Autophagy is a pro-survival process that regulates the degradation and renewal of cellular components, making it a crucial mechanism for cellular homeostasis. There are selective forms of autophagy that are specific to a number of substrates, such as pathogens (bacteria or viruses), protein aggregates or excess/damaged organelles. These processes involve as key players autophagy receptors, that link the cargo to be degraded to the autophagic machinery. Among them, NDP52 (also known as CALCOCO2) has been described to act as a "bridge" between the autophagy machinery and (1) damaged mitochondria in the mitophagy process; (2) pathogens during xenophagy or (3) proteins in the process of aggrephagy. The aim of this review is to summarize the major functions of NDP52, and to highlight the existence of two human NDP52 variants that have been described as risk or protective factors for Crohn's disease or Multiple Sclerosis and Alzheimer's disease patients, respectively. As these three diseases share common pathological features that lead to inflammation, such as mitochondria or gut microbiota dysfunctions, but also pathogenic infections, it seems clear that NDP52 could be a key player at the crossroad by acting indirectly on inflammation, and therefore a potential target for clinical applications and benefits.

The multidimensional regulatory mechanism of the gut-brain-immune axis in the context of inflammatory bowel disease (IBD) has garnered significant attention, particularly regarding how intestinal microbiota finely regulates immune responses through immune cells and sensory neurons.

Metabolites produced by intestinal microbiota influence the phenotype switching of immune cells via complex signalling pathways, thereby modulating their anti-inflammatory and pro-inflammatory functions during intestinal inflammation. Furthermore, sensory neurons exhibit heightened sensitivity to microbial-derived signals, which is essential for preserving intestinal balance and controlling pathological inflammation by integrating peripheral environmental signals with local immune responses. The dynamic equilibrium between immune cells and the neuroimmunoregulation mediated by sensory neurons collectively sustains immune homeostasis within the intestine. However, this coordination mechanism is markedly disrupted under the pathological conditions associated with IBD.

An in-depth exploration of the interactions among immune cells, gut microbiota and sensory neurons may yield significant insights into the pathological mechanisms underlying IBD and guide the creation of new treatment approaches.

The gut microbiota regulates the gut-brain-immune axis, modulating neuroimmune interactions in IBD. Microbiota-derived metabolites influence immune cells, thereby affecting neurons. Neurons secrete mediators, enabling bidirectional neuroimmune communication essential for intestinal homeostasis. Disruptions contribute to IBD, offering therapeutic targets.

Bacterial invasion into the cytoplasm of epithelial cells triggers the activation of the cellular autophagic machinery as a defense mechanism, a process known as xenophagy. In this study, we identified HEATR3, an LC3-interacting region (LIR)-containing protein, as a factor involved in this defense mechanism using quantitative mass spectrometry analysis. HEATR3 localizes intracellularly invading Salmonella, and HEATR3 deficiency promotes Salmonella proliferation in the cytoplasm. HEATR3 also localizes to lysosomes damaged by chemical treatment, suggesting that Salmonella recognition is facilitated by damage to the host cell membrane. HEATR3 deficiency impairs LC3 recruitment to damaged membranes and blocks the delivery of the target to the lysosome. These phenotypes were rescued by exogenous expression of wild-type HEATR3 but not by the LIR mutant, indicating the crucial role of the HEATR3-LC3 interaction in the receptor for selective autophagy. HEATR3 is delivered to lysosomes in an autophagy-dependent manner. Although HEATR3 recruitment to the damaged membrane was unaffected by ATG5 or FIP200 deficiency, it was markedly impaired by treatment with a calcium chelator, suggesting involvement upstream of the autophagic pathway. These findings suggest that HEATR3 serves as a receptor for selective autophagy and is able to identify damaged membranes, facilitate the removal of damaged lysosomes, and target invading bacteria within cells.

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

Targeting the interleukin (IL)-23 axis is an emerging treatment target for ulcerative colitis (UC), with several positive randomized controlled trials (RCTs). We aim to investigate the safety and efficacy of IL-23 inhibitors for the induction and maintenance treatment of moderate to severe UC.

A systematic review and meta-analysis synthesizing evidence from RCTs obtained from PubMed, Cochrane, Scopus, and Web of Science from inception to August 2024. We used the fixed-effects model to report dichotomous outcomes using the risk ratio (RR) with a 95% confidence interval (CI).

CRD42024589935.

