The gut microbiota plays a crucial role in human health, influencing metabolism, immune regulation, and neurological function. This review examines the genetic and immunological mechanisms governing microbiota composition, with a focus on key pattern recognition receptors, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and signaling proteins such as CARD9 and NOD2. We discuss how genetic polymorphisms in these receptors contribute to gut dysbiosis and disease susceptibility, particularly in inflammatory bowel disease (IBD) and neurodegenerative disorders like Parkinson's disease. Additionally, we explore emerging microbiota-targeted therapeutic strategies, including probiotics and precision medicine approaches. By synthesizing recent advancements, this review examines how genetic and immunological mechanisms regulate gut microbiota and influence disease susceptibility, emphasizing key therapeutic implications.

IκBζ, an atypical and largely unknown member of the IκB family, is a transcriptional coactivator of selective immune functions. Here, we investigated the role of keratinocyte-derived IκBζ upon infection with a multidrug-resistant S. aureus strain. Infection of keratinocytes rapidly induced IκBζ expression, leading to an elevated expression of antimicrobial peptides, IL-17/IL-36-responsive genes, and proteins involved in skin barrier function. Conversely, loss of IκBζ resulted in increased S. aureus internalization, epidermal tissue damage, and severe skin infections in vivo. This impaired host defense upon IκBζ depletion was characterized by reduced antimicrobial peptide expression, and diminished recruitment of neutrophils and CD4+ T-cells. Importantly, S. aureus-induced IκBζ expression required the internalization of the bacteria and its sensing by the intracellular receptor NOD2, which triggered IκBζ and its target gene expression. Thus, we identified NOD2-IκBζ signaling as a novel pathway acting as a key mediator for a protective host defense against pathogenic S. aureus infections in the skin.

Patients with asthma frequently experience recurrent symptoms including coughing, wheezing, shortness of breath, and chest tightness. Asthma is a common public health concern. It is characterized by chronic airway inflammation. However, The pathogenesis of asthma is complex. Inflammasomes are signaling platforms that regulate the inflammatory response. There is a correlation between inflammasomes and asthma. Pattern recognition receptors recognize danger signals and participate in inflammasome activation. Nucleotide-binding and oligomerization domain-containing 2 (NOD2), a pattern recognition receptor, senses microbial components and triggers immune responses. There have been studies showing a correlation between NOD2 and asthma. The nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) participates in the formation of inflammasomes. NLRP3 are involved in asthma pathogenesis. In this review, we discuss the roles of NOD2 and NLRP3 in the pathogenesis of asthma.

This review examines the role of genetic variations in the pathogenesis of small bowel (SB) ulcers associated with Crohn's disease (CD), NSAID enteropathy, and Cryptogenic Multifocal Ulcerous Stenosing Enteritis (CMUSE)/Chronic Non-Specific Ulcers of the Small Intestine (CNSU), aiming to address current diagnostic challenges.

Advances in molecular genetics have revealed significant genetic contributors to SB ulceration. In CD, the NOD2 gene on chromosome 16 and several additional risk variants identified through genome-wide association studies (GWAS)-with key insights from the International Inflammatory Bowel Disease Genetics Consortium-have enhanced our understanding of the pathobiology of the disease. In NSAID enteropathy, polymorphisms in CYP enzymes have been associated with altered drug metabolism and gastrointestinal complications. However, the genetic mechanisms underlying deep ulcers in NSAID enteropathy, as well as CMUSE/CNSU, remain poorly understood. Genetic insights are crucial for understanding SB ulcerative diseases. Future research should focus on identifying specific genetic determinants to improve diagnostic accuracy and therapeutic strategies.

Inflammatory Bowel Disease (IBD), a chronic condition characterized by gastrointestinal inflammation, is influenced by genetic and environmental factors. Emerging evidence suggests a "mouth-gut axis," with the oral cavity reflecting extra-intestinal manifestations of IBD. This study evaluated the oral health status of IBD patients and the potential of salivary calprotectin (SCP) as a biomarker for assessing IBD activity and oral health.

Oral health was assessed in 100 IBD patients [60 with Crohn's disease (CD) and 40 with ulcerative colitis (UC)] and 14 controls. Evaluations included the Decayed, Missing, and Filled Teeth (DMFT) Score, Periodontal Diagnosis and the need for dental or prosthetic treatment. Saliva and stool samples were collected to measure SCP and faecal calprotectin (FCP) levels using the Elia Calprotectin 2 Test. IBD activity was evaluated with FCP, the Harvey-Bradshaw Index for CD, and the Partial Mayo Score for UC.

The DMFT index mean was comparable between IBD patients (mean 7.99, SD 7.73) and controls (mean 10.00, SD 6.49). However, periodontal disease was significantly more prevalent in IBD patients (57% in CD, 70% in UC) than in controls (29%), with severe cases (stages III/IV) more frequent in IBD. Additionally, 89% of IBD patients required dental treatment, and 39% needed prosthetic rehabilitation. SCP levels showed no significant correlation with disease activity or oral health status, while FCP correlated with C-reactive protein and erythrocyte sedimentation rate.

This study underscores the need for improved oral health management in IBD patients and suggests that SCP may not be a reliable biomarker for monitoring IBD or periodontal disease.

