• Antiviral
• Interferon-induced transmembrane protein 3
• Pseudorabies virus
• Recombinant lactic acid bacteria

• Animals
• Mice
• Membrane Proteins/genetics
• Membrane Proteins/immunology
• Genetic Vectors
• Herpesvirus 1, Suid/immunology
• Female
• RNA-Binding Proteins/genetics
• RNA-Binding Proteins/immunology
• Viral Vaccines/immunology
• Viral Vaccines/administration & dosage
• Viral Vaccines/genetics
• Cytokines
• Mice, Inbred BALB C
• Administration, Oral
• Lung/virology
• Brain/virology

• engineered probiotic-based materials
• inflammatory bowel disease
• living materials
• probiotics

• Probiotics/therapeutic use
• Probiotics/administration & dosage
• Humans
• Inflammatory Bowel Diseases/therapy
• Inflammatory Bowel Diseases/microbiology
• Biocompatible Materials/therapeutic use
• Biocompatible Materials/chemistry
• Animals
• Gastrointestinal Microbiome

• Genetically engineered probiotic
• Gut microbiota
• Inflammatory bowel disease (IBD)
• Inflammatory factor
• Intestinal barrier
• Therapeutic protein

• Probiotics/therapeutic use
• Probiotics/administration & dosage
• Humans
• Inflammatory Bowel Diseases/therapy
• Inflammatory Bowel Diseases/microbiology
• Gastrointestinal Microbiome
• Genetic Engineering
• Animals
• Immunity, Mucosal

• Muc2
• Gut microbiota
• IL-36γ
• Next-generation sequencing
• gmLAB

• Animals
• Lactococcus lactis/genetics
• Lactococcus lactis/metabolism
• Mice
• Humans
• Interleukin-1/genetics
• Interleukin-1/metabolism
• Recombinant Proteins/genetics
• Recombinant Proteins/metabolism
• Nisin/genetics
• Nisin/pharmacology
• Gastrointestinal Microbiome
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/microbiology
• Intestines/microbiology
• Genetic Engineering
• Female
• Immunity, Mucosal

• Shinshu University

• Drug delivery carrier
• Enzyme
• Inflammatory bowel disease therapy
• Reactive oxygen species
• Stimuli-responsive nanoplatforms
• pH

• Inflammatory Bowel Diseases/drug therapy
• Humans
• Animals
• Drug Delivery Systems
• Nanoparticles/chemistry
• Nanoparticles/therapeutic use
• Anti-Inflammatory Agents/therapeutic use
• Anti-Inflammatory Agents/chemistry
• Drug Carriers/chemistry
• Nanoparticle Drug Delivery System/chemistry

• Rgg
• Streptococcus thermophilus
• heterologous protein production
• inducible promoter
• signalling peptide

• Quorum Sensing/genetics
• Bacterial Proteins/genetics
• Bacterial Proteins/metabolism
• Streptococcus thermophilus/genetics
• Streptococcus thermophilus/metabolism
• Animals
• Recombinant Proteins/genetics
• Recombinant Proteins/metabolism
• Mice
• Gene Expression Regulation, Bacterial
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Pheromones/metabolism
• Pheromones/genetics

• Paris-Saclay precompetitive IDEX-2017
• TWB Precompetitive project
• INRAE

• Apoptosis
• Efferocytosis
• Macrophage reprogramming
• Resolution of Inflammation
• Targeted nanomedicine

• Humans
• Macrophages
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Anti-Inflammatory Agents/metabolism
• Inflammation/metabolism
• Wound Healing
• Signal Transduction

• Cytokines
• Immune signalization
• Inflammation, Heterologous protein expression
• Lactic Acid Bacteria

• Humans
• Lactococcus lactis/metabolism
• Interleukins/metabolism
• Cytokines/metabolism
• Autoimmune Diseases/drug therapy
• Anti-Inflammatory Agents