Four records, reporting four induction trials and three maintenance trials, with 2,699 patients in the induction phase and 1,015 in the maintenance phase, were included. IL-23 inhibitors significantly increased the rate of clinical remission in the induction phase (RR: 2.19, 95%CI [1.72, 2.78]) and maintenance phase (RR: 1.55, 95%CI [1.26, 1.90]); endoscopic remission in induction phase (RR: 1.76, 95%CI [1.41, 2.18]) and maintenance phase (RR: 1.63, 95%CI [1.21, 1.85]); histo-endoscopic mucosal healing in induction phase (RR: 2.06, 95%CI [1.60, 2.64]) and maintenance phase (RR: 1.48, 95%CI [1.14, 1.90]). Also, IL-23 inhibitors significantly decreased the incidence of serious adverse events in the induction phase (RR: 0.37, 95%CI [0.26, 0.55]) and maintenance phase (RR: 0.53, 95%CI [0.33, 0.83]).

IL-23 inhibitors are effective as an induction and maintenance therapy for moderate to severe UC based on the significantly increased rates of clinical, endoscopic, and histological remission. Also, the safety profile of IL-23 inhibitors is favorable, with a significantly decreased incidence of serious adverse events compared to placebo.

Accumulation of free α-globin is a critical factor in the pathogenesis of β-thalassemia. Autophagy plays a crucial role in clearing toxic free α-globin, thereby reducing disease severity. However, the impact of natural mutations in autophagy-related genes (ATGs) on the phenotypic variability of β-thalassemia remains unclear. In this study, we systematically investigated the relationship between variants in ATGs and disease phenotypes in a cohort of 1022 patients with β-thalassemia, identifying 4 missense mutations in the autophagy and beclin 1 regulator 1 (AMBRA1) gene. Disruption of the Ambra1 gene in β-thalassemic mice was found to reduce autophagic clearance of α-globin in red blood cell precursors, exacerbating disease phenotypes. Functional characterization of the AMBRA1 gene and these mutations in patient-derived CD34+ cells, edited human umbilical cord blood-derived erythroid progenitor 2 (HUDEP-2) cells, and engineered HUDEP-2 β-thalassemic cells confirmed that AMBRA1 facilitates the autophagic clearance of free α-globin in human erythroid cells. Functional studies demonstrated that AMBRA1 missense mutants destabilize Unc-51-like kinase 1 protein, inhibit light chain 3 protein lipidation, and subsequently hinder autophagic flux, leading to increased α-globin deposition. Additionally, these mutations were associated with erythrotoxic effects in vitro, including increased intracellular reactive oxygen species levels, higher apoptosis rates, and impaired erythroid differentiation and maturation. This study sheds light on the molecular association between mutations in ATGs and the exacerbation of β-thalassemia, highlighting the potential role of the AMBRA1 gene as a promising diagnostic and therapeutic target for β-hemoglobinopathies.

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.

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.

Mutations that increase LRRK2 kinase activity have been linked to Parkinson's disease and Crohn's disease. LRRK2 is also activated by lysosome damage. However, the endogenous cellular mechanisms that control LRRK2 kinase activity are not well understood. In this study, we identify signaling through stimulator of interferon genes (STING) as an activator of LRRK2 via the conjugation of ATG8 to single membranes (CASM) pathway. We furthermore establish that multiple chemical stimuli that perturb lysosomal homeostasis also converge on CASM to activate LRRK2. Although CASM results in the lipidation of multiple ATG8 protein family members, we establish that LRRK2 lysosome recruitment and kinase activation are highly dependent on interactions with the GABARAP member of this family. Collectively, these results define a pathway that integrates multiple stimuli at lysosomes to control the kinase activity of LRRK2. Aberrant activation of LRRK2 via this pathway may be of relevance in both Parkinson's and Crohn's 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.

Intestinal epithelial tight junctions (TJs), a dynamically regulated barrier structure composed of occludin and claudin family of proteins, mediate the interaction between the host and the external environment by allowing selective paracellular permeability between the luminal and serosal compartments of the intestine. TJs are highly dynamic structures and can undergo constant architectural remodeling in response to various external stimuli. This is mediated by an array of intracellular signaling pathways that alters TJ protein expression and localization. Dysfunctional regulation of TJ components compromising the barrier homeostasis is an important pathogenic factor for pathological conditions including inflammatory bowel disease (IBD). Previous studies have elucidated the significance of TJ barrier integrity and key regulatory mechanisms through various in vitro and in vivo models. In recent years, considerable efforts have been made to understand the crosstalk between various signaling pathways that regulate formation and disassembly of TJs. This review provides a comprehensive view on the novel mechanisms that regulate the TJ barrier and permeability. We discuss the latest evidence on how ion transport, cytoskeleton and extracellular matrix proteins, signaling pathways, and cell survival mechanism of autophagy regulate intestinal TJ barrier function. We also provide a perspective on the context-specific outcomes of the TJ barrier modulation. The knowledge on the diverse TJ barrier regulatory mechanisms will provide further insights on the relevance of the TJ barrier defects and potential target molecules/pathways for IBD.