Not applicable.

Although nucleotide-binding oligomerization domain-containing protein 2 (NOD2) has been associated with diverse inflammatory states and some neurological diseases, its role in regulating sepsis-induced neuroinflammation remains unexplored. This study aimed to determine the role of NOD2 in modulating sepsis-induced neuroinflammation and to elucidate its potential mechanisms.

mRNA and protein expression levels of NOD2 were measured in the periventricular white matter (PWM) of C57BL/6 mice and the microglia. NOD2-/- mice were generated using the CRISPR/Cas9 technology, and the septic mouse model was established by using cecal ligation puncture (CLP). Microglia were transfected with siRNA specific to NOD2 or laccase domain-containing protein 1 (LACC1) or treated with the endoplasmic reticulum stress (ER stress) inhibitor 4-phenylbutyrate (4-PBA) in vitro under muramyl dipeptide (MDP)-induced neuroinflammation. Immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction were performed to evaluate neuroinflammation and ER stress. The ER structure was observed using transmission electron microscopy.

NOD2 expression level was upregulated in the mouse model of sepsis-induced neuroinflammation. The absence of NOD2 led to a protective effect against neuroinflammation, which was correlated with ER stress both in vitro and in vivo. LACC1 was identified as a notable mediator of ER stress, contributing to the exacerbation of neuroinflammation. Mechanistically, elevated NOD2 expression level promoted neuroinflammation by enhancing ER stress through LACC1. Notably, these effects were partially mitigated by LACC1 downregulation.

These findings highlight the pivotal role of NOD2 in promoting sepsis-induced neuroinflammation via regulating ER stress mediated by LACC1, and provide a new potential strategy for treating human neuroinflammation.

Inflammatory bowel disease (IBD) comprises chronic inflammatory conditions with complex mechanisms and diverse manifestations, posing significant clinical challenges. Traditional animal models and ethical concerns in human studies necessitate innovative approaches. This review provides an overview of human intestinal architecture in health and inflammation, emphasizing the role of microfluidics and on-chip technologies in IBD research. These technologies allow precise manipulation of cellular and microbial interactions in a physiologically relevant context, simulating the intestinal ecosystem microscopically. By integrating cellular components and replicating 3D tissue architecture, they offer promising models for studying host-microbe interactions, wound healing, and therapeutic approaches. Continuous refinement of these technologies promises to advance IBD understanding and therapy development, inspiring further innovation and cross-disciplinary collaboration.

The heterogeneity and suboptimal efficacy of biological treatments and small molecule drugs necessitate their precise selection based on biomarkers that predict therapeutic responses in inflammatory bowel disease. Recent studies have identified numerous novel biomarkers predictive of responses to biologics and small molecule modulators, utilizing a variety of omics approaches in inflammatory bowel disease. In this review, we systematically examine baseline omics biomarkers that predict responses to biological therapies and small molecule drugs, drawing on literature from PubMed. Our analysis spans multiple omics disciplines, including genomics, transcriptomics (both bulk RNA and single-cell RNA sequencing), proteomics, microbiomics, and metabolomics, with particular emphasis on the impact of models integrating multiple omics datasets. Additionally, to further the field of precision medicine, we evaluated specific biomarkers that may exhibit distinct effects on responses to multiple therapeutic interventions.

Nucleotide-binding oligomerization domain containing 2 (NOD2) detects conserved fragments of bacterial peptidoglycan in the cytosol and induces innate immune responses. Here, we found that the NOD2 signaling pathway was critically regulated by the deubiquitinating enzyme DUBA. DUBA-deficient macrophages were defective in NOD2 signaling and produced significantly lower amounts of cytokines and chemokines in response to muramyl dipeptide (MDP). DUBA potentiated NOD2-mediated signal transduction by maintaining the protein levels of NOD2 and receptor-interacting protein kinase 2 (RIPK2). Mechanistically, DUBA interacted with NOD2 and RIPK2 and removed K48-linked polyubiquitin chains from them through enzymatic activity, thereby inhibiting the proteasomal degradation of NOD2 and RIPK2. Macrophage-specific ablation of DUBA attenuated MDP-induced systematic inflammation and liver injury in mice. In addition, DUBA deficiency in macrophages rendered mice hypersensitive to DSS-induced colitis and eliminated the protective effect of MDP treatment in colitis. Thus, DUBA acts as an important regulator of NOD2-mediated signaling and innate immune responses.

Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, arise from various factors such as dietary, genetic, immunological, and microbiological influences. The gut microbiota plays a crucial role in the development and treatment of IBD, though the exact mechanisms remain uncertain. Current research has yet to definitively establish the beneficial effects of the microbiome on IBD. Bacteria and viruses (both prokaryotic and eukaryotic) are key components of the microbiome uniquely related to IBD. Numerous studies suggest that dysbiosis of the microbiota, including bacteria, viruses, and bacteriophages, contributes to IBD pathogenesis. Conversely, some research indicates that bacteria and bacteriophages may positively impact IBD outcomes. Additionally, plant metabolites play a crucial role in alleviating IBD due to their anti-inflammatory and microbiome-modulating properties. This systematic review discusses the role of the microbiome in IBD pathogenesis and evaluates the potential connection between plant metabolites and the microbiome in the context of IBD pathophysiology.