• Gut microbiota
• Inflammatory bowel disease
• Interplay
• Protease
• Proteolytic activity

• Humans
• Gastrointestinal Microbiome
• Proteolysis
• Inflammatory Bowel Diseases/therapy
• Intestines
• Intestinal Mucosa
• Dysbiosis

• Barrier function
• Colitis
• Trichinella spiralis

• Female
• Animals
• Mice
• Gastrointestinal Microbiome
• Trichinella
• Intestinal Barrier Function
• Colitis/chemically induced
• Colitis/therapy
• Inflammatory Bowel Diseases
• Inflammation
• Colitis, Ulcerative/pathology
• Colon/pathology
• Dextran Sulfate
• Disease Models, Animal
• Mice, Inbred C57BL

• microbiota
• trypsin
• elastase
• thrombin
• par receptors
• permeability
• pain

• Humans
• Irritable Bowel Syndrome
• Peptide Hydrolases
• Celiac Disease/therapy
• Inflammatory Bowel Diseases/therapy
• Inflammation

• R01 DK127998 NIDDK NIH HHS

• transcriptomics
• gene expression analysis
• genetics
• molecular biology
• biomarkers
• diseases
• gastroenterology
• medical research
• molecular medicine
• pathogenesis

• Humans
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/genetics
• Colitis, Ulcerative/metabolism
• Crohn Disease/diagnosis
• Crohn Disease/genetics
• Crohn Disease/metabolism
• Inflammatory Bowel Diseases
• Mucous Membrane/metabolism
• Receptors, Calcitriol/genetics

• Aage og Johanne Louis-Hansens Fond
• Herlev Hospital
• Colitis-Crohn Foreningen
• Torben og Alice Frimodts Fond
• Aase og Ejnar Danielsens Fond

• Biologics
• Delivery systems
• Inflammatory bowel diseases
• Mucosal healing
• Stability

• Humans
• Inflammatory Bowel Diseases/drug therapy
• Inflammation
• Drug Delivery Systems
• Cytokines/metabolism
• Biological Products/therapeutic use

• healing
• probiotics
• regenerative medicine
• tissue engineering

• Tissue Engineering
• Regenerative Medicine
• Probiotics
• Biocompatible Materials
• Wound Healing
• Humans
• Microbiota
• Animals

• colitis
• efficacy
• genetically modified probiotics
• inflammatory bowel disease

• 82170557 National Natural Science Foundation of China
• 2019YFA0905604 National Key R&D Program of China

• dysbiosis
• functional foods
• intestinal microbiota
• microencapsulation
• prebiotics
• probiotics

• colitis
• elafin
• inflammation
• inflammatory bowel disease
• protease
• trappin

• AKT
• MAFLD
• NAFLD
• PI3K
• cardio-metabolic disorders
• diabetes
• genetically modified probiotics
• mTOR
• obesity
• probiotics

• Humans
• Proto-Oncogene Proteins c-akt/metabolism
• Phosphatidylinositol 3-Kinases
• Probiotics/therapeutic use
• Metabolic Diseases/genetics
• Metabolic Diseases/prevention & control
• TOR Serine-Threonine Kinases/metabolism

• applied microbiology
• gastrointestinal diseases
• bacterial host response

• bacteriotherapy
• clinical application
• genetically engineered bacterium
• heterologous expression
• synthetic biotechnology

• National Natural Science Foundation of China

• Fibrosis
• Protease
• Receptor

Inflammatory bowel disease (IBD) is a gastrointestinal disease characterized by diarrhea, rectal bleeding, abdominal pain, and weight loss. Recombinant probiotics producing specific proteins with IBD therapeutic potential are currently considered novel drug substitutes. In this study, a Bifidobacterium bifidum BGN4-SK strain was designed to produce the antioxidant enzymes streptococcal superoxide dismutase (SOD) and lactobacillus catalase (CAT), and a B. bifidum BGN4-pBESIL10 strain was proposed to generate an anti-inflammatory cytokine, human interleukin (IL)-10. In vitro and in vivo efficacy of these genetically modified Bifidobacterium strains were evaluated for colitis amelioration.

