB-mediated inflammatory response. ACSL4 shows potential as a promising target for ferroptosis in the prevention and treatment of IBD and dysfunction of intestinal epithelial cells.

Patients with Inflammatory Bowel Disease Show Fewer Sex-Related Differences in Their Dietary Behavior Than the General Population: A Qualitative Analysis.

Since diet is generally recognized as an important factor directly modulating the gut microbiome, it is also considered a potential environmental triggering factor for the pathogenesis and onset of inflammatory bowel disease (IBD). While the habitual and sex-related dietary behavior of the general population has been the subject of extensive study and reporting, data on IBD patients' dietary behavior and especially its sex-related differences are underrepresented. However, as diet is an important factor in the course of IBD, we hypothesized that men and women with IBD have a different dietary profile than the general population. We performed a cohort analysis of a monocentric, cross-sectional study and compared the sex-related dietary behavior of 82 IBD patients (n = 40 women) to a sex- and age-matched cohort of the general German population [n = 328 (n = 160 women)]. Further on, disease-related quality of life and fecal calprotectin were correlated to the IBD patients' dietary behavior. While sex-related dietary behavior was frequently of statistical difference in the general population within the IBD cohort, only minor numerical differences were observed between the sexes, which were rarely statistically significant. However, correlation analyses of disease-related quality of life (IBDQ) and diet revealed significant differences in male IBD patients but not in female IBD patients (p = 0.007; r = 0.409 for energy intake (kJ/d); p = 0.003, r = 0.449 for adherence to Mediterranean diet). The dietary behavior of IBD patients showed more similarity between the sexes than the general German population. Distinct sex-related trends and differences in correlation with disease parameters demonstrated a significant difference for an adaptive dietary behavior, especially in IBD men.

Intestinal epithelial vitamin D receptor defense against inflammatory bowel disease via regulating microfold cells

Vitamin D receptor (VDR) is involved in the pathogenesis of inflammatory bowel disease (IBD). However, the mechanism of VDR in IBD is still unclear. Microfold cells (M cells) mediated antigen-sampling pathway is central in developing immune responses to pathogenic and commensal bacteria and related to IBD. We found that Intestinal epithelial cell-specific knockdown of VDR(VDRIEC-KO) increases the susceptibility of mice to experimental colitis induced by sodium dextran sulfate(DSS) by producing more M cells. Knockdown VDR in intestinal epithelial cells increased RANKL-induced microfold cells and promoted the ability of microfold cells to uptake S. Typhimurium (S. T.). Mechanistically, we demonstrated that knockdown VDR promoted the differentiation and maturation of M cells via the Spi-B-dependent pathway. We conclude that M cells may be a potential target of VDR for treating intestinal mucosal barrier dysfunction in IBD.

Bacteroides salyersiae Is a Candidate Probiotic Species with Potential Anti-Colitis Properties in the Human Colon: First Evidence from an In Vivo Mouse Model.

Previous studies have indicated a critical role of intestinal bacteria in the pathogenesis of ulcerative colitis (UC). B. salyersiae is a commensal species from the human gut microbiota. However, what effect it has on UC development has not been investigated. In the present study, we explored this issue and demonstrated for the first time that oral administration of B. salyersiae CSP6, a bacterium previously isolated from the fecal sample of a healthy individual, protected against dextran sulfate sodium (DSS)-induced colitis in C57BL/6J mice. In particular, B. salyersiae CSP6 improved mucosal damage and attenuated gut dysbiosis in the colon of DSS-fed mice. Specifically, B. salyersiae CSP6 decreased the population of pathogenic Escherichia-Shigella spp. and increased the abundance of probiotic Dubosiella spp. and Bifidobacterium pseudolongum. Additionally, by reshaping the colonic microbiota, B. salyersiae CSP6 remarkably increased the fecal concentrations of equol, 8-deoxylactucin, and tiglic acid, three beneficial metabolites that have been well documented to exert strong anti-inflammatory effects. Altogether, our study provides novel evidence that B. salyersiae is a candidate probiotic species with potential anti-colitis properties in the human colon, which has applications for the development of next-generation probiotics.

