Pathogenesis Of Inflammatory Bowel Disease Research Articles

Oral Delivery of miR146a Conjugated to Cerium Oxide Nanoparticles Improves an Established T Cell-Mediated Experimental Colitis in Mice

Background: Dysregulated inflammation and oxidative stress are strongly implicated in the pathogenesis of inflammatory bowel disease. We have developed a novel therapeutic that targets inflammation and oxidative stress. It is comprised of microRNA-146a (miR146a)-loaded cerium oxide nanoparticles (CNPs) (CNP-miR146a). We hypothesized that oral delivery of CNP-miR146a would reduce colonic inflammation in a mouse model of established, chronic, T cell-mediated colitis. Methods: The stability of CNP-miR146a and mucosal delivery was assessed in vitro with simulated gastrointestinal fluid and in vivo after oral gavage by quantitative real-time RT-PCR. The efficacy of orally administered CNP-miR146a was tested in mice with established colitis using the model of adoptive naïve T-cell transfer in recombinant activating gene 2 knockout (Rag2−/−) mice. Measured outcomes included histopathology; CD45+ immune cell infiltration; oxidative DNA damage (tissue 8-hydroxy-2′-deoxyguanosine; 8-OHdG); expression of IL-6 and TNF mRNA and protein, and flow cytometry analysis of lamina propria Th1 and Th17 cell populations. Results: miR146a expression remained stable in simulated gastric and intestinal conditions. miR146a expression increased in the intestines of mice six hours following oral gavage of CNP-miR146a. Oral delivery of CNP-miR146a in mice with colitis was associated with reduced inflammation and oxidative stress in the proximal and distal colons as evidenced by histopathology scoring, reduced immune cell infiltration, reduced IL-6 and TNF expression, and decreased populations of CD4+Tbet+IFNg+ Th1, CD4+RorgT+IL17+ Th17, as well as pathogenic double positive IFNg+IL17+ T cells. Conclusions: CNP-miR146a represents a novel orally available therapeutic with high potential to advance into clinical trials.

Fibroblast Heterogeneity in Inflammatory Bowel Disease

Intestinal fibroblasts are pivotal players in maintaining tissue homeostasis and orchestrating responses to injury and inflammation within the gastrointestinal (GI) tract. Fibroblasts contribute significantly to the pathogenesis of inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis (UC), by secreting pro-inflammatory cytokines, modulating immune cell activity, and promoting fibrosis. In addition, fibroblasts play crucial roles in tissue repair and regeneration following acute injury or chronic inflammation. The dysregulation of fibroblast functions can lead to fibrotic complications, such as intestinal strictures and obstruction, which are common in advanced stages of IBD. Understanding the complex interplay between fibroblasts and other cell types in the intestine is essential to elucidate the underlying mechanisms of intestinal diseases and identify novel therapeutic targets. Future research aimed at deciphering the heterogeneity of intestinal fibroblasts and their dynamic roles in disease progression holds promise for the development of precision therapies to mitigate fibrosis and inflammation in intestinal disorders.

The role of Interleukin-38 in modulating T cells in chronic Colitis: A mouse model study

BackgroundInterleukin (IL)-38 belongs to the IL-36 subfamily within the IL-1 family. Patients with inflammatory bowel diseases (IBD) exhibit higher levels of IL-38 in their intestinal tissue compared to healthy controls, suggesting that IL-38 may play a role in the pathogenesis of IBD. However, IL-38′s impact on T cell-mediated immune responses in gastrointestinal inflammation has not been investigated. Therefore, the objective of this work was to elucidate the role of IL-38 in modulating T cells in a mouse model of dextran sulfate sodium (DSS)-induced chronic colitis. MethodsRecombinant IL-38 (rIL-38) was administered intraperitoneally (i.p.) to mice with chronic colitis induced by DSS. Clinical symptoms, length of colon, and histologic alterations were assessed. Cytokine production was quantified using ELISA, and helper T (Th) cell subsets were evaluated via flow cytometry. ResultsAdministration of recombinant IL-38 (rIL-38) alleviated DSS-induced chronic colitis. In addition, animals with chronic colitis treated with rIL-38 exhibited a significant decrease in the spontaneous production of inflammatory cytokines by neutrophils in the lamina propria. Furthermore, rIL-38 treatment increased the absolute numbers and percentages of regulatory T cells (Tregs) but decreased the absolute numbers and percentages of Th1 and Th17 cells. Moreover, rIL-38 treatment also decreased IL-17A-producing γδT cells substantially. ConclusionThis study’s results show that IL-38 reduces the effects of chronic colitis caused by DSS by boosting Treg reactions and reducing Th1/Th17 reactions and IL-17A-producing γδT cells in LPL. Therefore, we propose that IL-38 has the potential to be utilized as a biological therapy agent for IBD.

Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1

Ulcerative colitis (UC) is characterized by increased cell death in intestinal epithelial cell (IEC), which compromises gut barrier function and activates inflammation. Aberrant mitochondrial dynamics have been implicated in various forms of cell death, but it is currently unclear if they play a role in IEC death and colitis pathogenesis. This study aims to investigate the contribution of aberrant mitochondrial dynamics to colitis progression using cellular models, animal models, and clinical samples. The results revealed that IEC in mice with Dextran sulfate sodium salt (DSS)-induced colitis exhibited dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and Z-DNA binding protein 1 (ZBP1)-dependent PANoptosis, which is a combination of apoptosis, necroptosis, and pyroptosis. However, these processes and the pathogenesis of DSS-induced colitis were significantly attenuated in IEC-specific Drp1 heterozygous knockout mice. Importantly, ZBP1-PANoptosis and Drp1-mediated mitochondrial fission were observed in IEC of UC patients, exhibiting a positive correlation with disease severity. Mechanistically, hyperactivated mitochondrial fission induced mitochondrial reactive oxygen species production leading to PANoptosis through ZBP1 sulfenylation at Cys327 independently of its Zα domain. Saquinavir, an FDA-approved drug identified through in-silico screening alongside in vivo and in vitro experiments, inhibits mitochondrial fission thereby enhancing therapeutic efficacy in mice with colitis.

PTPN22 and the pathogenesis of ulcerative colitis: Insights into T cell differentiation and the JAK/STAT signaling pathway

70 % of the ulcerative colitis (UC) linked gene loci are associated with other autoimmune or immunodeficient diseases. The phosphatase activity of PTPN22 can regulate the development of T cells and contribute to regulate the level of inflammation in autoimmune diseases. We produced PTPN22-CS thymus-specific transgenic mice, which suppressed PTPN22 enzyme activity in the thymocytes. Overexpressed PTPN22-CS facilitated the development of the thymocytes towards CD4+T cells and resulted in an increased proportion of the Th1 and Treg cells in the UC mesenteric lymph nodes. PTPN22-CS promoted the activation of the JAK/STAT signaling pathway in the Th1 and Treg cells that localized in the colon, resulting in an excessive production of inflammatory mediators such as IL-2 and IFN-γ. Consequently, PTPN22-CS contributes to the inflammatory response of ulcerative colitis. In summary, the tyrosine phosphatase activity of PTPN22 plays a role in modulating UC by regulating T cell differentiation and modulating the JAK/STAT signaling pathway, thereby influencing the inflammatory response in colonic. These findings provide new insight into the association between PTPN22 and the pathogenesis of UC.

Inhibition of the Wnt/β‑catenin signaling pathway and SOX9 by XAV939 did not alleviate inflammation in a dextran sulfate sodium‑induced ulcerative colitis model.