In a lipopolysaccharide (LPS)-stimulated HT-29 cell model, tumor necrosis factor (TNF)-α and IL-8 production was significantly suppressed in the B. bifidum BGN4-SK treatment, followed by B. bifidum BGN4-pBESIL10 treatment, when compared to the LPS-treated control. Synergistic effects on TNF-α suppression were also observed. In a dextran sodium sulphate (DSS)-induced colitis mouse model, B. bifidum BGN4-SK treatment significantly enhanced levels of antioxidant enzymes SOD, glutathione peroxidase (GSH-Px) and CAT, compared to the DSS-only group. B. bifidum BGN4-SK significantly ameliorated the symptoms of DSS-induced colitis, increased the expression of tight junction genes (claudin and ZO-1), and decreased pro-inflammatory cytokines IL-6, IL-1β and TNF-α.

These findings suggest that B. bifidum BGN4-SK ameliorated DSS-induced colitis by generating antioxidant enzymes, maintaining the epithelial barrier, and decreasing the production of pro-inflammatory cytokines. Although B. bifidum BGN4-pBESIL10 exerted anti-inflammatory effects in vitro, the enhancement of IL-10 production and alleviation of colitis were very limited.

The online version contains supplementary material available at 10.1186/s12934-022-01840-2.

• NICE system
• constitutive expression
• lactic acid bacteria
• plasmid-based vectors
• rolling-circle replication
• theta-mode of replication

• Bacterial therapeutics
• Drug delivery
• Genetic engineering
• Strategies and goals
• Tumor

Serine proteases are heavily present in the gastrointestinal tract where they are essential in numerous physiological processes. An imbalance in the proteolytic activity is a central mechanism underlying abdominal pain in irritable bowel syndrome (IBS). Therefore, protease inhibitors are emerging as a promising therapeutic tool to manage abdominal pain in this functional gastrointestinal disorder. With this review, we provide an up-to-date overview of the implications of serine proteases in the development of abdominal pain in IBS, along with a critical assessment of the current developments and prospects of protease inhibitors as a therapeutic tool. In particular, we highlight the current knowledge gap concerning the identity of dysregulated serine proteases that are released by the rectal mucosa of IBS patients. Finally, we suggest a workflow with state-of-the-art techniques that will help address the knowledge gap, guiding future research towards the development of more effective and selective protease inhibitors to manage abdominal pain in IBS.

• Fonds Wetenschappelijk Onderzoek

• FMT
• Gut microbiome
• Inflammation
• Live biotherapeutic products
• Mucosal immunity
• Probiotics

• SLPI
• barrier
• colitis
• inflammatory bowel disease
• intestinal epithelium
• mouse
• neutrophil
• protease inhibitor

• T cell transfer colitis mouse model
• T cells
• intestinal barrier
• protease-activated receptors
• serine protease inhibitor

Colorectal cancer (CRC) is a major cause of morbidity and mortality in Europe, and accounts for over 10% of all cancer-related deaths worldwide. These indicate an urgent need for novel therapeutic options in CRC. Here, we analysed if genetically modified non-pathogenic Lactococcus lactis bacteria can be used for local delivery of human recombinant Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) and induction of tumor cells death in vitro and in vivo in CRC mouse model. We showed that modified L. lactis bacteria were able to secrete biologically active human soluble TRAIL (L. lactis(hsTRAIL+)), which selectively eliminated human CRC cells in vitro, and was further strengthened by metformin (MetF). Our results from in vitro studies were confirmed in vivo using subcutaneous NOD-SCID mouse model of human CRC. The data showed a significant reduction of the tumor growth by intratumor injection of L. lactis(hsTRAIL+) bacteria producing hsTRAIL. This effect could be further enhanced by oral administration of MetF.

