• fecal microbiota transplantation
• gut microbiota
• herb medicine
• inflammatory diseases
• intestinal immunity

• Humans
• Colitis, Ulcerative/immunology
• Colitis, Ulcerative/therapy
• Colitis, Ulcerative/microbiology
• Gastrointestinal Microbiome/immunology
• Dysbiosis/immunology
• Immunity, Mucosal
• Intestinal Mucosa/immunology
• Intestinal Mucosa/microbiology
• Animals

• Environmental and immune factors
• Extracellular matrix
• Intestinal fibrosis
• Stenosis

• Humans
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/etiology
• Inflammatory Bowel Diseases/genetics
• Immunity, Innate
• Gastrointestinal Microbiome
• Adaptive Immunity

• R01 DK123233 NIDDK NIH HHS
• R01 DK132038 NIDDK NIH HHS

• F31 DK127687 NIDDK NIH HHS
• T32 HD007502 NICHD NIH HHS
• P30 DK058404 NIDDK NIH HHS
• R21 AI173599 NIAID NIH HHS
• R01 DK103831 NIDDK NIH HHS
• U54 CA274367 NCI NIH HHS
• R01 DK128200 NIDDK NIH HHS
• I01 CX002473 CSRD VA
• I01 CX002662 CSRD VA
• P30 CA068485 NCI NIH HHS
• R35 GM147470 NIGMS NIH HHS
• R01 DK134692 NIDDK NIH HHS

• CD
• HSP
• IBD
• UC
• epithelial barrier
• immune system.
• microbiota

• Humans
• Inflammatory Bowel Diseases/metabolism
• Inflammatory Bowel Diseases/pathology
• Inflammatory Bowel Diseases/etiology
• Inflammatory Bowel Diseases/microbiology
• Animals
• Heat-Shock Proteins/metabolism
• Heat-Shock Proteins/genetics
• Gastrointestinal Microbiome
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/immunology
• Intestinal Mucosa/microbiology
• Intestinal Mucosa/pathology
• Homeostasis
• Dysbiosis

• 82000760 National Natural Science Foundation of China
• JCYJ20220530160017037 Science and Technology Plan Project of Shenzhen

• CD
• Drug repositioning
• IBD
• UC.
• colonic inflammation
• drug redirecting
• drug rediscovery
• drug reprofiling
• large intestine

• Humans
• Drug Repositioning
• Animals
• Inflammatory Bowel Diseases/drug therapy
• Colitis, Ulcerative/drug therapy
• Crohn Disease/drug therapy
• Anti-Inflammatory Agents/therapeutic use
• Anti-Inflammatory Agents/pharmacology
• Gastrointestinal Agents/therapeutic use
• Gastrointestinal Agents/pharmacology

• CD
• IBD
• MMPs
• UC
• cytokines
• inflammatory bowel disease
• metalloproteinases

• Humans
• Inflammatory Bowel Diseases/genetics
• Colitis, Ulcerative
• Crohn Disease
• Cytokines
• Matrix Metalloproteinases/genetics

• Inflammatory bowel disease
• Intestinal permeability
• Mucus
• Tight junctions

• Humans
• Intestinal Mucosa/pathology
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/pathology
• Intestines/pathology
• Gastrointestinal Diseases
• Permeability
• Tight Junctions/pathology

• R01 DK115950 NIDDK NIH HHS
• R01-DK115950 NIH HHS

• RNA-binding protein
• autoantigen
• autoimmune disorder
• gene expression regulation
• heterogeneous nuclear ribonucleoprotein

• Humans
• Heterogeneous-Nuclear Ribonucleoproteins/genetics
• Heterogeneous-Nuclear Ribonucleoproteins/metabolism
• Autoimmune Diseases
• RNA/metabolism
• Autoantigens
• Biomarkers

• CD46
• Inborn errors of immunity
• SLE
• aHUS
• atypical hemolytic uremic syndrome
• haploinsufficiency
• next-generation sequencing
• penetrance
• primary immunodeficiency complement
• systemic lupus erythematosus

• Adult
• Child
• Humans
• Family
• Haploinsufficiency
• Health Status
• Heterozygote
• Cytokines
• Membrane Cofactor Protein/genetics

• ZIA HL006223 Intramural NIH HHS
• Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
• Japan Agency for Medical Research and Development
• Takeda Science Foundation
• Japan Society for the Promotion of Science
• Division of Intramural Research, National Institute of Allergy and Infectious Diseases
• University of Basel

• Crohn’s disease (CD)
• hydrogen sulfide (H2S)
• inflammatory bowel disease (IBD)
• ulcerative colitis (UC)