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a rare autoimmune disease with an unclear pathogenesis. The present study investigated the associations between autophagy-related protein 16-like 1 (ATG16L1) rs2241880(T300A) and rs4663421 and AAV. A total of 177 patients with AAV and 216 healthy controls were included. Propensity score matching was used to match the two groups of subjects in terms of sex, age and ethnicity. Analyses of the relationships between these genetic polymorphisms and AAV susceptibility, including comparisons of allele and genotype frequency distribution, linkage disequilibrium analysis and analysis of single nucleotide polymorphism (SNP) interactions between two loci were performed. The association between the loci and laboratory test results and renal pathology were also analysed. A total of 154 pairs of patients with AAV and healthy controls was successfully matched. Neither polymorphism was associated with AAV susceptibility. However, SNP interaction in the model constructed with the two loci was statistically significant (P=0.018), and the combination of the AA genotype of rs2241880(T300A) and GG genotype of rs4663421 was associated the highest disease risk. The differences in the Birmingham Vasculitis Activity Score (BVAS), C-reactive protein (CRP) levels and 24-h urine protein level between patients with the rs2241880(T300A) AA + AG genotypes and the GG genotype were statistically significant (P<0.05). Furthermore, significant differences in the severity of glomerulosclerosis and global sclerosis were detected between individuals with the AA + AG genotype and those with the GG genotype at the rs2241880(T300A) locus (P<0.05). Similarly, there were statistically significant differences in degree of segmental sclerosis between individuals with CC + CG genotypes and those with GG genotypes at the rs2243421 locus (P<0.05). In summary, the single gene polymorphisms of these loci were not associated with genetic susceptibility to AAV. However, SNP interactions may serve a role in the risk of AAV. The rs2241880(T300A) polymorphism may be associated with BVAS, CRP levels and 24-h urine protein level in AAV. These SNPs may be associated with glomerulosclerosis and segmental sclerosis.

The pathogenesis of inflammatory bowel disease (IBD) involves the dysregulation of multiple inflammatory pathways. The understanding of these mechanisms allows their selective targeting for therapeutic purposes. The discovery of Tumor Necrosis Factor-alpha's (TNF-α) role in mucosal inflammation ushered an exciting new era of drug development which now comprises agents targeting multiple pro-inflammatory signaling pathways, integrins, and leukocyte trafficking regulators.

This review provides an overview of the main molecular players of IBD, their translation into therapeutic targets and the successful development of the advanced agents modulating them. We combine basic science with clinical trials data to present a critical review of both the successful and failed drug development programs. A PubMed literature search was conducted to delve into the available literature and clinical trials.

The treatment landscape for IBD has rapidly expanded, particularly with the development of biologics targeting TNF-α, integrins, and S1P modulators, as well as newer agents such as IL-12/IL-23 inhibitors and JAK inhibitors, offering robust efficacy and safety profiles. However, challenges persist in understanding and effectively treating difficult-to-treat IBD, highlighting the need for continued research to uncover novel therapeutic targets and optimize patient outcomes.

Crohn's disease (CD) is the chronic inflammation of the terminal ileum and colon triggered by a dysregulated immune response to bacteria, but insights into specific molecular perturbations at the critical bacteria-epithelium interface are limited. Here, we report that the membrane mucin MUC17 protected small intestinal enterocytes against commensal and pathogenic bacteria. In noninflamed CD ileum, reduced MUC17 levels and a compromised glycocalyx barrier allowed recurrent bacterial contact with enterocytes. Muc17 deletion in mice rendered the small intestine particularly prone to atypical bacterial infection while maintaining resistance to colitis. The loss of Muc17 resulted in spontaneous deterioration of epithelial homeostasis and in the extraintestinal translocation of bacteria. Finally, Muc17-deficient mice harbored specific small intestinal bacterial taxa observed in patients with CD. Our findings highlight MUC17 as an essential region-specific line of defense in the small intestine with relevance for early epithelial defects in CD.

Inflammatory Bowel Disease (IBD), which includes Crohn's disease and ulcerative colitis, represents a complex and growing global health issue with a multifaceted origin. This review delves into the intricate relationship between gut microbiota, autophagy, and the development of IBD. The gut microbiota, a diverse community of microorganisms, plays a vital role in maintaining gut health, while imbalances in this microbial community, known as dysbiosis, are linked to IBD. Autophagy, a process by which cells recycle their components, is essential for gut homeostasis and the regulation of immune responses. When autophagy is impaired and dysbiosis occurs, they individually contribute to IBD, with their combined impact intensifying inflammation. The interconnectedness of gut microbiota, autophagy, and the host's immune system is central to the onset of IBD. The review also examines how diet influences gut microbiota and its subsequent effects on IBD. It highlights the therapeutic potential of targeting the microbiota and modulating autophagic pathways as treatment strategies for IBD. Understanding these interactions could lead to personalized therapies within the rapidly advancing fields of microbiome research and immunology.