Puerarin ameliorates colitis by direct suppression of macrophage M1 polarization in DSS mice

BackgroundUlcerative colitis (UC) is a type of inflammatory bowel disease primarily affecting the colon and rectum. The clinical symptoms of UC include persistent diarrhea, abdominal pain, and rectal bleeding, with chronic inflammation often limited to the mucosal layer of the colon. Macrophages play a significant role in the pathogenesis of UC in response to the presence of gut microbiota. Puerarin is an active compound derived from the root of pueraria lobata, a traditional Chinese herbal medicine, and exhibits potent anti-inflammatory properties in various diseases and disease models including UC-like colitis in mice. However, how the molecule achieves its therapeutic effect in colitis by re-polarizing macrophages remains poorly understood. PurposeUtilizing in vivo and in vitro experimental methods along with multi-omics analysis, we aimed to elucidate the potential mechanism by which puerarin targets macrophages to treat colitis. MethodsThe inflammation induced by DSS was assessed both locally in the gut and systemically, and the anti-inflammatory effect of puerarin was evaluated using molecular and histological assays such as H&E staining, qPCR, ELISA, Western blot, and immunofluorescence. Intestinal permeability parameters were measured by in vivo imaging, immunofluorescence, Western blot, qPCR, and PAS staining. The central role of macrophages in colitis was investigated through macrophage depletion/infusion using cytological methods. The direct effects of puerarin on the macrophages were examined by CCK8, flow cytometry, and qPCR in vitro. Additionally, 16S rRNA sequencing and metabolomics analysis of gut contents were conducted. Identification of key pathogenic flora was facilitated by a trans-omic approach and validated both in vitro and in vivo. ResultsPuerarin exerted a direct and robust suppression of M1-like polarization of macrophages in vitro, which was sufficient to confer therapeutic benefits in terms of colonic lesions and systemic inflammation in DSS mice. Puerarin also reduced the abundance of Akkermansia muciniphila in the gut, which was significantly upregulated in DSS mice in our experimental context. Further study demonstrated that puerarin effectively suppressed M1-like macrophage activation induced by Akkermansia muciniphila secreted protein Amuc_2172, thereby altering the pathology in the DSS model. ConclusionOur data suggest that the pathogenesis of DSS colitis is mediated by host cellular responses to toxic foreign molecules and the gut microbiota, and targeting specific cell populations, such as macrophages, with puerarin holds potential therapeutic value.

Exploration of the Human Microbiome’s Role in Health and Disease through the Lens of Genetics

The human microbiome is a complex ecosystem of bacteria residing in the body. It plays a crucial role in safeguarding the overall well-being of individuals while also making them more vulnerable to various diseases. The human microbiota, genetics, and health have a complex connection, which is significant for maintaining health and preventing infections. The microbiome has a role in several gastrointestinal, skin, dental, and systemic diseases, such as obesity, diabetes, and autoimmune disorders. Genetic variation and lifestyle and dietary choices modify the microbiome composition, thereby influencing the risk of developing severe infections. The microbiome impacts host gene expression and acts as a biomarker for several diseases. The gut microbiome and genes are linked in the pathogenesis of obesity and inflammatory bowel disease. Therefore, this review focuses on the relationship between the microbiome and genetics and elucidation of the complexity of this connection. Future research-based microbiome interventions to prevent diseases could lead to strategies for personalized medicine that enhance treatment efficacy and health outcomes.

Anti-DEFA5 Monoclonal Antibody Clones 1A8 and 4F5 Immunoreactive Bioassay for Diagnosing Inflammatory Bowel Disease.