We present an introduction to the neuroimmune axis with a focus on the gastrointestinal system, its role in numerous chronic multisystem disorders, and emerging tools and therapies to diagnose and treat these conditions.

There have recently been tremendous breakthroughs in our understanding of how the nervous, immune, and endocrine systems, as well as the extracellular matrix and microbiota, interact within the gastrointestinal system to modulate health and disease.

The pathogenesis of inflammatory bowel disease (IBD) involves a complex interplay between genetic, environmental, and microbial factors. Many of these environmental determinants are modifiable, offering opportunities to prevent disease or delay its onset. Advances in the study of preclinical IBD cohorts offer the potential to identify biomarkers that predict individuals at high risk of developing IBD, enabling targeted environmental interventions aimed at reducing IBD incidence. This review summarizes findings from 79 meta-analyses on modifiable environmental factors associated with the development of IBD. Identified risk factors include smoking, Western diets, ultra-processed foods, and early life antibiotic use, while protective factors include breastfeeding, Mediterranean diets rich in fiber, plant-based foods, and fish, along with an active physical lifestyle. Despite the promise shown by observational data, interventional or randomized controlled studies evaluating the efficacy of modifying environmental risk factors remain limited and mostly focus on dietary intervention. This review aims to inform the design of higher quality interventional and randomized controlled studies for disease prevention while providing actionable guidance to healthcare providers on reducing the risk of developing IBD through environmental modifications.

Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host-microbiota interactions and stable long-term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ-on-chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease-driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host-microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota-related therapies and personalized medicine for IBD treatment is discussed.

NOD2 mutations are associated with impaired gut mucosal barrier function. According to the systemic inflammation hypothesis, bacterial translocation is central in the development of decompensation. The aim was to evaluate whether the presence of NOD2 variants is associated with the development of first decompensation.

Secondary analysis of prospectively collected consecutive patients with compensated cirrhosis, who were screened between 2014 and 2018. Patients with and without NOD2 variants were compared and stratified analysis according to the presence of varices was performed.

360 patients [239 (66%) men, median age 61 (53-69) years, 70 (19%) with NOD2 variants, 90 (25%) with varices] were followed for a median of 9 (4-16) months. Similar baseline characteristics were observed across NOD2 status groups, except for beta-blocker use (45% vs. 32% amongst variant carriers vs. non-carriers, p = 0.05). During follow-up, 34 patients (12%) developed their first decompensation, with no differences according to NOD2 status [HR 1.75 (95% CI 0.84-3.67)]. On multivariate analysis, only MELD remained an independent predictor of decompensation. Amongst patients with varices (n = 90), 18 (24.4%) carried a NOD2 variants, with a higher incidence of first decompensation [HR 3.00 (95% CI 1.08-8.32)], primarily due to ascites [HR 3.32 (95% CI 1.07-10.32)]. In this subgroup, MELD [HR 1.18 (95% CI 1.06-1.32)] and NOD2 variants [HR 2.91 (95% CI 0.95-8.89)] were determined to be independent predictors of decompensation.

The presence of NOD2 risk variants leads to a greater incidence of first decompensation only in compensated patients with varices.

The majority of patients with Crohn's disease, despite an ever-increasing number of advanced therapies, require abdominal surgery during their lifetime. In this review article, the authors provide a comprehensive overview of abdominal surgery for Crohn's disease, with an evidence-based focus on surgery for upper gastrointestinal Crohn's disease, bowel-preserving surgery with strictureplasties, selection of ileocolic anastomotic technique for terminal ileal Crohn's disease, extended resections and proctectomy for Crohn's proctocolitis, intentional ileoanal pouch for Crohn's disease, and several "hot topics" including early surgery for ileocolic Crohn's disease, and surgical approaches that target the mesentery including the Kono-S anastomosis and extended mesenteric excision.

Inflammatory bowel disease (IBD) represents a significant disease burden marked by chronic inflammation and complications that adversely affect patients' quality of life. Effective diagnostic strategies involve clinical assessments, endoscopic evaluations, imaging studies, and biomarker testing, where early diagnosis is essential for effective management and prevention of long-term complications, highlighting the need for continual advancements in diagnostic methods. The intricate interplay between genetic factors and the outcomes of biological therapy is of critical importance. Unraveling the genetic determinants that influence responses and failures to biological therapy holds significant promise for optimizing treatment strategies for patients with IBD on biologics. Through an in-depth examination of current literature, this review article synthesizes critical genetic markers associated with therapeutic efficacy and resistance in IBD. Understanding these genetic actors paves the way for personalized approaches, informing clinicians on predicting, tailoring, and enhancing the effectiveness of biological therapies for improved outcomes in patients with IBD.

NOD2 is an intracellular innate immune receptor that detects bacterial peptidoglycan fragments. Although nominally soluble, some NOD2 is associated with the plasma membrane and endosomal compartments for microbial surveillance. This membrane targeting is achieved through post-translational S-acylation of NOD2 by the protein acyltransferase ZDHHC5. Membrane attachment is necessary to initiate a signaling cascade in response to cytosolic peptidoglycan fragments. Ultimately, this signaling results in the production of antimicrobial peptides and proinflammatory cytokines. In most cases, S-acylation is a reversible post-translational modification with removal of the fatty acyl chain catalyzed by one of several acyl protein thioesterases. Deacylation of NOD2 by such an enzyme will displace it from the plasma membrane and endosomes, thus preventing signaling.