The Wnt/β-catenin signaling pathway has been reported to be hyperactivated during the pathogenesis of ulcerative colitis (UC). The present study aimed to explore the therapeutic efficacy of the Wnt/β-catenin signaling inhibitor XAV939 in mitigating UC symptoms. Utilizing a dextran sulfate sodium (DSS)-induced UC mouse model, the present study aimed to evaluate the impact of XAV939 on intestinal morphology through hematoxylin and eosin staining and to measure the expression levels of critical proteins in the Wnt/β-catenin signaling cascade. XAV939 did not exert a significant influence on the morphological features and inflammatory status of the intestinal epithelium. However, XAV939 was found to effectively suppress the Wnt/β-catenin signaling pathway and its downstream target SOX9. This suppression implied a reduction in the differentiation of intestinal stem cells into secretory cell progenitor cells. Additionally, XAV939 was ineffective at reversing the DSS-induced decrease in expression levels of Villin and peroxisome proliferator-activated receptor γ, which suggested that it did not facilitate the differentiation of intestinal absorptive cells. The present findings indicated that the Wnt/β-catenin signaling pathway may not be the predominant mechanism in the pathogenesis of DSS-induced UC.

Genetically predict the association between 91 human blood cell perturbation phenotypes and IBD: A Mendelian randomization study

Inflammatory bowel disease (IBD), encompassing Crohn disease and ulcerative colitis, is a group of persistent and recurrent gastrointestinal disorders. Despite the prevalence of these conditions, no studies have been conducted to examine the connection between altered human blood cell phenotypes and the underlying mechanisms of IBD pathogenesis. By utilizing summary statistics from genome-wide association studies, we executed a systematic two-sample Mendelian randomization (MR) investigation on 91 genetically determined blood cell perturbation traits in relation to 3 separate IBD phenotypes. Our analysis sought to delineate the putative causal links between these blood cell perturbation phenotypes and IBD, thereby contributing to a more nuanced comprehension of the pathophysiological underpinnings and offering a foundation for the development of novel therapeutic approaches. The forward MR analysis identified 7 human blood cell perturbation phenotypes associated with various IBD outcomes, while the reverse MR analysis revealed that 9 human blood cell perturbation phenotypes were influenced by various IBD phenotypes. The study has uncovered human blood cell perturbation phenotypes associated with various IBD diseases, contributing to a deeper understanding of the pathogenesis of IBD. It also provides new insights for early clinical diagnosis, disease activity monitoring, immune surveillance, prognosis assessment, and personalized treatment.

Advances in research on the role of high carbohydrate diet in the process of inflammatory bowel disease (IBD).

Inflammatory bowel disease (IBD) is a chronic, systemic gastrointestinal disorder characterized by episodic inflammation that requires life-long management. Although the etiology of IBD is not fully understood, it is hypothesized to involve a multifaceted interplay among genetic susceptibility, the host immune response, and environmental factors. Previous studies have largely concluded that IBD is associated with this complex interplay; however, more recent evidence underscores the significant role of dietary habits as risk factors for the development of IBD. In this review, we review the molecular mechanisms of high-sugar and high-fat diets in the progression of IBD and specifically address the impacts of these diets on the gut microbiome, immune system regulation, and integrity of the intestinal barrier, thereby highlighting their roles in the pathogenesis and exacerbation of IBD.

METTL14 regulates inflammation in ulcerative colitis via the lncRNA DHRS4-AS1/miR-206/A3AR axis

As a chronic inflammatory bowel disease, the pathogenesis of ulcerative colitis (UC) has not been fully elucidated. N6-methyladenosine (m6A) modification, observed in various RNAs, is implicated in inflammatory bowel diseases. Methyltransferase-like 14 (METTL14) is the major subunit of the methyltransferase complex catalyzing m6A modifications. Here, we designated to examine the regulatory effects and mechanisms of METTL14 on long non-coding RNA (lncRNA) during UC progression. METTL14 knockdown decreased cell viability, promoted apoptosis, increased cleaved PARP and cleaved Caspase-3 levels, while reducing Bcl-2 levels. METTL14 knockdown also led to a significant increase in NF-κB pathway activation and inflammatory cytokine production in the Caco-2 cells treated with TNF-α. Moreover, the suppression of METTL14 aggravated colonic damage and inflammation in our dextran sulfate sodium (DSS)-induced murine colitis model. METTL14 silencing suppressed DHRS4-AS1 expression by reducing the m6A modification of DHRS4-AS1 transcripts. Furthermore, DHRS4-AS1 mitigated inflammatory injury by targeting the miR-206/adenosine A3 receptor (A3AR) axis. DHRS4-AS1 overexpression counteracted the enhancing impact of METTL14 knockdown on TNF-α-induced inflammatory injury in Caco-2 cells. In conclusion, our findings suggest that METTL14 protects against colonic inflammatory injury in UC via regulating the DHRS4-AS1/miR-206/A3AR axis, thus representing a potential therapeutic target for UC.