Background Robust evidence suggests that the aberrant expression of α defensin 5 protein (DEFA5) in colon inflammatory bowel diseases (IBDs) underlies the distinct pathogenesis of Crohn's colitis, can be exploited as a reliable diagnostic biomarker to differential diagnosis of Crohn's colitis (CC) from Ulcerative colitis (UC) in otherwise indeterminate colitis (IC). We evaluated the specificity of the commercially available anti-DEFA5 antibodies and showed further validation of their appropriateness for a given application is required. Methods We established two mouse monoclonal DEFA5 antibody clones 1A8 and 4F5 by immunizing the mice with purified recombinant protein and validated the specificity, selectivity and cross reactivity in recognizing the endogenous and recombinant DEFA5 protein, especially for Immunohistochemistry, Western blot, Immunoprecipitation, or enzyme-linked immunosorbent assay. Results Clones 1A8 and 4F5 recognized effectively the endogenous DEFA5 in active human diverticulitis (DV), UC, CC or IC disease samples, including transiently transfected HEK293T cells expressing DEFA5 with high degree of specificity and minimal non-confounding cross reactivity. Conclusions 1A8 and 4F5 clones are worth studying in larger IBD cohorts to fully address whether DEFA5 expression may be used as a diagnostic biomarker to discrimination of the diagnosis of UC from CC or IC into authentic CC or UC or a colitis with different pathological characteristics.

Case-control study of IL23R rs76418789 polymorphism, smoking, and ulcerative colitis in Japan

BackgroundInterleukin (IL)-23 is involved in the pathogenesis of ulcerative colitis (UC). A genome-wide significant association between IL23R p.G149R (rs76418789) and UC was previously identified in Japan and Korea. This case-control study aims to examine this association within the Japanese population. MethodsThe study included 384 cases diagnosed with UC within the past 4 years and 661 control subjects. Adjustment was made for sex, age, and smoking. ResultsThe frequency of the AA genotype of rs76418789 was 0.0 % in cases and 0.5 % in control subjects. In comparison to study subjects with the GG genotype of rs76418789, those with the GA or AA genotype had a significantly reduced risk of UC, with an adjusted odds ratio of 0.67 (95 % confidence interval: 0.44–0.999). A significant multiplicative interaction was observed between rs76418789 and having ever smoked influencing UC (p for interaction = 0.03). A significant positive association was found between having ever smoked and UC in individuals with at least one A allele, while no such positive relationship was observed in those with the GG genotype. ConclusionIL23R SNP rs76418789 showed a significant association with UC. This study provides new evidence regarding the interaction between rs76418789 and smoking in relation to UC.

Hereditary Colorectal Cancer Syndromes and Inflammatory Bowel Diseases: Risk Management and Surveillance Strategies.

Background and aims: Hereditary colorectal cancer syndromes (HCCS), including familial adenomatous polyposis (FAP) and Lynch syndrome (LS), are the two most important high-risk conditions for colorectal cancer (CRC). Inflammatory bowel disease (IBD) increases the risk by two to six times compared with that in the general population. The intersection of these two conditions has rarely been documented in literature. We aimed to summarize the prevalence, pathogenesis, and current evidence-based management of IBD and HCCS and the underlying molecular mechanisms of accelerated carcinogenesis due to combined inflammation and genetic predisposition. Methods: PubMed and Scopus were searched until June 2024 to identify relevant studies investigating the epidemiology, pathogenesis, and management of IBD and coexisting hereditary CRC syndromes. Results: Co-occurrence of IBD and hereditary CRC syndromes is exceptionally uncommon. Individuals with LS and IBD tend to develop CRC at a younger age than those without IBD, with patients with ulcerative colitis facing particularly elevated risks. The interaction between mismatch deficiency and chronic inflammation requires further investigation.

Spatio-temporally controlled all-in-one hydrogel microspheres for ulcerative colitis treatment based on cocktail strategy