Crohn's disease (CD) is a chronic, complex inflammatory condition with increasing incidence and prevalence worldwide. However, the causes of CD remain incompletely understood. We identified CD-related metabolites, inflammatory factors, and key genes by Mendelian randomization (MR), multi-omics integration, machine learning (ML), and SHAP.

We first performed a mediation MR analysis on 1400 serum metabolites, 91 inflammatory factors, and CD. We found that certain phospholipids are causally related to CD. In the scRNA-seq data, monocytes were categorized into high and low metabolism groups based on their glycerophospholipid metabolism scores. The differentially expressed genes of these two groups of cells were extracted, and transcription factor prediction, cell communication analysis, and GSEA analysis were performed. After further screening of differentially expressed genes (FDR<0.05, log2FC>1), least absolute shrinkage and selection operator (LASSO) regression was performed to obtain hub genes. Models for hub genes were built using the Catboost, XGboost, and NGboost methods. Further, we used the SHAP method to interpret the models and obtain the gene with the highest contribution to each model. Finally, qRT-PCR was used to verify the expression of these genes in the peripheral blood mononuclear cells (PBMC) of CD patients and healthy subjects.

MR results showed 1-palmitoyl-2-stearoyl-gpc (16:0/18:0) levels, 1-stearoyl-2-arachidonoyl-GPI (18:0/20:4) levels, 1-arachidonoyl-gpc (20:4n6) levels, 1-palmitoyl-2-arachidonoyl-gpc (16:0/20:4n6) levels, and 1-arachidonoyl-GPE (20:4n6) levels were significantly associated with CD risk reduction (FDR<0.05), with CXCL9 acting as a mediation between these phospholipids and CD. The analysis identified 19 hub genes, with Catboost, XGboost, and NGboost achieving AUC of 0.91, 0.88, and 0.85, respectively. The SHAP methodology obtained the three genes with the highest model contribution: G0S2, S100A8, and PLAUR. The qRT-PCR results showed that the expression levels of S100A8 (p = 0.0003), G0S2 (p < 0.0001), and PLAUR (p = 0.0141) in the PBMC of CD patients were higher than healthy subjects.

MR findings suggest that certain phospholipids may lower CD risk. G0S2, S100A8, and PLAUR may be potential pathogenic genes in CD. These phospholipids and genes could serve as novel diagnostic and therapeutic targets for CD.

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.

Food protein-induced enterocolitis syndrome (FPIES) is a food allergy primarily affecting infants, often leading to vomiting and shock. Due to its poorly understood pathophysiology and lack of specific biomarkers, diagnosis is frequently delayed. Understanding FPIES genetics can shed light on disease susceptibility and pathophysiology-key to developing diagnostic, prognostic, preventive and therapeutic strategies. Using a well-characterised cohort of patients we explored the potential genome-wide susceptibility factors underlying FPIES.

Blood samples from 41 patients with oral food challenge-proven FPIES were collected for a comprehensive whole exome sequencing association study.

Notable genetic variants, including rs872786 (RBM8A), rs2241880 (ATG16L1) and rs2289477 (ATG16L1), were identified as significant findings in FPIES. A weighted SKAT model identified six other associated genes including DGKZ and SIRPA. DGKZ induces TGF-β signalling, crucial for epithelial barrier integrity and IgA production; RBM8A is associated with thrombocytopenia absent radius syndrome, frequently associated with cow's milk allergy; SIRPA is associated with increased neutrophils/monocytes in inflamed tissues as often observed in FPIES; ATG16L1 is associated with inflammatory bowel disease. Coexpression correlation analysis revealed a functional correlation between RBM8A and filaggrin gene (FLG) in stomach and intestine tissue, with filaggrin being a known key pathogenic and risk factor for IgE-mediated food allergy. A transcriptome-wide association study suggested genetic variability in patients impacted gene expression of RBM8A (stomach and pancreas) and ATG16L1 (transverse colon).

This study represents the first case-control exome association study of FPIES patients and marks a crucial step towards unravelling genetic susceptibility factors underpinning the syndrome. Our findings highlight potential factors and pathways contributing to FPIES, including epithelial barrier dysfunction and immune dysregulation. While these results are novel, they are preliminary and need further validation in a second cohort of patients.

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.

