• antibiotic growth promoter (AGP)
• cecum
• gut microbiome
• host expression
• host-microbe interaction
• phytogenic feed additive (PFA)
• poultry

• Mice
• Animals
• Metalloendopeptidases
• Galectin 3/genetics
• Galectin 3/metabolism
• Metalloproteases/metabolism
• Proteolysis
• Mice, Knockout
• Homeostasis

• Deutsche Forschungsgemeinschaft
• Austrian Science Fund
• Vetenskapsrådet
• Knut and Alice Wallenberg foundation

• proteases
• cryoelectron microscopy
• kinetics

• Humans
• Fetuin-B
• Cryoelectron Microscopy
• Metalloendopeptidases/metabolism
• Metalloproteases
• Enzyme Precursors
• Zinc

• Bioinformatics
• Crohn's disease
• Genomics
• Inflammatory bowel disease
• Pathology

• Inflammation
• Intestine
• Meprin
• Mucus
• Shedding

• IBD
• P2Y6
• intestinal inflammation
• mucus
• nucleotides

• AIEC-host interaction
• AIEC-targeting therapy
• Crohn’s disease
• adherent-invasive Escherichia coli
• intestinal environment
• microbiota
• virulence gene

• Animals
• Crohn Disease/metabolism
• Crohn Disease/microbiology
• Enteropathogenic Escherichia coli/genetics
• Enteropathogenic Escherichia coli/metabolism
• Enteropathogenic Escherichia coli/pathogenicity
• Host-Pathogen Interactions
• Humans
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/microbiology

• U1071 Institut National de la Santé et de la Recherche Médicale
• USC-2018 Institut National de la Recherche Agronomique
• ECO201906008953 Fondation pour la Recherche Médicale
• 16-IDEX-0001 IDEX-ISITE initiative

Adherent-invasive Escherichia coli (AIEC) strains have been extensively related to Crohn’s disease (CD) etiopathogenesis. Higher AIEC prevalence in CD patients versus controls has been reported, and its mechanisms of pathogenicity have been linked to CD physiopathology. In CD, the therapeutic armamentarium remains limited and non-curative; hence, the necessity to better understand AIEC as a putative instigator or propagator of the disease is certain. Nonetheless, AIEC identification is currently challenging because it relies on phenotypic assays based on infected cell cultures which are highly time-consuming, laborious and non-standardizable. To address this issue, AIEC molecular mechanisms and virulence genes have been studied; however, a specific and widely distributed genetic AIEC marker is still missing. The finding of molecular tools to easily identify AIEC could be useful in the identification of AIEC carriers who could profit from personalized treatment. Also, it would significantly promote AIEC epidemiological studies. Here, we reviewed the existing data regarding AIEC genetics and presented those molecular markers that could assist with AIEC identification. Finally, we highlighted the problems behind the discovery of exclusive AIEC biomarkers and proposed strategies to facilitate the search of AIEC signature sequences.

• Crohn’s disease
• Adherent-invasive Escherichia coli
• Molecular markers
• Genetics
• Inflammatory bowel disease
• Signature sequences

• Drug targets
• Interactome
• Protein interaction network
• Regulatory network
• SARS-CoV-2
• Small intestine

Once bound to the epithelium, pathogenic bacteria have to cross epithelial barriers to invade their human host. In order to achieve this goal, they have to destroy the adherens junctions insured by cell adhesion molecules (CAM), such as E-cadherin (E-cad). The invasive bacteria use more or less sophisticated mechanisms aimed to deregulate CAM genes expression or to modulate the cell-surface expression of CAM proteins, which are otherwise rigorously regulated by a molecular crosstalk essential for homeostasis. Apart from the repression of CAM genes, a drastic decrease in adhesion molecules on human epithelial cells can be obtained by induction of eukaryotic endoproteases named sheddases or through synthesis of their own (prokaryotic) sheddases. Cleavage of CAM by sheddases results in the release of soluble forms of CAM. The overexpression of soluble CAM in body fluids can trigger inflammation and pro-carcinogenic programming leading to tumor induction and metastasis. In addition, the reduction of the surface expression of E-cad on epithelia could be accompanied by an alteration of the anti-bacterial and anti-tumoral immune responses. This immune response dysfunction is likely to occur through the deregulation of immune cells homing, which is controlled at the level of E-cad interaction by surface molecules α_E integrin (CD103) and lectin receptor KLRG1. In this review, we highlight the central role of CAM cell-surface expression during pathogenic microbial invasion, with a particular focus on bacterial-induced cleavage of E-cad. We revisit herein the rapidly growing body of evidence indicating that high levels of soluble E-cad (sE-cad) in patients’ sera could serve as biomarker of bacterial-induced diseases.