To identify the enzymes responsible for NOD2 deacylation, we used engineered cell lines with RNA interference and small-molecule inhibitors. These approaches were combined with confocal microscopy, acyl-resin-assisted capture, immunoblotting, and cytokine multiplex assays.

We identified α/β-hydrolase domain-containing protein 17 isoforms (ABHD17A, ABHD17B, and ABHD17C) as the acyl protein thioesterases responsible for NOD2 deacylation. Inhibiting ABHD17 increased the plasma membrane localization of wild-type NOD2 and a subset of poorly acylated Crohn's disease-associated variants. This enhanced NOD2 activity, increasing NF-κB activation and pro-inflammatory cytokine production in epithelial cells.

These findings demonstrate that ABHD17 isoforms are negative regulators of NOD2. The results also suggest that targeting ABHD17 isoforms could restore functionality to specific Crohn's disease-associated NOD2 variants, offering a potential therapeutic strategy.

Inflammatory bowel disease (IBD) represents a group of chronic inflammatory disorders of the gastrointestinal tract. Despite substantial advances in our understanding of IBD pathogenesis, the currently available therapeutic options remain limited in their efficacy and often come with significant side effects. Therefore, there is an urgent need to explore novel approaches for the management of IBD. One promising avenue of investigation revolves around the use of histone deacetylase (HDAC) inhibitors, which have garnered considerable attention for their potential in modulating gene expression and curbing inflammatory responses. This review emphasizes the pressing need for innovative drugs in the treatment of IBD, and drawing from a wealth of preclinical studies and clinical trials, we underscore the multifaceted roles and the therapeutic effects of HDAC inhibitors in IBD models and patients. This review aims to contribute significantly to the understanding of HDAC inhibitors' importance and prospects in the management of IBD, ultimately paving the way for improved therapeutic strategies in this challenging clinical landscape.

Crohn's disease (CD) is a chronic inflammatory bowel disease with a multifactorial pathogenesis involving environmental and genetic factors. Since the late 20th century, the discovery of the first susceptibility gene (NOD2, previously referred to as CARD15) for CD has paved the way for further investigations into the correlations between clinical features and genetics, and its potential impact on clinical practice has fueled the research in the last 2 decades. Recent therapeutic advancements involving novel biologic drugs and small molecules have shifted inflammatory bowel disease management from a disease-centered to a patient-centric approach. To date, the role of NOD2 has not been fully understood yet. Recent data suggest that its clinical impact may be greater than currently recognized. This review overviews the most common NOD2 variants' role in real-life clinical practice. These genetic variants increase the risk of developing the disease and can aid in tailoring diagnosis and treatment. They are associated with the stricturing phenotype and ileal involvement and increase the risk of steroid refractoriness. In the meantime, limited and inconclusive evidence exists regarding their predictive role in response to azathioprine, biologic drugs, and small molecules. Eventually, their role in increasing the risk for surgery is evident, especially in those with the L1007fs variant. If further trials will support the initial evidence reported so far, NOD2 genetic variants will emerge as possible candidates for developing precision medicine in CD.

Inflammatory bowel diseases (IBD) represent chronic inflammatory multisystemic disorders that primarily involve the gastrointestinal tract. Patients with ulcerative colitis (UC) and Crohn's disease (CD) exhibit a higher prevalence of thyroid disorders compared to the general population. The aim of this review is to summarize the literature on concomitant IBD and thyroid disorders, specifically autoimmune thyroid diseases such as Graves' disease (GD) and Hashimoto's thyroiditis (HT), as well as thyroid cancer, with a focus on children and adolescents. We provide an overview of the age-related differences between children and adults in the prevalence of this association. Literature shows that relatively few studies have been conducted on this subject in pediatric populations. The etiopathogenetic similarities between IBD and autoimmune thyroiditis are undeniable. Nevertheless, current data does not indicate a unanimous association between GD and HT and chronic IBD (both CD and UC). Although evidence suggests a potential association between IBD and thyroid cancer, particularly papillary thyroid cancer, the precise nature of this relationship varies across studies and is influenced by multiple factors. The limited information regarding the relationship between IBD and thyroid disorders in children highlights a significant knowledge gap. Since the thyroid plays a critical role in the pediatric population's development, it is essential to promptly recognize and treat thyroid diseases. A thyroid function monitoring and future research exploring the genetic and immunologic connections are essential to enhance our understanding of the interrelation between IBD and thyroid disorders.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is primarily known for its gastrointestinal manifestations. However, emerging evidence suggests a potential link between IBD and an increased risk of stroke, likely mediated by chronic systemic inflammation, endothelial dysfunction, and a prothrombotic state. Despite this growing recognition, the exact mechanisms and extent of this association remain unclear, highlighting a critical knowledge gap. This review aims to systematically analyze the association between IBD and stroke, exploring the underlying vascular mechanisms and identifying potential risk factors contributing to cerebrovascular events in IBD patients. A comprehensive literature search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines across PubMed, Scopus, and Google Scholar using keywords such as "IBD," "Stroke," "Chronic inflammation," "Cerebrovascular risk," and "Gut-brain axis." After screening 150 studies and applying inclusion and exclusion criteria, six studies were included in the final synthesis. The findings suggest that chronic inflammation in IBD plays a key role in increasing stroke risk through endothelial dysfunction and a heightened prothrombotic state, with additional risk factors such as atrial fibrillation during active IBD flares further contributing to cerebrovascular events. While biologic therapies, including tumor necrosis factor (TNF)-alpha inhibitors, are effective in reducing systemic inflammation, their impact on mitigating stroke risk remains inconclusive. Given the potential role of IBD as an independent risk factor for stroke, a multidisciplinary approach to management is crucial. Addressing modifiable risk factors through pharmacologic interventions such as biologics, statins, and antiplatelet agents, alongside lifestyle modifications, could help reduce cerebrovascular complications in IBD patients. Further research is needed to explore personalized therapeutic strategies and establish clearer preventive guidelines for this at-risk population.