Gut Bacterial Composition and Nutritional Implications in Mexican and Spanish Individuals with Inflammatory Bowel Disease Compared to Healthy Controls.

The intestinal microbiota plays a key role in the pathogenesis of inflammatory bowel disease (IBD), with its composition varying based on geographic location and dietary factors. This study was performed to examine and compare the bacterial composition of the gut microbiota in Mexican and Spanish individuals with IBD and healthy controls, while also considering the nutritional aspects. This study involved 79 individuals with IBD and healthy controls from Mexico and Spain. The fecal microbiota composition was analyzed using 16S rRNA gene sequencing, and the dietary intake and anthropometric measurements were collected. Alpha diversity analysis revealed a lower Chao1 index of the bacterial genera in the IBD groups. Beta diversity analysis showed significant differences in the bacterial composition, suggesting inter-individual variability within the healthy and IBD groups. Additionally, the relative abundance of the bacterial genera varied across the four groups. Faecalibacterium was more abundant in the IBD groups; Prevotella was found exclusively in the Mexican groups, and Akkermansia was found only in the Spanish groups. Akkermansia was positively correlated with meat and protein intake, Prevotella with lean mass, and Bacteroides with calorie intake. These findings highlight the importance of considering geographic and nutritional factors in future research on the gut microbiome's role in IBD pathogenesis.

Endoplasmic Reticular Stress and Pathogenesis of Experimental Colitis: Mechanism of Action of 5-Amino Salicylic Acid.

Inflammatory bowel diseases which are characterized by endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) signaling pathway, are commonly treated with 5-amino salicylic acid (5-ASA). The objective of this study was to investigate the role of 5-amino salicylic acid in the UPR-signaling pathway in experimental colitis. Colitis was induced in male Sprague-Dawley rats by intrarectal instillation of trinitrobenzene sulfonic acid. Animals received 5-amino salicylic acid (100 mg/kg body weight) two hours before the induction of colitis and repeated daily until day 7. The animals were sacrificed on day 7 and tissues were collected for analysis. The expression of protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK), a mediator of UPR-signaling increased significantly (p < 0.05), while inositol requiring enzyme type-1 (IRE1) and the CCAAT/enhancer-binding homologous protein (CHOP) remained unaltered in the inflamed colon. The expression of glucose regulated protein-78, activator of transcription factor-4 and phosphorylated eukaryotic initiation factor-2α (eIF2αP) increased (p < 0.05) in the inflamed colon. However, the levels of eIF2α protein and mRNA expression remained unchanged. Myeloperoxidase activity, colon weight and infiltration of inflammatory cells increased significantly (p < 0.05) in the submucosa whereas the body weight decreased. These changes were significantly inhibited by 5-amino salicylate treatment. These findings suggest that the anti-inflammatory properties of 5-amino salicylic acid are mediated through the inhibition of the PERK signaling pathway.

PHLDA1 protects intestinal barrier function via restricting intestinal epithelial cells apoptosis in inflammatory bowel disease