• NSAID enteritis
• alcoholic and non-alcoholic steatohepatitis
• colorectal cancer
• fecal microbiota transplantation
• gut microbiota
• inflammatory bowel disease
• pancreatic cancer
• primary sclerosing cholangitis

• Crohn’s disease
• Granuloma formation
• Orofacial granulomatosis
• Perianal disease
• Phenotype

• Akkermansia muciniphila
• gut microbiome
• inflammatory bowel disease
• interleukin-10-deficient mice
• intestinal barrier
• mucin

• Instituto de Salud Carlos III

• Crohn’s disease
• DL-endopeptidase
• NOD2
• gut microbiota
• metagenomics

• Bone marrow
• Colorectal cancer
• Hydrogen sulfide
• Inflammatory bowel disease
• Transsulfuration pathway
• Ulcerative colitis

• R01 CA175803 NCI NIH HHS
• T32 DK007639 NIDDK NIH HHS

• diet
• gastrointestinal tract
• gut microbiota
• immune
• inflammatory bowel disease (IBD)

• National Research Foundation of Korea
• Institute of Information and Communications Technology

• 3D organoids
• dietary intervention
• dog
• inflammatory bowel diseases
• one health

The nucleotide oligomerization domain (NOD)-like receptor 2 (NOD2) is an intracellular pattern recognition receptor that detects components of peptidoglycans from bacterial cell walls. NOD2 regulates bowel microorganisms, provides resistance against infections such as diarrhea, and reduces the risk of inflammatory bowel diseases in humans and mice. We previously demonstrated that a specific porcine NOD2 polymorphism (NOD2-2197A > C) augments the recognition of peptidoglycan components. In this study, the relationships between porcine NOD2-2197A/C genotypes affecting molecular functions and symptoms in a porcine circovirus 2b (PCV2b)-spreading Duroc pig population were investigated. The NOD2 allele (NOD2-2197A) with reduced recognition of the peptidoglycan components augmented the mortality of pigs at the growing stage in the PCV2b-spreading population. Comparison of NOD2 allele frequencies in the piglets before and after invasion of PCV2b indicated that the ratio of NOD2-2197A decreased in the population after the PCV2b epidemic. This data indicated that functional differences caused by NOD2-2197 polymorphisms have a marked impact on pig health and livestock productivity. We suggest that NOD2-2197CC is a PCV2 disease resistant polymorphism, which is useful for selective breeding by reducing mortality and increasing productivity.

• PCV2
• disease resistance
• pattern recognition receptors
• post-weaning multisystemic wasting syndrome
• swine

• Animals
• Capsid Proteins/genetics
• Circoviridae Infections/genetics
• Circoviridae Infections/mortality
• Circoviridae Infections/pathology
• Circoviridae Infections/transmission
• Circovirus/genetics
• Circovirus/immunology
• Circovirus/pathogenicity
• Disease Resistance/genetics
• Female
• Genetic Predisposition to Disease
• Genotype
• Host-Pathogen Interactions/genetics
• Male
• Nod2 Signaling Adaptor Protein/genetics
• Phylogeny
• Polymorphism, Single Nucleotide
• Swine/genetics
• Swine/virology
• Swine Diseases/genetics
• Swine Diseases/mortality
• Swine Diseases/pathology
• Swine Diseases/transmission

• IBD
• dog
• epithelial barrier
• intestinal permeability
• microbiota
• mouse

• R01 GM099537 NIGMS NIH HHS

• Crohn’s disease
• inflammation
• inflammatory reflex
• ulcerative colitis
• vagus nerve stimulation

A significant portion of molecular biology investigates signalling pathways and thus depends on an up-to-date and complete resource of functional protein–protein associations (PPAs) that constitute such pathways. Despite extensive curation efforts, major pathway databases are still notoriously incomplete. Relation extraction can help to gather such pathway information from biomedical publications. Current methods for extracting PPAs typically rely exclusively on rare manually labelled data which severely limits their performance.

We propose PPA Extraction with Deep Language (PEDL), a method for predicting PPAs from text that combines deep language models and distant supervision. Due to the reliance on distant supervision, PEDL has access to an order of magnitude more training data than methods solely relying on manually labelled annotations. We introduce three different datasets for PPA prediction and evaluate PEDL for the two subtasks of predicting PPAs between two proteins, as well as identifying the text spans stating the PPA. We compared PEDL with a recently published state-of-the-art model and found that on average PEDL performs better in both tasks on all three datasets. An expert evaluation demonstrates that PEDL can be used to predict PPAs that are missing from major pathway databases and that it correctly identifies the text spans supporting the PPA.