Viral myocarditis, characterised by inflammation of the heart muscle, presents a significant challenge to global public health, particularly affecting younger individuals and often progressing to dilated cardiomyopathy (DCM), a leading cause of heart failure. Despite ongoing research efforts, viable treatments for this condition remain elusive. Recent studies have shed light on the complex interplay between the innate immune response and autophagy mechanisms, revealing their pivotal roles in the pathogenesis of viral myocarditis and subsequent DCM development. This review aims to delve into the recent advancements in understanding the molecular mechanisms and pathways that intersect innate immunity and autophagy in the context of viral myocarditis. Furthermore, it explores the potential therapeutic implications of these findings, offering insights into promising avenues for the management and treatment of this debilitating condition.

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.

Inflammation is characterized by a metabolic switch promoting glycolysis and lactate production. Hexokinases (HK) catalyze the first reaction of glycolysis and inhibition of epithelial HK2 protected from colitis in mice. HK2 expression has been described as elevated in patients with intestinal inflammation; however, there is conflicting data from few cohorts especially with severely inflamed individuals; thus, systematic studies linking disease activity with HK2 levels are needed.

We examined the relationship between HK2 expression and inflammation severity using bulk transcriptome data derived from the mucosa of thoroughly phenotyped inflammatory bowel disease (IBD) patients of two independent cohorts including both subtypes Crohn's disease (CD) and ulcerative colitis (UC). Publicly available single-cell RNA sequencing data were analyzed, and immunofluorescence staining on colonic biopsies of unrelated patients with intestinal inflammation was performed to confirm the RNA-based findings on cellular and protein level.

HK2 expression gradually increased from mild to intermediate inflammation, yet strongly declined at high inflammation scores. Expression of epithelial marker genes also declined at high inflammation scores, whereas that of candidate immune marker genes increased, indicating a cellular remodeling of the mucosa during inflammation with an infiltration of HK2-negative immune cells and a loss of terminal differentiated epithelial cells in the apical epithelium-the main site of HK2 expression. Normalizing for the enterocyte loss clearly identified epithelial HK2 expression as gradually increasing with disease activity and remaining elevated at high inflammation scores. HK2 protein expression was mostly restricted to brush border enterocytes, and these cells along with HK2 levels vanished with increasing disease severity.

Our findings clearly define dysregulated epithelial HK2 expression as an indicator of disease activity in intestinal inflammation and suggest targeted HK2-inhibition as a potential therapeutic avenue.

The maintenance of intestinal homeostasis depends on a complex interaction between the immune system, intestinal epithelial barrier, and microbiota. Alteration in one of these components could lead to the development of inflammatory bowel diseases (IBD). Variants within the autophagy gene ATG16L1 have been implicated in susceptibility and severity of Crohn's disease (CD). Individuals carrying the risk ATG16L1 T300A variant have higher caspase 3-dependent degradation of ATG16L1 resulting in impaired autophagy and increased cellular stress. ATG16L1-deficiency induces enhanced IL-1β secretion in dendritic cells in response to bacterial infection. Infection of ATG16L1-deficient mice with a persistent strain of murine norovirus renders these mice highly susceptible to dextran sulfate sodium colitis. Moreover, persistent norovirus infection leads to intestinal virus specific CD8+ T cells responses. Both Toll-like receptor 7 (TLR7), which recognizes single-stranded RNA viruses, and ATG16L1, which facilitates the delivery of viral nucleic acids to the autolysosome endosome, are required for anti-viral immune responses.

However, the role of the enteric virome in IBD is still poorly understood. Here, we investigate the role of TLR7 and ATG16L1 in intestinal homeostasis and inflammation. At steady state, Tlr7-/- mice have a significant increase in large intestinal lamina propria (LP) granzyme B+ tissue-resident memory CD8+ T (TRM) cells compared to WT mice, reminiscent of persistent norovirus infection. Deletion of Atg16l1 in myeloid (Atg16l1ΔLyz2 ) or dendritic cells (Atg16l1ΔCd11c ) leads to a similar increase of LP TRM. Furthermore, Tlr7-/- and Atg16l1ΔCd11c mice were more susceptible to dextran sulfate sodium colitis with an increase in disease activity index, histoscore, and increased secretion of IFN-γ and TNF-α. Treatment of Atg16l1ΔCd11c mice with the TLR7 agonist Imiquimod attenuated colonic inflammation in these mice. Our data demonstrate that ATG16L1-deficiency in myeloid and dendritic cells leads to an increase in LP TRM and consequently to increased susceptibility to colitis by impairing the recognition of enteric viruses by TLR7.

In conclusion, the convergence of ATG16L1 and TLR7 signaling pathways plays an important role in the immune response to intestinal viruses. Our data suggest that activation of the TLR7 signaling pathway could be an attractive therapeutic target for CD patients with ATG16L1 risk variants.