Inflammatory bowel disease (IBD) represents a cluster of chronic idiopathic inflammatory disorders situated at the nexus of intricate interplays. The primary aim of the present investigation is to perform an umbrella review of metaanalyses, systematically offering a comprehensive overview of the evidence concerning risk factors for IBD.

To achieve this, we searched reputable databases, including PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews, from inception through April 2023. Two authors independently assessed the methodological quality of each metaanalysis using the AMSTAR tool and adhered to evidence classification criteria.

In total, we extracted 191 unique risk factors in meta-analyses, including 92 significantly associated risk factors. The top ten risk factors were human cytomegalovirus (HCMV) infection, IBD family history, periodontal disease, poliomyelitis, campylobacter species infection, hidradenitis suppurativa, psoriasis, use of proton pump inhibitors, chronic obstructive pulmonary disease, and western dietary pattern.

In conclusion, this umbrella review extracted 62 risk factors and 30 protective factors, most of which were related to underlying diseases, personal lifestyle and environmental factors. The findings in this paper help to develop better prevention and treatment measures to reduce the incidence of IBD, delay its progression, and reduce the burden of IBD-related disease worldwide.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023417175.

The single nucleotide polymorphism in NOD2 (rs2066847) is associated with conditions that may predispose to the development of gastrointestinal disorders, as well as the known BRCA1 and BRCA2 variants classified as risk factors in many cancers. In our study, we analyzed these variants in a group of patients with pancreatitis and pancreatic cancer to clarify their role in pancreatic disease development. The DNA was isolated from whole blood samples of 553 patients with pancreatitis, 83 patients with pancreatic cancer, 44 cases of other pancreatic diseases, and 116 healthy volunteers. The NOD2 (rs2066847), BRCA1 (rs80357914) and BRCA2 (rs276174813) were genotyped. The statistically significant 3-fold increased risk of pancreatic cancer was detected among the patients with rs2066847 polymorphism (OR = 2.77, p-value = 0.019). We did not find the studied polymorphisms in BRCA1 (rs80357914) and BRCA2 (rs276174813). However, the adjacent polymorphisms have been detected only in patients with pancreatic diseases. The studied variant in NOD2 occurs more frequently in pancreatic patients and significantly increases the risk of pancreatic cancer. It can be considered as a genetic risk factor that predisposes to cancer development. The analyzed regions in BRCA1 and BRCA2 may be a potential target in further search for a genetic marker of pancreatic diseases.

NOD2 is an intracellular innate immune receptor that detects bacterial peptidoglycan fragments. Although nominally soluble, some NOD2 is associated with the plasma membrane and endosomal compartments for microbial surveillance. This membrane targeting is achieved through post-translational S-acylation of NOD2 by the protein acyltransferase ZDHHC5. Membrane attachment is necessary to initiate a signaling cascade in response to cytosolic peptidoglycan fragments. Ultimately, this signaling results in the production of antimicrobial peptides and pro-inflammatory cytokines. In most cases, S-acylation is a reversible post-translational modification with removal of the fatty acyl chain catalyzed by one of several acyl protein thioesterases. Deacylation of NOD2 by such an enzyme will displace it from the plasma membrane and endosomes, thus preventing signaling.

To identify the enzymes responsible for NOD2 deacylation, we used engineered cell lines with RNA interference and small-molecule inhibitors. These approaches were combined with confocal microscopy, acyl-resin-assisted capture, immunoblotting, and cytokine multiplex assays.

We identified α/β-hydrolase domain-containing protein 17 isoforms (ABHD17A, ABHD17B, and ABHD17C) as the acyl protein thioesterases responsible for NOD2 deacylation. Inhibiting ABHD17 increased the plasma membrane localization of wild-type NOD2 and a subset of poorly acylated Crohn's disease-associated variants. This enhanced NOD2 activity, increasing NF-κB activation and pro-inflammatory cytokine production in epithelial cells.

These findings demonstrate that ABHD17 isoforms are negative regulators of NOD2. The results also suggest that targeting ABHD17 isoforms could restore functionality to specific Crohn's disease-associated NOD2 variants, offering a potential therapeutic strategy.