• E-cadherin
• bacteria-inducing cancer
• bacterial invasion
• pathophysiology
• sheddases

• proteases
• x-ray crystallography

• Amino Acid Sequence/genetics
• Animals
• Astacoidea/chemistry
• Astacoidea/ultrastructure
• Binding Sites
• Crystallography, X-Ray
• Fertility/genetics
• Fetuin-B/genetics
• Fetuin-B/ultrastructure
• Humans
• Metalloendopeptidases/genetics
• Metalloendopeptidases/ultrastructure
• Metalloproteases/antagonists & inhibitors
• Metalloproteases/chemistry
• Metalloproteases/genetics
• Metalloproteases/ultrastructure
• Mice
• Protein Conformation
• Protein Structure, Secondary/genetics
• Proteolysis
• Zinc/chemistry

• Salmonella
• inflammation
• intestinal fibrosis
• proteases

• CCL2
• IL-18
• IL-1β
• IL-6
• IL-6R
• Inflammation
• Meprin A
• Meprin α
• Meprin β
• Metalloproteinase

• bacterial adherence
• chronic ulcerative colitis
• crohn’s disease
• e. coli
• inflammatory bowel disease

• ectodomain shedding
• host-microbiome interaction
• intestinal mucus barrier
• metalloprotease
• mucus

• Adhesins, Bacterial/metabolism
• Amino Acid Sequence/genetics
• Animals
• Cell Membrane/metabolism
• Cysteine Endopeptidases/metabolism
• Epithelial Cells/metabolism
• Female
• Gingipain Cysteine Endopeptidases
• HEK293 Cells
• Humans
• Male
• Metalloendopeptidases/genetics
• Metalloendopeptidases/metabolism
• Metalloproteases/metabolism
• Mice, Transgenic
• Mucin-2/genetics
• Mucin-2/metabolism

• R01 DK093697 NIDDK NIH HHS

Soluble Interleukin-6 receptor (sIL-6R) mediated trans-signaling is an important pro-inflammatory stimulus associated with pathological conditions, such as arthritis, neurodegeneration and inflammatory bowel disease. The sIL-6R is generated proteolytically from its membrane bound form and A Disintegrin And Metalloprotease (ADAM) 10 and 17 were shown to perform ectodomain shedding of the receptor in vitro and in vivo. However, under certain conditions not all sIL-6R could be assigned to ADAM10/17 activity. Here, we demonstrate that the IL-6R is a shedding substrate of soluble meprin α and membrane bound meprin β, resulting in bioactive sIL-6R that is capable of inducing IL-6 trans-signaling. We determined cleavage within the N-terminal part of the IL-6R stalk region, distinct from the cleavage site reported for ADAM10/17. Interestingly, meprin β can be shed from the cell surface by ADAM10/17 and the observation that soluble meprin β is not capable of shedding the IL-6R suggests a regulatory mechanism towards trans-signaling. Additionally, we observed a significant negative correlation of meprin β expression and IL-6R levels on human granulocytes, providing evidence for in vivo function of this proteolytic interaction.

The membrane bound metalloprotease meprin β is important for collagen fibril assembly in connective tissue formation and for the detachment of the intestinal mucus layer for proper barrier function. Recent proteomic studies revealed dozens of putative new substrates of meprin β, including the amyloid precursor protein (APP). It was shown that APP is cleaved by meprin β in distinct ways, either at the β-secretase site resulting in increased levels of Aβ peptides, or at the N-terminus releasing 11 kDa, and 20 kDa peptide fragments. The latter event was discussed to be rather neuroprotective, whereas the ectodomain shedding of APP by meprin β reminiscent to BACE-1 is in line with the amyloid hypothesis of Alzheimer's disease, promoting neurodegeneration. The N-terminal 11 kDa and 20 kDa peptide fragments represent physiological cleavage products, since they are found in human brains under different diseased or non-diseased states, whereas these fragments are completely missing in brains of meprin β knock-out animals. Meprin β is not only a sheddase of adhesion molecules, such as APP, but was additionally demonstrated to cleave within the prodomain of ADAM10. Activated ADAM10, the α-secretase of APP, is then able to shed meprin β from the cell surface thereby abolishing the β-secretase activity. All together meprin β seems to be a novel player in APP processing events, even influencing other enzymes involved in APP cleavage.