Due to the complex pathogenesis of ulcerative colitis (UC), particularly excessive reactive oxygen species (ROS), gut microbiota dysbiosis, and hyperpolarization of M1 macrophages, the cocktail strategy is urgently needed to obtain a sufficient therapeutic outcome. Meanwhile, the accurate lesion location targeting of these combined therapeutic agents is still crucial. Herein, based on NPs-in-MPs approach, a novel integrated “all-in-one” oral delivery system (BMM/MPs), containing the natural gut microbiota regulator berberine, MnO2 nanoenzymes, and cell penetrating peptides-decorated magnolol liposomes to regulate macrophage polarization, was constructed to address these above issues in sequence. BMM/MPs could non-destructively cross the gastrointestinal tract, enduringly detain, and dissociate in the colon site due to the pH-sensitive properties. Conceivably, the released MnO2 nanoenzymes depleted the excess ROS at the colitis location into O2, sequentially promoting the acceleration of hydrogel microspheres rupture and oxidative damage remission. Accordingly, the oral administration of BMM/MPs exhibited remarkably satisfactory therapeutic effects against DSS-induced UC mice, by ameliorating the representative symptoms, scavenging ROS, relieving inflammation, and inhibiting M1 macrophage polarization at colon sites. Meanwhile, the dysbiosis of microbes was effectively regulated by facilitating SCFAs production. This study provides a feasible strategy for administration in the treatment of UC.

Lymphocyte subsets for predicting inflammatory bowel disease progression and treatment response: a systematic review.

Lymphocytes play a key role in the pathogenesis of inflammatory bowel disease (IBD) and are widely explored as promising prognostic indicators. We aimed to outline the existing evidences on the capability of lymphocyte subpopulations to predict disease progression and treatment response in patients with IBD. The protocol for this review was registered in PROSPERO (registration ID: CRD 42022364126). Systematic retrieval was conducted using PubMed, Embase, and Web of Science databases. Original articles on the prognostic value of lymphocyte subsets in IBD published up to April 8, 2023 were eligible for inclusion. The Newcastle-Ottawa Scale was used to evaluate the risk of bias. Twenty studies were ultimately included: eight evaluated the prediction of disease progression and 12 focused on the prediction of treatment response. According to the Newcastle-Ottawa Scale, three studies were of high quality, 16 were of moderate quality, and only one was of low quality. T-cell subpopulations, including CD4+ T cells, CD8+ T cells, and γδ T cells, are revealed to have prognostic capacity. Transmembrane tumor necrosis factor α-bearing lymphocytes, CD4+ T cells, CD8+ T cells, and Plasma cells are found to have the potential to predict the response to anti-TNFα agents. In contrast memory T cells, CD4+ T cells, and naïve B cells may predict the response to vedolizumab. This systematic review identified several potential lymphocyte subset-related predictors. If verified in large cohort prospective studies, these findings could aid clinical decision-making. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022364126.

Cardiovascular Risk in Patients with Inflammatory Bowel Diseases-The Role of Endothelial Dysfunction.

Inflammatory bowel disease (IBD) is associated with an increased risk of cardiovascular disease (CVD). Cardiovascular pathology in people with IBD has not been well studied to date, and a direct link between cardiovascular events and IBD has not been established. The mechanisms underlying this association include the parallel and dynamic interaction of inflammation, modulation of the composition of the gut microbiota, endothelial dysfunction, thrombogenicity, and increased endothelial and epithelial permeability. Endothelial dysfunction is a common aspect of the pathogenesis of IBD and atherosclerotic CVD and can be considered one of the most important factors leading to the development and progression of cardiovascular pathology in patients with IBD. The purpose of this literature review is to describe the mechanisms underlying the development of endothelial dysfunction and disorders of the structure and function of the gut-vascular barrier in the pathogenesis of the cardiovascular manifestation of IBD.

Mouse adaptation of human inflammatory bowel diseases microbiota enhances colonization efficiency and alters microbiome aggressiveness depending on the recipient colonic inflammatory environment

BackgroundUnderstanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis.ResultsOur study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10−/− mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10−/− mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10−/− host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10−/− mice than the distinct microbiota reassembled in non-inflamed WT hosts.ConclusionsOur findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer.9-8iLEe2BorBmu_z2q_8UWVideo

Clickable nanozyme enhances precise colonization of probiotics for ameliorating inflammatory bowel disease