The past 2 decades have witnessed extraordinary advances in our understanding of the genetic factors influencing inflammatory bowel disease (IBD), providing a foundation for the approaching era of genomic medicine. On behalf of the NIDDK IBD Genetics Consortium, we herein survey 11 grand challenges for the field as it embarks on the next 2 decades of research utilizing integrative genomic and systems biology approaches. These involve elucidation of the genetic architecture of IBD (how it compares across populations, the role of rare variants, and prospects of polygenic risk scores), in-depth cellular and molecular characterization (fine-mapping causal variants, cellular contributions to pathology, molecular pathways, interactions with environmental exposures, and advanced organoid models), and applications in personalized medicine (unmet medical needs, working toward molecular nosology, and precision therapeutics). We review recent advances in each of the 11 areas and pose challenges for the genetics and genomics communities of IBD researchers.

Inflammatory bowel disease (IBD), a chronic inflammatory condition of the human intestine, comprises Crohn's disease (CD) and ulcerative colitis (UC). IBD causes severe gastrointestinal symptoms and increases the risk of developing colorectal carcinoma. Although the etiology of IBD remains ambiguous, complex interactions between genetic predisposition, microbiota, epithelial barrier, and immune factors have been implicated. The disruption of intestinal homeostasis is a cardinal characteristic of IBD. Patients with IBD exhibit intestinal microbiota dysbiosis, impaired epithelial tight junctions, and immune dysregulation; however, the relationship between them is not completely understood. As the largest body surface is exposed to the external environment, the gastrointestinal tract epithelium is continuously subjected to environmental and endogenous stressors that can disrupt cellular homeostasis and survival. Heat shock proteins (HSPs) are endogenous factors that play crucial roles in various physiological processes, such as maintaining intestinal homeostasis and influencing IBD progression. Specifically, HSPs share an intricate association with microbes, intestinal epithelium, and the immune system. In this review, we aim to elucidate the impact of HSPs on IBD development by examining their involvement in the interactions between the intestinal microbiota, epithelial barrier, and immune system. The recent clinical and animal models and cellular research delineating the relationship between HSPs and IBD are summarized. Additionally, new perspectives on IBD treatment approaches have been proposed.

Whole-genome sequencing was used to identify a dominant inherited NLRP12 c.1382dup mutation in refractory familial Crohn's disease (CD) patients. Additionally, we observed a T insertion at position 1382 in the third exon of NLRP12, leading to a frameshift mutation. Isolation of peripheral blood from mutation carriers and subsequent experiments demonstrated increased interleukin (IL)-1β in CD patients with the NLRP12 c.1382dup mutation. However, the mechanisms by which the NLRP12 c.1382dup mutation mediates IL-1β remain unclear. Our research findings reveal a close correlation between elevated p-ERK levels and increased expression of NLRP3 and IL-1β in the presence of the NLRP12 c.1382dup mutation. Further experiments demonstrate that inhibiting p-ERK with PD98059 effectively reduces the production of NLRP3 and IL-1β. This discovery provides new insights into the pathogenesis of CD, highlighting the significant role of the ERK/NLRP3/IL-1β pathway in the progression of CD. Not only does this offer novel therapeutic targets for treating CD, but it also lays the groundwork for the development of treatment strategies targeting this pathway.

In the intestinal tract, where numerous intestinal bacteria reside, intestinal epithelial cells produce and release various antimicrobial molecules that form a complex barrier on the mucosal surface. These barrier molecules can be classified into two groups based on their functions: those that exhibit bactericidal activity through chemical reactions, such as antimicrobial peptides, and those that physically hinder bacterial invasion, like mucins, which lack bactericidal properties. In the small intestine, where Paneth cells specialize in producing antimicrobial peptides, the chemical barrier molecules primarily inhibit bacterial growth. In contrast, in the large intestine, where Paneth cells are absent, allowing bacterial growth, the primary defense mechanism is the physical barrier, mainly composed of mucus, which controls bacterial movement and prevents their invasion of intestinal tissues. The expression of these barrier molecules is regulated by metabolites produced by bacteria in the intestinal lumen and cytokines produced by immune cells in the lamina propria. This regulation establishes a defense mechanism that adapts to changes in the intestinal environment, such as alterations in gut microbial composition and the presence of pathogenic bacterial infections. Consequently, when the integrity of the gut mucosal barrier is compromised, commensal bacteria and pathogenic microorganisms from outside the body can invade intestinal tissues, leading to conditions such as intestinal inflammation, as observed in cases of inflammatory bowel disease.

Patients with ulcerative colitis (UC) undergoing proctocolectomy and ileal pouch-anal anastomosis (IPAA) may eventually require biologic therapy. Factors associated with biologic therapy after IPAA have not been previously studied.

All patients with UC after total proctocolectomy and IPAA who were followed at Rabin Medical Center comprehensive pouch clinic and who consented to prospective observational follow-up were included. The primary outcome was the initiation of biologic therapy after IPAA. Cox proportional hazard models were used to evaluate potential associations.