The current approach to treating inflammatory bowel disease (IBD) primarily focuses on managing inflammation rather than maintaining the integrity of the intestinal barrier. In our study, we sought to investigate the potential role of PHLDA1 in preserving intestinal barrier function as a promising strategy for treating IBD. We observed a significant decrease in PHLDA1 expression in intestinal epithelial cells (IECs) of both IBD patients and mice with chemically induced colitis. This deficiency of PHLDA1 led to increased apoptosis of IECs, resulting in a compromised epithelial barrier and the invasion of commensal bacteria into the mucosa. Consequently, this microbial invasion substantially exacerbated colonic inflammation in mice with the specific knockout of PHLDA1 in IECs (Phlda1IEC−KO) compared to their control littermates. Mechanistically, we found evidence of PHLDA1 interacting with MCL1 to protect against K48-linked polyubiquitylation at the K40 lysine residue, thus preventing ubiquitin-proteasome degradation through the MCL1 ubiquitin ligase E3 (Mule). We further confirmed that the PHLDA1-MCL1-Mule signaling pathway plays a critical role in the development of IBD. Notably, our study demonstrated that enhancing MCL1 levels or reducing Mule expression using adeno-associated virus (AAV) attenuated experimental colitis in Phlda1IEC−KO mice. Collectively, our findings emphasize the significance of PHLDA1 in the pathogenesis of IBD and propose that targeting the PHLDA1-MCL1-Mule signaling pathway could be a viable approach for combating IBD.

Research progress of probiotics and their protective strategy in the field of inflammatory bowel disease treatment: A review.

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disease characterized by recurrent episodes and difficult-to-cure symptoms. Although the pathogenesis of IBD is closely related to host genetic susceptibility, intestinal microbiota, environmental factors, and immune responses, leading to mucosal damage and increased intestinal permeability. Intestinal mucosal injury in IBD patients causes pathogenic bacteria and pathogenic factors to invade the intestine, leading to disturb the structure and metabolic products of intestinal flora. Researchers have found that probiotics, as live microbial agents, can effectively inhibit the growth of pathogenic bacteria, regulate intestinal flora, optimize intestinal microecology, restore intestinal homeostasis, and promote intestinal mucosal repairing. During the oral delivery process, probiotics are susceptible to adverse physiological factors, leading to reduced bioavailability. Additionally, the oxidative stress microenvironment induced by intestinal mucosal damage makes it difficult for probiotics to colonize the intestinal tract of IBD patients, thereby affecting their probiotic effect. This research mainly introduces and reviews the advantages and disadvantages of probiotics and their protective strategies in the treatment of IBD, and prospects the future development trends of probiotics and their protective strategies. Probiotics can effectively inhibit the growth of harmful microorganisms, regulate the structure of the intestinal microbiota, and promote mucosal repairing, thereby reducing immune stress and alleviating intestinal inflammation, providing a new perspective for the treatment of IBD. The development of single-cell encapsulation technology not only effectively maintaining the biological activity of probiotics during oral delivery, but also endowing probiotics with additional biological functions naturally achieved through surface programming, which has multiple benefits for intestinal health.

Gut microbiota-derived tryptophan metabolites regulated by Wuji Wan to attenuate colitis through AhR signaling activation

Disruption of the intestinal mucosal barrier caused by gut dysbiosis and metabolic imbalance is the underlying pathology of inflammatory bowel disease (IBD). Traditional Chinese medicine Wuji Wan (WJW) is commonly used to treat digestive system disorders and showed therapeutic potential for IBD. In this interdisciplinary study, we aim to investigate the pharmacological effects of WJW against experimental colitis by combining functional metabolomics and gut-microbiota sequencing techniques. Treatment with WJW altered the profile of the intestinal microbiota and notably increased the abundance of Lactobacillus, thereby facilitating the conversion of tryptophan into indole-3-acetic acid (IAA) and indoleacrylic acid (IA). These indole derivatives activated the aryl hydrocarbon receptor (AhR) pathway, which reduced colonic inflammation and restored the expression of intestinal barrier proteins. Interestingly, the beneficial effects of WJW on gut barrier function improvement and tryptophan metabolism were disappeared in the absence of gut microbiota. Finally, pre-treatment with the AhR antagonist CH-223191 confirmed the essential role of IAA-mediated AhR activation in the therapeutic effects of WJW. Overall, WJW enhanced intestinal barrier function and reduced colonic inflammation in a murine colitis model by modulating Lactobacillus–IAA–AhR signaling pathway. This study provides novel insights into colitis pathogenesis and presents an effective therapeutic and preventive approach against IBD.