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) induces apoptosis of many cancer cells, including CRC cells, being non-harmful for normal ones. However, recombinant form of human TRAIL failed in clinical trial when administered intravenously. To assess the importance of TRAIL in CRC patients, new form of TRAIL delivery would be required. Here we used genetically modified, non-pathogenic Lactococcus lactis bacteria as a vehicle for local delivery of human soluble TRAIL (hsTRAIL) in CRC. Operating under the Nisin Controlled Gene Expression System (NICE), the modified bacteria (L. lactis(hsTRAIL+)) were able to induce cell death of HCT116 and SW480 human cancer cells and reduce the growth of HCT116-tumor spheres in vitro. This effect was cancer cell specific as the cells of normal colon epithelium (FHC cells) were not affected by hsTRAIL-producing bacteria. Metformin (MetF), 5-fluorouracil (5-FU) and irinotecan (CPT-11) enhanced the anti-tumor actions of hsTRAIL in vitro. In the NOD-SCID mouse model, treatment of subcutaneous HCT116-tumors with L. lactis(hsTRAIL+) bacteria given intratumorally, significantly reduced the tumor growth. This anti-tumor activity of hsTRAIL in vivo was further enhanced by oral administration of MetF. These findings indicate that L. lactis bacteria could be suitable for local delivery of biologically active human proteins. At the same time, we documented that anti-tumor activity of hsTRAIL in experimental therapy of CRC can be further enhanced by MetF given orally, opening a venue for alternative CRC-treatment strategies.

• Lactococcus lactis
• TRAIL
• colorectal cancer

• Food fermentation
• Industrial microbiology
• Lactic acid bacteria
• Probiotics
• Therapeutic proteins

• Cancer
• Chronic inflammation
• Mucosal immunology
• SLPI
• Tissue homeostasis

• Gastrointestinal
• Inflammatory bowel disease
• Nanomedicine
• Polymeric nano-materials
• RNAi
• SCFA.

There is growing evidence that intestinal proteases have a role in the pathogenesis of gastrointestinal inflammatory diseases. Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), has an additional source of proteases represented by infiltrated and activated inflammatory cells. The aim of our study was to determine proteolytic system activity in patients with CD and UC. We limited the number of proteases tested by determining proteases active in acidic, neutral and alkaline pH.

The study included 40 patients with IBD – 20 CD patients and 20 UC patients. The control group consisted of 20 healthy subjects. Among the 20 CD patients, 17 were treated with aminosalicylates, 14 with azathioprine, and 4 with corticosteroids, while 8 patients were undergoing biological treatment. Among the 20 UC patients, 19 were treated with aminosalicylates, 8 with azathioprine, and 3 with corticosteroids. The total protein concentration was assayed by the Lowry method. The optimal pH was assayed in pH from 2.2 to 12.8, separated by 0.2 intervals. Proteolytic activities were determined against different substrates (gelatine, haemoglobin, ovalbumin, albumin, cytochrome C, and casein), and haemoglobin was the optimal substrate. Protease activities were determined according to Anson method. Determination of the activities of natural inhibitors of acidic, neutral and alkaline proteases is based on the Lee and Lin method.

Decreases were observed in the activities of acid proteases (pH 5), alkaline proteases (pH 7), and neutral proteases (pH 7.6 and 8.6) in the groups of CD patients in remission in comparison with the active phase. In the group of patients with biologically treated CD patients, acid protease activity (pH 5.0) was lower than in CD patients not receiving biological treatment. Activities of neutral (pH 7.0) and alkaline (pH 7.6 and 8.6) proteases in the plasma of patients with UC in remission were lower in comparison to the active phase. Activities of acid (pH 5.0) and alkaline (8.6) protease inhibitors were higher in CD patients in the active phase in comparison to remission. In UC patients with exacerbation of the disease, the activity of alkaline (pH 8.6) protease inhibitors was increased compared to remission.