Convincing evidence suggests that aberrant gut microbiota changes play a critical role in the progression and pathogenesis of inflammatory bowel disease (IBD). Probiotic therapeutic interventions targeting the microbiota may provide alternative avenues to treat IBD, but currently available probiotics often suffer from low intestinal colonization and limited targeting capability. Here, we developed azido (N3)-modified Prussian blue nanozyme (PB@N3) spatio-temporal guidance enhances the targeted colonization of probiotics to alleviate intestinal inflammation. First, clickable PB@N3 targets intestinal inflammation, simultaneously, it scavenges reactive oxygen species (ROS). Subsequently, utilizing “click” chemistry to spatio-temporally guide targeted colonization of dibenzocyclooctyne (DBCO)-modified Lactobacillus reuteri DSM 17938 (LR@DBCO). The “click” reaction between PB@N3 and LR@DBCO has excellent specificity and efficacy both in vivo and in vitro. Despite the complex physiological environment of IBD, “click” reaction can prolong the retention time of probiotics in the intestine. Dextran sulfate sodium (DSS)-induced colitis mice model, demonstrates that the combination of PB@N3 and LR@DBCO effectively mitigates levels of ROS, enhances the colonization of probiotics, modulates intestinal flora composition and function, regulates immune profiles, restores intestinal barrier function, and alleviates intestinal inflammation. Hence, PB@N3 spatio-temporal guidance enhances targeted colonization of LR@DBCO provides a promising medical treatment strategy for IBD.

Characterization of novel CD8+ regulatory T cells and their modulatory effects in murine model of inflammatory bowel disease

Dysregulation of mucosal immune system has been proposed to be critical in the pathogenesis of inflammatory bowel diseases (IBDs). Regulatory T cells (Tregs) play an important role in regulating immune responses. Tregs are involved in maintaining intestinal homeostasis and exerting suppressive function in colitis. Our previous studies showed that a novel forkhead box protein P3 (Foxp3) negative Tregs (Treg-of-B cells), induced by culturing naïve CD4+ T cells with B cells, could protect against colitis and downregulate T helper (Th) 1 and Th17 cell cytokines in T cell-mediated colitis. In the present study, we aimed to induce Treg-of-B cells in the CD8+ T-cell population and investigate their characteristics and immunomodulatory functions. Our results showed that CD8+ Treg-of-B cells expressed Treg-associated markers, including lymphocyte-activation gene-3 (LAG3), inducible co-stimulator (ICOS), programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), tumor necrosis factor receptor superfamily member-4 (TNFRSF4, OX40), and tumor necrosis factor receptor superfamily member-18 (TNFRSF18, GITR), but did not express Foxp3. CD8+ Treg-of-B cells produced higher concentration of inhibitory cytokine interleukin (IL)-10, and expressed higher levels of cytotoxic factor granzyme B and perforin after stimulation, compared to those of CD8+CD25- T cells. Moreover, CD8+ Treg-of-B cells suppressed T cell proliferation in vitro and alleviated colonic inflammation in chronic dextran sulfate sodium (DSS)-induced colitis. In conclusion, our study identified a novel subpopulation of CD8+ Tregs with suppressive effects through cell contact. These CD8+ Treg-of-B cells might have therapeutic potential for IBDs.

Inherent preference for polyunsaturated fatty acids instigates ferroptosis of Treg cells that aggravates high-fat-diet-related colitis

Inflammatory bowel disease (IBD) has high prevalence in Western counties. The high fat content in Western diets is one of the leading causes for this prevalence; however, the underlying mechanisms have not been fully defined. Here, we find that high-fat diet (HFD) induces ferroptosis of intestinal regulatory T (Treg) cells, which might be the key initiating step for the disruption of immunotolerance and the development of colitis. Compared with effector Tcells, Treg cells favor lipid metabolism and prefer polyunsaturated fatty acids (PUFAs) for the synthesis of membrane phospholipids. Therefore, consumption of HFD, which has high content of PUFAs such as arachidonic acid, cultivates vulnerable Tregs that are fragile to lipid peroxidation and ferroptosis. Treg-cell-specific deficiency of GPX4, the key enzyme in maintaining cellular redox homeostasis and preventing ferroptosis, dramatically aggravates the pathogenesis of HFD-induced IBD. Taken together, these studies expand our understanding of IBD etiology.