• APP
• N-terminal truncated Aβ
• meprin β
• proteolysis
• shedding

In this study we determined protein and gene expression in the caeca of newly hatched chickens inoculated with cecal contents sourced from hens of different ages. Over 250 proteins exhibited modified expression levels in response to microbiota inoculation. The most significant inductions were observed for ISG12-2, OASL, ES1, LYG2, DMBT1-L, CDD, ANGPTL6, B2M, CUZD1, IgM and Ig lambda chain. Of these, ISG12-2, ES1 and both immunoglobulins were expressed at lower levels in germ-free chickens compared to conventional chickens. In contrast, CELA2A, BRT-2, ALDH1A1, ADH1C, AKR1B1L, HEXB, ALDH2, ALDOB, CALB1 and TTR were expressed at lower levels following inoculation of microbiota. When chicks were given microbiota preparations from different age donors, the recipients mounted differential responses to the inoculation which also differed from the response profile in naturally colonised birds. For example, B2M, CUZD1 and CELA2A responded differently to the inoculation with microbiota of 4- or 40-week-old hens. The increased or decreased gene expression could be recorded 6 weeks after the inoculation of newly hatched chickens. To characterise the proteins that may directly interact with the microbiota we characterised chicken proteins that co-purified with the microbiota and identified a range of host proteins including CDD, ANGPTL6, DMBT1-L, MEP1A and Ig lambda. We propose that induction of ISG12-2 results in reduced apoptosis of host cells exposed to the colonizing commensal microbiota and that CDD, ANGPTL6, DMBT1-L, MEP1A and Ig lambda reduce contact of luminal microbiota with the gut epithelium thereby reducing the inflammatory response.

• Bacterial Adhesion
• Escherichia coli/physiology
• Escherichia coli Infections/complications
• Escherichia coli Infections/history
• France
• History, 20th Century
• History, 21st Century
• Inflammatory Bowel Diseases/history
• Inflammatory Bowel Diseases/microbiology

• R01 DK047700 NIDDK NIH HHS
• R01 DK073338 NIDDK NIH HHS

A trillion of microorganisms colonize the mammalian intestine. Most of them have coevolved with the host in a symbiotic relationship and some of them have developed strategies to promote their replication in the presence of competing microbiota. Recent evidence suggests that perturbation of the microbial community favors the emergence of opportunistic pathogens, in particular adherent-invasive Escherichia coli (AIEC) that can increase incidence and severity of gut inflammation in the context of Crohn's disease (CD). This review will report the importance of AIEC as triggers of intestinal inflammation, focusing on their impact on epithelial barrier function and stimulation of mucosal inflammation. Beyond manipulation of immune response, restoration of gut microbiota as a new treatment option for CD patients will be discussed.

Important advances during the last decade have been made in understanding the complex etiopathogenesis of Crohn’s disease (CD). While many gaps in our knowledge still exist, it has been suggested that the etiology of CD is multifactorial including genetic, environmental and infectious factors. The most widely accepted theory states that CD is caused by an aggressive immune response to infectious agents in genetically predisposed individuals. The rise of genome-wide association studies allowed the identification of loci and genetic variants in several components of host innate and adaptive immune responses to microorganisms in the gut, highlighting an implication of intestinal microbiota in CD etiology. Moreover, numerous independent studies reported a dysbiosis, i.e., a modification of intestinal microbiota composition, with an imbalance between the abundance of beneficial and harmful bacteria. Although microorganisms including viruses, yeasts, fungi and bacteria have been postulated as potential CD pathogens, based on epidemiological, clinicopathological, genetic and experimental evidence, their precise role in this disease is not clearly defined. This review summarizes the current knowledge of the infectious agents associated with an increased risk of developing CD. Therapeutic approaches to modulate the intestinal dysbiosis and to target the putative CD-associated pathogens, as well as their potential mechanisms of action are also discussed.