Gastrointestinal disorders encompass a spectrum of conditions affecting various organs within the digestive system, such as the esophagus, stomach, colon, rectum, pancreas, liver, small intestine, and bile ducts. The role of autophagy in the etiology and progression of gastrointestinal diseases has garnered significant attention. This paper seeks to evaluate the impact and mechanisms of autophagy in gastrointestinal disorders by synthesizing recent research findings. Specifically, we delve into inflammation-related gastrointestinal conditions, including ul-cerative colitis, Crohn's disease, and pancreatitis, as well as gastrointestinal cancers such as esophageal, gastric, and colorectal cancers. Additionally, we provide commentary on a recent publication by Chang et al in the World Journal of Gastroenterology. Our objective is to offer fresh perspectives on the mechanisms and therapeutic approaches for these gastrointestinal ailments. This review aims to offer new perspectives on the mechanisms and therapeutic strategies for gastrointestinal disorders by critically analyzing relevant publications. As discussed, the role of autophagy in gastrointestinal diseases is complex and, at times, contentious. To harness the full therapeutic potential of autophagy in treating these conditions, more in-depth research is imperative.

The estrogen receptor 1 gene (ESR1) plays a crucial role in breast and mammary development in humans. Alterations such as gene amplification, genomic rearrangements, and missense mutations in the ESR1 gene are reported to increase the risk of breast cancer in humans. The purpose of this study is to analyze the missense mutations and molecular modeling of ESR1, focusing on the pathogenic SNP H516N, for a better understanding of disease risk and future benefits for therapeutic benefits. This SNP was selected based on its location in the binding pocket of ESR1 and its predicted impact on drug binding. The in silico analysis was performed by applying various computational approaches to identify highly pathogenic SNPs in the binding pocket of ESR1. The effect of the SNP was explored through docking and intra-molecular interaction studies. All SNPs in ESR1 were identified followed by the identification of the highly pathogenic variant located in the binding pocket of ESR1. The mutant model of the pathogenic SNP H516N was generated, and hydroxytamoxifen was docked with the wild-type and the mutant model. The mutant model lost the formation of stable hydrogen bonds with the active site residues and hydroxytamoxifen, which may result in reduced binding affinity and therefore, will predict the patient's response to estrogenic inhibitors.

Autophagy, a highly conserved catabolic process that targets various types of cellular cargoes to lysosomal degradation, is one of the most important biological mechanisms critical for cellular homeostasis. Components of these cellular cargoes can range from individual proteins to invading pathogens, and degrading these materials is important for maintaining organismal health and survival. The process of autophagy is carried out by complex molecular mechanisms, and a growing body of evidence indicates that these mechanisms intersect with those involved in the cell death pathways. In this review, we examine several emerging studies elucidating the role of autophagy in RIP1-mediated cell death signaling, with particular emphasis on impaired autophagy caused by ATG16L1 deficiency. We also discuss how autophagy in RIP1-mediated cell death affects intestinal homeostasis in preclinical models, and the implications of the intersection between RIP1 and autophagy for understanding the intestinal pathologies associated with inflammatory bowel disease (IBD). Finally, we highlight the potential benefits of therapeutic targeting of RIP1 and autophagy proteins, while also proposing areas of research that will likely elucidate new links between autophagy and cell death signaling.

Monocytes and macrophages play an indispensable role in maintaining intestinal homeostasis and modulating mucosal immune responses in inflammatory bowel disease (IBD). Although numerous studies have described macrophage properties in IBD, the underlying mechanisms whereby the monocyte-macrophage lineage modulates intestinal homeostasis during gut inflammation remain elusive.

In this review, we decipher the cellular and molecular mechanisms governing the generation of intestinal mucosal macrophages and fill the knowledge gap in understanding the origin, maturation, classification, and functions of mucosal macrophages in intestinal niches, particularly the phagocytosis and bactericidal effects involved in the elimination of cell debris and pathogens. We delineate macrophage-mediated immunoregulation in the context of producing pro-inflammatory and anti-inflammatory cytokines, chemokines, toxic mediators, and macrophage extracellular traps (METs), and participating in the modulation of epithelial cell proliferation, angiogenesis, and fibrosis in the intestine and its accessory tissues. Moreover, we emphasize that the maturation of intestinal macrophages is arrested at immature stage during IBD, and the deficiency of MCPIP1 involves in the process via ATF3-AP1S2 signature. In addition, we confirmed the origin potential of IL-1B+ macrophages and defined C1QB+ macrophages as mature macrophages. The interaction crosstalk between the intestine and the mesentery has been described in this review, and the expression of mesentery-derived SAA2 is upregulated during IBD, which contributes to immunoregulation of macrophage. Moreover, we also highlight IBD-related susceptibility genes (e.g., RUNX3, IL21R, GTF2I, and LILRB3) associated with the maturation and functions of macrophage, which provide promising therapeutic opportunities for treating human IBD.