Out of 400 patients receiving their care at the pouch clinic, 148 patients consented to prospective observational follow-up and constituted the study cohort. The median age at diagnosis was 21 years and the age at IPAA was 30 years. Median time-to-biologic therapy initiation post-IPAA was 9.2 years, with 34 patients (23%) initiating biologic therapy: Associated factors for initiating biologic therapy post-IPAA were preoperative treatment with biologic therapy and immunomodulatory therapy (hazard ratio [HR] 6.1 and 3.6, respectively, P < .001); Arab descent (HR 5.3, P < .001); heterozygosity of NOD2 variant rs2066845 (HR 5.1, P = .03); past smoking status (HR 2.3, P = .03); 3-stage IPAA (HR 2.3, P = .02); immediate postoperative complications (HR 2.1, P = .033); and pediatric-onset UC (HR 2.1, P = .03). None of the patients undergoing IPAA due to dysplasia (n = 27) required biologic therapy.

Several demographic, disease-related, surgery-related, and genetic factors associated with post-IPAA biologic therapy were identified. Physicians treating patients with UC undergoing colectomy should incorporate these factors into their decision-making process. These patients may benefit from closer postoperative follow-up, and earlier initiation of biologic therapy should be considered.

The global burden of Inflammatory bowel disease (IBD) has been rising over the last decades. IBD is an intestinal disorder with a complex and largely unknown etiology. The disease is characterized by a chronically inflamed gastrointestinal tract, with intermittent phases of exacerbation and remission. This compromised intestinal barrier can contribute to, enhance, or even enable the toxicity of drugs, food-borne chemicals and particulate matter. This review discusses whether the rising prevalence of IBD in our society warrants the consideration of IBD patients as a specific population group in toxicological safety assessment. Various in vivo, ex vivo and in vitro models are discussed that can simulate hallmarks of IBD and may be used to study the effects of prevalent intestinal inflammation on the hazards of these various toxicants. In conclusion, risk assessments based on healthy individuals may not sufficiently cover IBD patient safety and it is suggested to consider this susceptible subgroup of the population in future toxicological assessments.

Inflammatory bowel disease (IBD) is a disorder causing chronic inflammation in the gastrointestinal tract, and its pathophysiological mechanisms are still under investigation. Here, we find that mice deficient of YOD1, a deubiquitinating enzyme, are highly susceptible to dextran sulfate sodium (DSS)-induced colitis. The bone marrow transplantation experiment reveals that YOD1 derived from hematopoietic cells inhibits DSS colitis. Moreover, YOD1 exerts its protective role by promoting nucleotide-binding oligomerization domain 2 (NOD2)-mediated physiological inflammation in macrophages. Mechanistically, YOD1 inhibits the proteasomal degradation of receptor-interacting serine/threonine kinase 2 (RIPK2) by reducing its K48 polyubiquitination, thereby increasing RIPK2 abundance to enhance NOD2 signaling. Consistently, the protective function of muramyldipeptide, a NOD2 ligand, in experimental colitis is abolished in mice deficient of YOD1. Importantly, YOD1 is upregulated in colon-infiltrating macrophages in patients with colitis. Collectively, this study identifies YOD1 as a novel regulator of colitis.

The incidence of inflammatory bowel disease (IBD), a chronic gastrointestinal disorder, is rapidly increasing worldwide. Unfortunately, the current therapies for IBD are often hindered by premature drug release and undesirable side effects. With the advancement of nanotechnology, the innovative targeted nanotherapeutics are explored to ensure the accurate delivery of drugs to specific sites in the colon, thereby reducing side effects and improving the efficacy of oral administration. The emphasis of this review is to summarize the potential pathogenesis of IBD and highlight recent breakthroughs in carbohydrate-based nanoparticles for IBD treatment, including their construction, release mechanism, potential targeting ability, and their therapeutic efficacy. Specifically, we summarize the latest knowledge regarding environmental-responsive nano-systems and active targeted nanoparticles. The environmental-responsive drug delivery systems crafted with carbohydrates or other biological macromolecules like chitosan and sodium alginate, exhibit a remarkable capacity to enhance the accumulation of therapeutic drugs in the inflamed regions of the digestive tract. Active targeting strategies improve the specificity and accuracy of oral drug delivery to the colon by modifying carbohydrates such as hyaluronic acid and mannose onto nanocarriers. Finally, we discuss the challenges and provide insight into the future perspectives of colon-targeted delivery systems for IBD treatment.

The mammalian intestine is colonized by trillions of microorganisms that are collectively referred to as the gut microbiota. The majority of symbionts have co-evolved with their host in a mutualistic relationship that benefits both. Under certain conditions, such as in Crohn's disease, a subtype of inflammatory bowel disease, some symbionts bloom to cause disease in genetically susceptible hosts. Although the identity and function of disease-causing microorganisms or pathobionts in Crohn's disease remain largely unknown, mounting evidence from animal models suggests that pathobionts triggering Crohn's disease-like colitis inhabit certain niches and penetrate the intestinal tissue to trigger inflammation. In this Review, we discuss the distinct niches occupied by intestinal symbionts and the evidence that pathobionts triggering Crohn's disease live in the mucus layer or near the intestinal epithelium. We also discuss how Crohn's disease-associated mutations in the host disrupt intestinal homeostasis by promoting the penetration and accumulation of pathobionts in the intestinal tissue. Finally, we discuss the potential role of microbiome-based interventions in precision therapeutic strategies for the treatment of Crohn's disease.