FBXO22 inhibits colitis and colorectal carcinogenesis by regulating the degradation of the S2448-phosphorylated form of mTOR

Inflammatory bowel disease (IBD) is a considerable threat to human health with a significant risk for colorectal cancer (CRC). However, currently, both the molecular pathogenesis and therapeutic treatment of IBD remain limited. In this report, using both systemic and intestinal epithelium-specific gene knockout mouse models, we demonstrate that FBXO22, a substrate receptor within the SKP1-Cullin 1-F-box family of E3 ubiquitin ligases, plays an inhibitory role in the Azoxymethane/Dextran Sodium Sulfate-induced colorectal inflammatory responses and CRC. FBXO22 targets the serine 2448-phosphorylated form of mammalian mechanistic target of rapamycin (pS2448-mTOR) for ubiquitin-dependent degradation. This proteolytic targeting effect is established based on multiple lines of evidence including the results of colon tissue immunoblots, analysis of cultured cells with altered abundance of FBXO22 by depletion or overexpression, comparison of protein decay rate, effects on mTOR substrates S6K1 and 4E-BP1, analysis of protein-protein interactions, phosphor-peptide binding and competition, as well as reconstituted and cellular ubiquitination. Finally, we have shown that mTOR inhibitor rapamycin (RAPA) was able to alleviate the effects of fbxo22 deletion on colorectal inflammatory response and CRC. These RAPA effects are correlated with the ability of RAPA to inhibit pS2448-mTOR, pS6K1, and p4E-BP1. Collectively, our data support a suppressive role for FBXO22 in colorectal inflammation signaling and CRC initiation by targeting pS2448-mTOR for degradation.

Gain-of-Function Variant in Spleen Tyrosine Kinase Regulates Macrophage Migration and Functions to Promote Intestinal Inflammation.

Spleen tyrosine kinase (Syk) is a widely-expressed cytoplasmic non-receptor tyrosine kinase involved in regulating various signaling pathways and plays an important role in chronic inflammation and autoimmune diseases. Gain-of-function SYK variants have been implicated in pediatric inflammatory bowel diseases. This study aimed to investigate the effects of gain-of-function SYK variants on the susceptibility to experimental colitis and macrophage function. Colitis was induced using dextran sodium sulfate and dinitrobenzene sulfonic acid in mice harboring a gain-of-function variant in SYK (SykS544Y). Intestinal inflammation was assessed via disease activity index, histological analysis, and Western blotting. The frequencies of macrophages, phagocytosis, and reactive oxygen species (ROS) production in bone marrow-derived macrophages (BMDM) were measured via flow cytometry. Chemokines and BMDM chemotaxis were analyzed using real-time quantitative reverse transcription polymerase chain reaction and Transwell assays. The expression of nucleotide-binding domain leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome-related proteins were detected using immunohistochemistry, enzyme-linked immunoassay and Western blotting. SykS544Y mice exhibited increased susceptibility to experimental colitis, and macrophage infiltration in colon tissues significantly increased. We observed increased expression of macrophage chemokines in colon tissues and enhanced chemotaxis in SykS544Y BMDM. Additionally, we detected increased levels of fluorescent microspheres and 2.7-dichloride-hydro fluorescein diacetate-labeled ROS in SykS544Y BMDM. Moreover, enhanced levels of NLRP3 inflammasome-related proteins were observed in the colon tissues and BMDM from SykS544Y mice. Gain-of-function variant in SYK may contribute to the pathogenesis of pediatric inflammatory bowel diseases by promoting macrophage migration, phagocytosis, ROS production and activation of NLRP3 inflammasomes.

Expression of IL-7RαlowCX3CR1+ CD8+ T Cells and α4β7 Integrin Tagged T Cells Related to Mucosal Immunity in Children with Inflammatory Bowel Disease.