1. Our research may suggest that the immunomodulatory treatment used in IBD, aimed at reducing the level of leukocytes and reduction of inflammation, may contribute to a reduction in protease activity. 2. The decrease of protease activities in patients with CD and UC in remission may be a marker suggesting the patients’ response to the treatment.

• Crohn’s disease
• proteases
• ulcerative colitis

• living therapeutics
• microbial engineering
• microbiota
• synthetic biology

• alcoholic liver disease
• nutrition
• fatty acids

• Animals
• Cadherins/physiology
• Dietary Fats/administration & dosage
• Ethanol/pharmacology
• Fatty Acids, Omega-3/metabolism
• Gene Expression Profiling
• Gene Expression Regulation/drug effects
• Intestinal Mucosa/drug effects
• Intestinal Mucosa/growth & development
• Intestinal Mucosa/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic

• P20 GM113226 NIGMS NIH HHS
• P20GM113226 NIGMS NIH HHS
• P50 AA024337 NIAAA NIH HHS
• R01AA024102-01A1 NIH HHS
• P20GM103436 NIH HHS
• U01 AA026936 NIAAA NIH HHS
• F32 AA027950 NIAAA NIH HHS
• T32 ES011564 NIEHS NIH HHS
• U01 AA026980 NIAAA NIH HHS
• I01BX000350 VA
• R01 AA023681 NIAAA NIH HHS
• U01AA022489 NIH HHS
• I01 BX000350 BLRD VA
• T32ES011564 NIH HHS
• R01 AA024102 NIAAA NIH HHS
• P50AA024337 NIAAA NIH HHS
• L30 AA027913 NIAAA NIH HHS
• 1F32AA027950 NIAAA NIH HHS
• National Institutes of Health
• National Institute on Alcohol Abuse and Alcoholism
• U.S. Department of Veterans Affairs
• National Institute of General Medical Sciences

The increased incidence of inflammatory bowel disease (IBD) in Western and rapidly Westernizing developing countries poses a global pandemic threat. The development of affordable drugs for treating IBD worldwide is thus a priority. Genetically modified lactic acid bacteria (gmLAB) as microbial therapeutics are inexpensive protein producers suitable for use as carriers of protein to the intestinal mucosa. Here, we successfully constructed gmLAB hypersecreting interleukin 1 receptor antagonist (IL-1Ra). Oral administration of these gmLAB suppressed body weight reduction and exacerbation of the disease activity index score in mice with acute colitis and decreased the number of CD4⁺ IL-17A⁺ cells in the mesenteric lymph nodes. These data suggest that the gmLAB deliver IL-1Ra to the colon, where it inhibits IL-1 signaling. We thus developed a novel IBD therapeutic that blocks IL-1 signaling using a gmLAB protein delivery system. This system could be an inexpensive oral microbial therapeutic.

Genetically reprogrammed bacteria can facilitate the efficient delivery of a therapeutic protein for treating inflammatory bowel disease (IBD). Interleukin 1 receptor antagonist (IL-1Ra) inhibits the immune cells that attack the intestinal lining in IBD patients, but current administration strategies are associated with serious side effects. Takeshi Shimosato and colleagues at Shinshu University in Nagano, Japan, have engineered the microbe Lactococcus lactis to secrete high levels of IL-1Ra. The researchers dosed mice orally with these bacteria, which released IL-1Ra into the intestinal tissue. This treatment proved safe and effectively reduced inflammation and associated symptoms in a mouse model of ulcerative colitis. L. lactis has previously been tested as a probiotic in clinical trials, and may therefore offer an appealing alternative to subcutaneous administration of IBD drugs in human patients.