Inflammatory bowel disease (IBD) is an inflammatory disorder of the gastrointestinal tract. The present study attempted to understand the codon usage preferences in genes associated with IBD progression. Compositional analysis, codon usage bias (CUB), Relative synonymous codon usage (RSCU), RNA structure, and expression analysis were performed to obtain a comprehensive picture of codon usage in IBD genes. Compositional analysis of 62 IBD-associated genes revealed that G and T are the most and least abundant nucleotides, respectively. ApG, CpA, and TpG dinucleotides were overrepresented or randomly used, while ApC, CpG, GpT, and TpA dinucleotides were either underrepresented or randomly used in genes related to IBD. The codons influencing the codon usage the most in IBD genes were CGC and AGG. A comparison of codon usage between IBD, and pancreatitis (non-IBD inflammatory disease) indicated that only codon CTG codon usage was significantly different between IBD and pancreatitis. At the same time, there were codons ATA, ACA, CGT, CAA, GTA, CCT, ATT, GCT, CGG, TTG, and CAG for whom codon usage was significantly different for IBD and housekeeping gene sets. The results suggest similar codon usage in at least two inflammatory disorders, IBD and pancreatitis. The analysis helps understand the codon biology, factors affecting gene expression of IBD-associated genes, and the evolution of these genes. The study helps reveal the molecular patterns associated with IBD.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, but the molecular mechanisms underlying IBD are incompletely understood. In this study, we explored the role and regulating mechanism of otubain 2 (OTUB2), a deubiquitinating enzyme, in IBD.

To study the function of OTUB2 in IBD, we generated Otub2-/- mice and treated them with dextran sulfate sodium (DSS) to induce experimental colitis. Bone marrow transplantation was performed to identify the cell populations that were affected by OTUB2 in colitis. The molecular mechanism of OTUB2 in signal transduction was studied by various biochemical methods.

OTUB2 was highly expressed in colon-infiltrating macrophages in both humans with IBD and mice with DSS-induced experimental colitis. Colitis was significantly aggravated in Otub2-/- mice and bone marrow chimeric mice receiving Otub2-/- bone marrow. OTUB2-deficiency impaired the production of cytokines and chemokines in macrophages in response to the NOD2 agonist muramyl dipeptide (MDP). Upon MDP stimulation, OTUB2 promoted NOD2 signaling by stabilizing RIPK2. Mechanistically, OTUB2 inhibited the proteasomal degradation of RIPK2 by removing K48-linked polyubiquitination on RIPK2, which was mediated by the active C51 residue in OTUB2. In mice, OTUB2 ablation abolished the protective effects of MDP administration in colitis.

This study identified OTUB2 as a novel regulator of intestinal inflammation.

Nod2 is involved in innate immune responses to bacteria, regulation of metabolism, and sensitivity to cancer. A Nod2 polymorphism is associated with breast cancer, but the role of Nod2 in the development and progression of breast cancer is unknown.

Here, we tested the hypothesis that Nod2 protects mice from breast cancer using the 4T1 orthotopic model of mammary tumorigenesis. WT and Nod2-/- mice were injected with 4T1 mammary carcinoma cells and the development of tumors was monitored. A detailed analysis of the tumor transcriptome was performed and genes that were differentially expressed and pathways that were predicted to be altered between WT and Nod2-/- mice were identified. The activation of key signaling molecules involved in metabolism and development of cancer was studied.

Our data demonstrate that Nod2-/- mice had a higher incidence and larger tumors than WT mice. Nod2-/- mice had increased expression of genes that promote DNA replication and cell division, and decreased expression of genes required for lipolysis, lipogenesis, and steroid biosynthesis compared with WT mice. Nod2-/- mice also had lower expression of genes required for adipogenesis and reduced levels of lipids compared with WT mice. The tumors in Nod2-/- mice had decreased expression of genes associated with PPARα/γ signaling, increased activation of STAT3, decreased activation of STAT5, and no change in the activation of ERK compared with WT mice.

We conclude that Nod2 protects mice from the 4T1 orthotopic breast tumor, and that tumors in Nod2-/- mice are predicted to have increased DNA replication and cell proliferation and decreased lipid metabolism compared with WT mice.

Inflammatory bowel disease (IBD) is a complex and recurring inflammatory disorder that affects the gastrointestinal tract and is influenced by genetic predisposition, immune dysregulation, the gut microbiota, and environmental factors. Advanced therapies, such as biologics and small molecules, target diverse immune pathways to manage IBD. Nanoparticle (NP)-based drugs have emerged as effective tools, offering controlled drug release and targeted delivery. This review highlights NP modifications for anti-inflammatory purposes, utilizing changes such as those in size, charge, redox reactions, and ligand-receptor interactions in drug delivery systems. By using pathological and microenvironmental cues to guide NP design, precise targeting can be achieved. In IBD, a crucial aspect of NP intervention is targeting specific types of cells, such as immune and epithelial cells, to address compromised intestinal barrier function and reduce overactive immune responses. This review also addresses current challenges and future prospects, with the goal of advancing the development of NP-mediated strategies for IBD treatment.