In summary, this review provides a comprehensive, comprehensive, in-depth and novel description of the characteristics and functions of macrophages in IBD, and highlights the important role of macrophages in the molecular and cellular process during IBD.

Crohn disease (CD) is an inflammatory bowel disease whose pathogenesis involves inappropriate immune responses toward gut microbiota on genetically predisposed backgrounds. Notably, CD is associated with single-nucleotide polymorphisms affecting several genes involved in macroautophagy/autophagy, the catabolic process that ensures the degradation and recycling of cytosolic components and microorganisms. In a clinical translation perspective, monitoring the autophagic activity of CD patients will require some knowledge on the intrinsic functional status of autophagy. Here, we focused on monocyte-derived dendritic cells (DCs) to characterize the intrinsic quantitative features of the autophagy flux. Starting with DCs from healthy donors, we documented a reprogramming of the steady state flux during the transition from the immature to mature status: both the autophagosome pool size and the flux were diminished at the mature stage while the autophagosome turnover remained stable. At the cohort level, DCs from CD patients were comparable to control in term of autophagy flux reprogramming capacity. However, the homozygous presence of ATG16L1 rs2241880 A>G (T300A) and ULK1 rs12303764 (G/T) polymorphisms abolished the capacity of CD patient DCs to reprogram their autophagy flux during maturation. This effect was not seen in the case of CD patients heterozygous for these polymorphisms, revealing a gene dose dependency effect. In contrast, the NOD2 rs2066844 c.2104C>T (R702W) polymorphism did not alter the flux reprogramming capacity of DCs. The data, opening new clinical translation perspectives, indicate that polymorphisms affecting autophagy-related genes can differentially influence the capacity of DCs to reprogram their steady state autophagy flux when exposed to proinflammatory challenges.Abbreviation: BAFA1: bafilomycin A1, CD: Crohn disease; DC: dendritic cells; HD: healthy donor; iDCs: immature DCs; IL: interleukin; J: autophagosome flux; LPS: lipopolysaccharide; MHC: major histocompatibility complex; nA: autophagosome pool size; SNPs: single-nucleotide polymorphisms; PCA: principal component analysis; TLR: toll like receptor; τ: transition time; TNF: tumor necrosis factor.

Autophagy refers to a set of degradative mechanisms whereby cytoplasmic contents are targeted to the lysosome. This is best described for macroautophagy, where a double-membrane compartment (autophagosome) is generated to engulf cytoplasmic contents. Autophagosomes are decorated with ubiquitin-like ATG8 molecules (ATG8s), which are recruited through covalent lipidation, catalysed by the E3-ligase-like ATG16L1 complex. LC3 proteins are ATG8 family members that are often used as a marker for autophagosomes. In contrast to canonical macroautophagy, conjugation of ATG8s to single membranes (CASM) describes a group of non-canonical autophagy processes in which ATG8s are targeted to pre-existing single-membrane compartments. CASM occurs in response to disrupted intracellular pH gradients, when the V-ATPase proton pump recruits ATG16L1 in a process called V-ATPase-ATG16L1-induced LC3 lipidation (VAIL). Recent work has demonstrated a parallel, alternative axis for CASM induction, triggered when the membrane recruitment factor TECPR1 recognises sphingomyelin exposed on the cytosolic face of a membrane and forms an alternative E3-ligase-like complex. This sphingomyelin-TECPR1-induced LC3 lipidation (STIL) is independent of the V-ATPase and ATG16L1. In light of these discoveries, this Cell Science at a Glance article summarises these two mechanisms of CASM to highlight how they differ from canonical macroautophagy, and from each other.

Bowel strictures are well recognized as one of the most severe complications in Crohn's disease, with variable impacts on the prognosis and often needing surgical or endoscopic treatment. Distinguishing inflammatory strictures from fibrotic ones is of primary importance due to the different therapeutic approaches required. Indeed, to better understand the pathogenesis of fibrosis, it is crucial to investigate molecular processes involving genetic factors, cytokines, alteration of the intestinal barrier, and epithelial and endothelial damage, leading to an increase in extracellular matrix synthesis, which ultimately ends in fibrosis. In such a complex mechanism, the gut microbiota also seems to play a role. A better comprehension of molecular processes underlying bowel fibrosis, in addition to radiological and histopathological findings, has led to the identification of high-risk patients for personalized follow-up and testing of new therapies, primarily in preclinical models, targeting specific pathways involving Transforming Growth Factor-β, interleukins, extracellular matrix balance, and gut microbiota. Our review aims to summarize current evidence about molecular factors involved in intestinal fibrosis' pathogenesis, paving the way for potential diagnostic biomarkers or anti-fibrotic treatments for stricturing Crohn's disease.