PEDL is freely available at https://github.com/leonweber/pedl. The repository also includes scripts to generate the used datasets and to reproduce the experiments from this article.

Supplementary data are available at Bioinformatics online.

• Colitis
• DPLG3
• Immunoproteasome
• Inflammatory bowel disease
• NF-κB

Recent investigations have shown that different conditions such as diet, the overuse of antibiotics or the colonization of pathogenic microorganisms can alter the population status of the intestinal microbiota. This modification can produce a change from homeostasis to a condition known as imbalance or dysbiosis; however, the role-played by dysbiosis and the development of inflammatory bowel diseases (IBD) has been poorly understood. It was actually not until a few years ago that studies started to develop regarding the role that dendritic cells (DC) of intestinal mucosa play in the sensing of the gut microbiota population. The latest studies have focused on describing the DC modulation, specifically on tolerance response involving T regulatory cells or on the inflammatory response involving reactive oxygen species and tissue damage. Furthermore, the latest studies have also focused on the protective and restorative effect of the population of the gut microbiota given by probiotic therapy, targeting IBD and other intestinal pathologies. In the present work, the authors propose and summarize a recently studied complex axis of interaction between the population of the gut microbiota, the sensing of the DC and its modulation towards tolerance and inflammation, the development of IBD and the protective and restorative effect of probiotics on other intestinal pathologies.

• Crohn’s disease
• dendritic cells
• gut microbiota
• inflammatory bowel disease
• probiotic
• ulcerative colitis

Intestinal fibrosis is thought to be a consequence of excessive tissue repair, and constitutes a common problem in patients with Crohn’s disease (CD). While fibrosis seems to require inflammation as a prerequisite it is unclear whether the severity or persistence of inflammation influences the degree of fibrosis. Our aim was to investigate the role of sustained inflammation in fibrogenesis. For the initiation of fibrosis in vivo the models of Il10^−/− spontaneous colitis, dextran sodium sulfate (DSS)-induced chronic colitis and heterotopic transplantation were used. In Il10^−/− mice, we determined a positive correlation between expression of pro-inflammatory factors (Il1β, Tnf, Ifnγ, Mcp1 and Il6). We also found a positive correlation between the expression of pro-fibrotic factors (Col3a1 Col1a1, Tgfβ and αSma). In contrast, no significant correlation was determined between the expression of pro-inflammatory Tnf and pro-fibrotic αSma, Col1a1, Col3a1, collagen layer thickness and the hydroxyproline (HYP) content. Results from the DSS-induced chronic colitis model confirmed this finding. In the transplantation model for intestinal fibrosis a pronounced increase in Mcp1, inos and Il6 in Il10^−/− as compared to WT grafts was observed, indicating more severe inflammation in Il10^−/− grafts. However, the increase of collagen over time was virtually identical in both Il10^−/− and WT grafts. Severity of inflammation during onset of fibrogenesis did not correlate with collagen deposition. Although inflammation might be a pre-requisite for the initiation of fibrosis our data suggest that it has a minor impact on the progression of fibrosis. Our results suggest that development of fibrosis and inflammation may be disconnected. This may be important for explaining the inefficacy of anti-inflammatory treatments agents in most cases of fibrotic inflammatory bowel diseases (IBD).

• Crohn’s disease
• IBD
• biological therapies
• chronic inflammation
• dysbiosis
• dysregulated immune response
• immunopathogenesis
• ulcerative colitis

• Sjögren's syndrome
• autoimmunity
• crohn's disease
• lupus erythematosus
• oral microbiome
• rheumatoid arthritis

NOD2 contributes to the innate immune response and to the homeostasis of the intestinal mucosa. In response to its bacterial ligand, NOD2 interacts with RICK and activates the NF-κB and MAPK pathways, inducing gene transcription and synthesis of proteins required to initiate a balanced immune response. Mutations in NOD2 have been associated with an increased risk of Crohn’s Disease (CD), a disabling inflammatory bowel disease (IBD). Because NOD2 signaling plays a key role in CD, it is important to further characterize the network of protein interacting with NOD2. Using yeast two hybrid (Y2H) screens, we identified new NOD2 interacting proteins (NIP). The primary interaction was confirmed by coimmunoprecipitation and/or bioluminescence resonance energy transfer (BRET) experiments for 11 of these proteins (ANKHD1, CHMP5, SDCCAG3, TRIM41, LDOC1, PPP1R12C, DOCK7, VIM, KRT15, PPP2R3B, and C10Orf67). These proteins are involved in diverse functions, including endosomal sorting complexes required for transport (ESCRT), cytoskeletal architecture and signaling regulation. Additionally, we show that the interaction of 8 NIPs is compromised with the 3 main CD associated NOD2 mutants (R702W, G908R and 1007fs). Furthermore, to determine whether these NOD2 protein partners could be encoded by IBD susceptibility genes, a transmission disequilibrium test (TDT) was performed on 101 single nucleotide polymorphisms (SNPs) and the main corresponding haplotypes in genes coding for 15 NIPs using a set of 343 IBD families with 556 patients. Overall this work did not increase the number of IBD susceptibility genes but extends the NOD2 protein interaction network and suggests that NOD2 interactome and signaling depend upon the NOD2 mutation profile in CD.