The study aimed to investigate the recruiting of T lymphocytes including IL-7Rαlow CX3CR1+ effector memory (EM) CD8+ T cells and α4β7 integrin tagged T cells to inflamed intestinal mucosa. Whole blood and mucosal tissues of intestine were collected from 40 children with or without inflammatory bowel disease (IBD). T cell surface staining and immunohistochemistry were done with several antibodies in peripheral blood mononuclear cells (PBMCs) and intestinal mucosa, respectively. Serum levels of cytokines were measured by ELISA. The frequency of IL-7RαlowCX3CR1+ EM CD8+ T cells in the PBMC was significantly higher in the ulcerative colitis group than in the control group (57.9±17.80% vs. 33.9±15.70%, p=0.021). The frequency of integrin α4β7+ CD4+ T cells in the PBMC was significantly lower in the ulcerative colitis group than in the control group (53.2±27.6% vs. 63.9±13.2%, p=0.022). Serum concentration of TNF-α was higher in the Crohn's disease group than in the control group (26.13±5.01 pg/mL vs. 19.65±6.07 pg/mL, p=0.008). Of the three groups, the ulcerative colitis group had the highest frequency of integrin α4β7+ T cells based on immunohistochemistry analyses for intestinal tissues, followed by the Crohn's disease group and the control group (4.63±1.29 cells vs. 2.0±0.57 cells vs. 0.84±0.52 cells, p<0.001). Trafficking immune cells with effector memory CD8+ T cells clarified by IL-7RαlowCX3CR1+ and integrin α4β7+ CD4+ T cells might be highly associated with the pathogenesis of ulcerative colitis.

The PGAM5–NEK7 interaction is a therapeutic target for NLRP3 inflammasome activation in colitis

The innate immune sensor NLRP3 inflammasome overactivation is involved in the pathogenesis of ulcerative colitis. PGAM5 is a mitochondrial phosphatase involved in NLRP3 inflammasome activation in macrophages. However, the role of PGAM5 in ulcerative colitis and the mechanisms underlying PGAM5 regulating NLRP3 activity remain unknown. Here, we show that PGAM5 deficiency ameliorates dextran sodium sulfate (DSS)-induced colitis in mice via suppressing NLRP3 inflammasome activation. By combining APEX2-based proximity labeling focused on PGAM5 with quantitative proteomics, we identify NEK7 as the new binding partner of PGAM5 to promote NLRP3 inflammasome assembly and activation in a PGAM5 phosphatase activity-independent manner upon inflammasome induction. Interfering with PGAM5–NEK7 interaction by punicalagin inhibits the activation of the NLRP3 inflammasome in macrophages and ameliorates DSS-induced colitis in mice. Altogether, our data demonstrate the PGAM5–NEK7 interaction in macrophages for NLRP3 inflammasome activation and further provide a promising therapeutic strategy for ulcerative colitis by blocking the PGAM5–NEK7 interaction.

Selenium, Immunity, and Inflammatory Bowel Disease.

Dietary intervention is a subject of growing interest in the management of inflammatory bowel disease (IBD), as new incident cases across the globe are rapidly rising, suggesting environmental factors as contributing elements. Dietary components and micronutrients have been associated with IBD pathogenesis or reductions in disease severity. Selenium, a diet-derived essential micronutrient that is important for proper immune system function, has received limited attention in the context of IBD. Selenium deficiency is a common finding in patients with IBD, but few clinical trials have been published to address the consequences of this deficiency. Here, we review the physiological and immunological roles of selenium and its putative role in IBD, and draw attention to knowledge gaps and unresolved issues, with the goal of stimulating more research on selenium in IBD.

Gut Microbiome as a Target of Intervention in Inflammatory Bowel Disease Pathogenesis and Therapy

Inflammatory bowel disease (IBD) is a chronic complicated inflammatory gut pathological disorder and is categorized into ulcerative colitis (UC) and Crohn’s disease (CD). Although the cause of IBD is unclear, dysbiosis of the gut microbiota is thought to be a key factor in the disease’s progression. The gut microbiome serves as a metabolic organ and promotes wellness by carrying out several biological activities. Any modification in the makeup of the gut microbiome leads to several pathological conditions, including IBD. In this review, we emphasize the key metabolic processes that control host–microbiome interaction and its impact on host health. We also discuss the association between microbiome dysbiosis (bacteriome, virome, and mycobiome) and the progression of IBD. Finally, we will highlight microbiome-based therapy as a novel and promising strategy to treat and manage IBD.