Transcription factor EB (TFEB), a master lysosomal biogenesis and autophagy regulator, is crucial for cellular homeostasis, and its abnormality is related to diverse inflammatory diseases. Genetic variations in autophagic genes are associated with susceptibility to inflammatory bowel disease (IBD); however, little is known about the role and mechanism of TFEB in disease pathogenesis. In this study, we found that the genetic deletion of TFEB in mouse intestinal epithelial cells (IEC) caused intestinal barrier dysfunction, leading to increased susceptibility to experimental colitis. Mechanistically, TFEB functionally protected IEC in part through peroxisome proliferator-activated receptor gamma coactivator 1alpha (TFEB-PGC1α axis) induction, which consequently suppressed reactive oxygen species. TFEB can directly regulate PGC-1α transcription to control antioxidation level. Notably, TFEB expression is impaired and downregulated in the colon tissues of IBD patients. Collectively, our results indicate that intestinal TFEB participates in oxidative stress regulation and attenuates IBD progression.

Few studies have been conducted on gene-environment interactions in the Chinese population with Crohn's disease (CD). We aimed to investigate the association between single nucleotide polymorphisms (SNPs) on the T helper 17 (Th17) cell and CD susceptibility/performance in Chinese individuals.

We conducted a case-control and case-only study at the Peking Union Medical College Hospital. Four SNPs related to the Th17 cell pathway genes were prioritized, including rs2284553 (interferon gamma receptor 2), rs7517847 (interleukin 23 receptor), rs7773324 (interferon regulatory factor 4), and rs4263839 (tumor necrosis factor superfamily 15). SNP frequency was calculated, and gene-environment interaction was assessed by multifactor dimensionality reduction analysis.

Altogether 159 CD patients and 316 healthy controls were included. All analyzed SNPs were found in Hardy-Weinberg equilibrium (P > 0.05). The frequency of rs2284553-A allele and rs4263839-A allele were lower in CD patients compared with controls (P < 0.05). While the rs4263839-A allele was more prevalent in ileocolonic CD patients than in those with isolated small intestinal or colonic disease (P = 0.035). Gene-environment interactions revealed associations between rs2284553 and breastfeeding, sunshine exposure, and fridge-stored food, affecting age at diagnosis, intestinal involvement, and intestinal stricture. Interaction of rs4263839 and breastfeeding influenced small intestinal lesions and intestinal stricture in CD.

This study provided information on the genetic background in Chinese CD patients. Incorporating these SNPs into predictive models may improve risk assessment and outcome prediction. Gene-environment interaction contributes to the understanding of CD pathogenesis.

Inflammatory bowel disease (IBD) comprises a group of idiopathic intestinal disorders, including ulcerative colitis and Crohn's disease, significantly impacting the quality of life for affected individuals. The effective management of these conditions remains a persistent challenge. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a complex molecular structure, regulates the production of pro-inflammatory cytokines such as interleukin-1β. Abnormal activation of the NLRP3 inflammasome plays a pivotal role in the development of IBD, making it a compelling target for therapeutic intervention. Our research revealed that cinnamaldehyde (CA), a major bioactive compound found in the leaves of Cinnamomum osmophloeum kaneh, demonstrated a remarkable ability to alleviate colitis induced by dextran sulfate sodium (DSS) in a mouse model. This effect was attributed to CA's ability to downregulate the activation of the NLRP3 inflammasome and reduce the expression of pro-inflammatory mediators in the colon. In the mechanism study, we observed that CA inhibited the NLRP3 inflammasome in macrophages, at least partially, by enhancing the autophagic response, without reducing mitochondrial damage. These findings collectively suggest that CA holds significant potential as a therapeutic agent for enhancing the management of IBD, offering a promising avenue for further research and development.

SNPs could either cause a disorder or directly alter the efficacy of a particular treatment and act as biological markers. The SNP rs7587633 C/T present in the intronic region of the ATG16L1 gene has been studied for its role in psoriasis vulgaris and Palmoplantar pustulosis. To genotype rs7587633 C/T using PCR-RFLP no restriction site is present for any of the restriction enzymes at the SNP position. To develop an artificial-RFLP method for genotyping rs7587633 C/T, the forward primer was designed in such a way that it resulted in the creation of an EcoRI restriction site in the amplified product which could further be digested with EcoRI to find the genotype of the individual. The newly developed A-RFLP method was applied to genotype the SNP rs7587633 C/T in DNA samples of 100 healthy control individuals. The allelic and genotypic frequencies of the SNPs were 0.80(C), 0.20(T) and 65%(CC), 31%(CT) and 4%(TT), respectively. In conclusion, we developed an A-RFLP method to genotype the SNP rs7587633 C/T which is not present in any of the natural restriction sites and this method could be applied to genotype this SNP in various populations/diseases to find its role.