• Cell Line
• Crohn Disease/genetics
• Crohn Disease/metabolism
• Humans
• Macrophages/metabolism
• Mutation
• NF-kappa B/genetics
• NF-kappa B/metabolism
• Nod2 Signaling Adaptor Protein/genetics
• Nod2 Signaling Adaptor Protein/metabolism
• Polymorphism, Single Nucleotide
• Protein Interaction Mapping

• orofacial granulomatosis
• crohn's disease
• nod2 gene
• genetic association

The aim of this study was to verify the hypothesis originated from bioinformatics and literature reviews that hnNRP A1 may be a new immune target of Behçet's disease (BD).

First, bioinformatics was used to show the correlation between hnRNP A1 and A2/B1 in amino acid sequences and three dimensional structures. Second, hnRNP A1 was expressed, purified, and immunologically confirmed by systematic immunology methods including: Western blotting, immunoprecipitation and Dot-ELISA. Then, ELISA was used to screen the anti-hnRNP A1 autoantibodies in newly confirmed clinical samples and the clinical significance was compared between anti-hnRNP A1 antibody positive and negative groups. Finally, the endothelial cells antigen profile of one anti-hnRNP A1 antibody positive BD patient was detected using immunoprecipitation with liquid chromatography tandem mass spectrometry (LC–TMS).

In total 720 subjects enrolled and tested in this study. Our results demonstrated hnRNP A1 as a new immune target of BD. The reactivity of BD serum IgG antibodies against hnRNP A1 was significantly higher than healthy controls (P < 0.0001), and deep vein thrombosis (DVT) showed a significant higher in the anti-hnRNP A1 antibodies positive group (P < 0.05).

•

Bioinformatics was used to predict that hnRNP A1 may play a role in BD.

Behçet's disease (BD) is a chronic systemic autoimmune disease. The pathogenesis of BD is still not clear, and the diagnosis is based on typical clinical syndromes. Autoantigen identification was considered a key to solve this problem. This study was to verify the hypothesis suggested by bioinformatics that hnRNP A1 may be a new autoantigen of BD. Among the 720 subjects enrolled and systemic tested, our results demonstrated hnRNP A1 as a new autoantigen of BD, and associated with deep vein thrombosis.

• Autoantigen
• Behçet's disease
• Bioinformatics
• HnRNP A1

• Aging
• NOD-like receptors
• inflammasome
• innate immunity
• oral mucosa

• Aging/genetics
• Animals
• Carrier Proteins/biosynthesis
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Female
• Gene Expression
• Immunity, Innate/genetics
• Inflammasomes/biosynthesis
• Inflammasomes/genetics
• Inflammasomes/metabolism
• Interleukin-1beta/biosynthesis
• Macaca mulatta
• Male
• Mouth Mucosa/immunology
• Mouth Mucosa/metabolism
• Mouth Mucosa/pathology
• NLR Proteins/biosynthesis
• NLR Proteins/genetics
• NLR Proteins/metabolism
• Neuronal Apoptosis-Inhibitory Protein/biosynthesis
• Neuronal Apoptosis-Inhibitory Protein/genetics
• Neuronal Apoptosis-Inhibitory Protein/metabolism
• Periodontitis/genetics
• Periodontitis/metabolism
• Periodontitis/pathology
• RNA, Messenger/biosynthesis
• Real-Time Polymerase Chain Reaction
• Signal Transduction

• UL1 TR000117 NCATS NIH HHS
• 5P20GM103436-13 NIGMS NIH HHS
• UL1TR000117 NCATS NIH HHS
• P30 GM110788 NIGMS NIH HHS
• P20 GM103436 NIGMS NIH HHS
• P40 RR003640 NCRR NIH HHS
• P20GM103538 NIGMS NIH HHS
• P40RR03640 NCRR NIH HHS
• P20 GM103538 NIGMS NIH HHS