• Crohn’s disease
• Intestinal microbiota
• Dysbiosis
• Adherent-invasive Escherichia coli
• Probiotics
• Antibiotics
• Fecal microbiota transplantation

• Anti-Bacterial Agents/therapeutic use
• Bacteria/drug effects
• Bacteria/growth & development
• Bacteria/immunology
• Crohn Disease/diagnosis
• Crohn Disease/genetics
• Crohn Disease/immunology
• Crohn Disease/microbiology
• Crohn Disease/therapy
• Dysbiosis
• Host-Pathogen Interactions
• Humans
• Intestines/immunology
• Intestines/microbiology
• Microbiota
• Probiotics/therapeutic use
• Risk Factors
• Treatment Outcome

Escherichia coli (E. coli), and particularly the adherent invasive E. coli (AIEC) pathotype, has been increasingly implicated in the ethiopathogenesis of Crohn’s disease (CD). E. coli strains with similar pathogenic features to AIEC have been associated with other intestinal disorders such as ulcerative colitis, colorectal cancer, and coeliac disease, but AIEC prevalence in these diseases remains largely unexplored. Since AIEC was described one decade ago, substantial progress has been made in deciphering its mechanisms of pathogenicity. However, the molecular bases that characterize the phenotypic properties of this pathotype are still not well resolved. A review of studies focused on E. coli populations in inflammatory bowel disease (IBD) is presented here and we discuss about the putative role of this species on each IBD subtype. Given the relevance of AIEC in CD pathogenesis, we present the latest research findings concerning AIEC host-microbe interactions and pathogenicity. We also review the existing data regarding the prevalence and abundance of AIEC in CD and its association with other intestinal diseases from humans and animals, in order to discuss the AIEC disease- and host-specificity. Finally, we highlight the fact that dietary components frequently found in industrialized countries may enhance AIEC colonization in the gut, which merits further investigation and the implementation of preventative measures.

• Adherent invasive Escherichia coli
• Inflammatory bowel disease
• Crohn’s disease
• Pathogenesis
• Epidemiology

• Ehlers–Danlos syndrome
• connective tissue
• fibrosis
• proteolysis
• proteomics

• Animals
• Colon/immunology
• Colon/metabolism
• Colon/microbiology
• Gene Expression
• Group II Phospholipases A2/genetics
• Group II Phospholipases A2/immunology
• Host Specificity
• Interferons/genetics
• Interferons/immunology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/microbiology
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Microbiota/genetics
• Microbiota/immunology
• Oligonucleotide Array Sequence Analysis
• Species Specificity
• Symbiosis/genetics
• Symbiosis/immunology

The metalloproteases meprin α and meprin β exhibit structural and functional features that are unique among all extracellular proteases. Although meprins were discovered more than 30 years ago, their precise substrates and physiological roles have been elusive. Both enzymes were originally found to be highly expressed in kidney and intestine, which focused research on these particular tissues and associated pathologies. Only recently it has become evident that meprins exhibit a much broader expression pattern, implicating functions in angiogenesis, cancer, inflammation, fibrosis and neurodegenerative diseases. Different animal models, as well as proteomics approaches for the identification of protease substrates, have helped to reveal more precise molecular signalling events mediated by meprin activity, such as activation and release of pro-inflammatory cytokines. APP (amyloid precursor protein) is cleaved by meprin β in vivo, reminiscent of the β-secretase BACE1 (β-site APP-cleaving enzyme 1). The subsequent release of Aβ (amyloid β) peptides is thought to be the major cause of the neurodegenerative Alzheimer's disease. On the other hand, ADAM10 (a disintegrin and metalloprotease domain 10), which is the constitutive α-secretase, was shown to be activated by meprin β, which is itself shed from the cell surface by ADAM10. In skin, both meprins are overexpressed in fibrotic tumours, characterized by massive accumulation of fibrillar collagens. Indeed, procollagen III is processed to its mature form by meprin α and meprin β, an essential step in collagen fibril assembly. The recently solved crystal structure of meprin β and the unique cleavage specificity of these proteases identified by proteomics will help to generate specific inhibitors that could be used as therapeutics to target meprins under certain pathological conditions.