• Adaptive Immunity/immunology
• Adult
• Alarmins/genetics
• Alarmins/physiology
• Causality
• Child
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/epidemiology
• Colitis, Ulcerative/genetics
• Colitis, Ulcerative/immunology
• Crohn Disease/diagnosis
• Crohn Disease/epidemiology
• Crohn Disease/genetics
• Crohn Disease/immunology
• Cultural Evolution
• Gene Expression Regulation/genetics
• Humans
• Immunity, Innate/immunology
• Inflammasomes/immunology
• MicroRNAs/genetics
• Microbiota/immunology
• Regulatory Sequences, Ribonucleic Acid/genetics

Interleukin-10 and Interleukin-12 are produced primarily by pathogen-activated antigen-presenting cells, particularly macrophages and dendritic cells. IL-10 and IL-12 play very important immunoregulatory roles in host defense and immune homeostasis. Being anti- and pro-inflammatory in nature, respectively, their functions are antagonistically opposing. A comprehensive and in-depth understanding of their immunological properties and signaling mechanisms will help develop better clinical intervention strategies in therapy for a wide range of human disorders. Here, we provide an update on some emerging concepts, controversies, unanswered questions, and opinions regarding the immune signaling of IL-10 and IL-12.

• IL-10
• IL-12
• immune signaling

NOD2 (nucleotide-binding and oligomerization domain 2) was initially reported as a susceptibility gene for Crohn's disease, with several studies focused on elucidating its molecular mechanism in the progression of Crohn's disease. We now know that NOD2 is an intracellular bacterial sensing receptor, and that MDP-mediated NOD2 activation drives inflammatory signaling. Various mutations in NOD2 have been reported, with NOD2 loss of function being associated with the development of Crohn's disease and other autoimmune diseases. These results suggest that NOD2 not only has an immune stimulatory function, but also an immune regulatory function. Atherosclerosis is a chronic inflammatory disease of the arterial wall; its pathologic progression is highly dependent on the immune balance. This immune balance is regulated by infiltrating monocytes and macrophages, both of which express NOD2. These findings indicate a potential role of NOD2 in atherosclerosis. The purpose of this review is to outline the known roles of NOD2 signaling in the pathogenesis of atherosclerosis.

• Atherosclerosis
• Chronic inflammatory disease
• Immune balance
• NOD2

• Animal models
• Crohn׳s disease
• Experimental colitis
• Inflammatory bowel disease
• Translation
• Ulcerative colitis

• Animals
• Disease Models, Animal
• Humans
• Immunity, Innate
• Immunity, Mucosal
• Inflammatory Bowel Diseases/etiology
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/pathology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/pathology
• Species Specificity
• Translational Research, Biomedical/methods

Although Toll-like receptor 4 (TLR4)- and nucleotide-binding oligomerization domain 2 (NOD2)-mediated signaling mechanisms have been extensively studied individually, the crosstalk between them in the regulation of intestinal mucosal defense and tissue homeostasis has been underappreciated. Here, we uncover some novel activities of NOD2 by gene expression profiling revealing the global nature of the cross-regulation between TLR4- and NOD2-mediated signaling. Specifically, NOD2 is able to sense the intensity of TLR4-mediated signaling, resulting in either synergistic stimulation of Interluekin-12 (IL-12) production when the TLR signaling intensity is low; or in the inhibition of IL-12 synthesis and maintenance of intestinal mucosal homeostasis when the TLR signaling intensifies. This balancing act is mediated through receptor-interacting serine/threonine kinase 2, and the transcriptional regulator CCAAT/enhancer-binding protein α (C/EBPα) via its serine 248 phosphorylation by Protein Kinase C. Mice deficient in C/EBPα in the hematopoietic compartment are highly susceptible to chemically induced experimental colitis in an IL-12-dependent manner. Additionally, in contrast to the dogma, we find that the major Crohn’s disease-associated NOD2 mutations could cause a primarily immunodeficient phenotype by selectively impairing TLR4-mediated IL-12 production and host defense. To restore the impaired homeostasis would be a way forward to developing novel therapeutic strategies for inflammatory bowel diseases.

• Animals
• Antigens, Bacterial/immunology
• Bacterial Infections/immunology
• Host-Pathogen Interactions
• Humans
• Immunity, Innate
• Inflammation/immunology
• Nod1 Signaling Adaptor Protein/immunology
• Nod2 Signaling Adaptor Protein/immunology
• Peptidoglycan/immunology
• Receptors, Pattern Recognition/immunology
• Signal Transduction