• Copper
• Hepatic dysfunction
• Inflammatory responses
• Liver
• MAPKs
• Mouse
• NF-κB

• Animals
• Copper/toxicity
• Cyclooxygenase 2/metabolism
• Female
• Interleukin-1beta/metabolism
• Interleukin-2/metabolism
• Liver/drug effects
• Liver/immunology
• Liver/metabolism
• Liver/pathology
• Liver Function Tests
• Male
• Mice
• Mice, Inbred ICR
• Mitogen-Activated Protein Kinases/metabolism
• NF-kappa B/metabolism
• Random Allocation
• Signal Transduction

Background: Psoriasis is a pathological condition characterized by immune system dysfunction and inflammation. Patients with psoriasis are more likely to develop a wide range of disorders associated with inflammation. Serum levels of various substances and their combinations have been associated with the presence of the disease (psoriasis) and have shown the potential to reflect its activity. The aim of the present study is to contribute to the elucidation of pathophysiological links between psoriasis, its pro-inflammatory comorbidity metabolic syndrome (MetS), and the expression of clusterin and elafin, which are reflected in the pathophysiological “portfolio” of both diseases. Material and methods: Clinical examinations (PASI score), ELISA (clusterin, elafin), and biochemical analyses (parameters of MetS) were performed. Results: We found that patients with psoriasis were more often afflicted by MetS, compared to the healthy controls. Clusterin and elafin levels were higher in the patients than in the controls but did not correlate to the severity of psoriasis. Conclusion: Our data suggest that patients with psoriasis are more susceptible to developing other systemic inflammatory diseases, such as MetS. The levels of clusterin and elafin, which are tightly linked to inflammation, were significantly increased in the patients, compared to the controls, but the presence of MetS in patients did not further increase these levels.

• clusterin
• elafin
• metabolic syndrome
• psoriasis

• Adult
• Body Mass Index
• Case-Control Studies
• Clusterin/genetics
• Comorbidity
• Elafin/genetics
• Female
• Gene Expression Regulation/genetics
• Humans
• Inflammation/genetics
• Inflammation/metabolism
• Inflammation/pathology
• Male
• Metabolic Syndrome/complications
• Metabolic Syndrome/genetics
• Metabolic Syndrome/metabolism
• Metabolic Syndrome/pathology
• Middle Aged
• Psoriasis/complications
• Psoriasis/genetics
• Psoriasis/metabolism
• Psoriasis/pathology
• Severity of Illness Index

Elafin is an antimicrobial and anti-inflammatory protein. We hypothesize that elafin expression correlates with diabetes. Among non-diabetic and prediabetic groups, men have significantly higher serum elafin levels than women. Men with type 2 diabetes mellitus (T2DM) have significantly lower serum elafin levels than men without T2DM. Serum elafin levels are inversely correlated with fasting blood glucose and hemoglobin A1c levels in men with T2DM, but not women with T2DM. Lentiviral elafin overexpression inhibited obesity, hyperglycemia, and liver steatosis in high-fat diet (HFD)-treated male mice. Elafin-overexpressing HFD-treated male mice had increased serum leptin levels, and serum exosomal miR181b-5p and miR219-5p expression. Transplantation of splenocytes and serum exosomes from elafin-overexpressing HFD-treated donor mice reduced food consumption and fat mass, and increased adipose tissue leptin mRNA expression in HFD-treated recipient mice. Elafin improved leptin sensitivity via reduced interferon-gamma expression and induced adipose leptin expression via increased miR181b-5p and miR219-5p expression. Subcutaneous and oral administration of modified elafin inhibited obesity, hyperglycemia, and liver steatosis in the HFD-treated mice. Circulating elafin levels are associated with hyperglycemia in men with T2DM. Elafin, via immune-derived miRNAs and cytokine, activates leptin sensitivity and expression that subsequently inhibit food consumption, obesity, hyperglycemia, and liver steatosis in HFD-treated male mice.

• Animals
• Gastrointestinal Microbiome/immunology
• Gastrointestinal Microbiome/physiology
• Homeostasis/immunology
• Host Microbial Interactions/immunology
• Humans
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/metabolism
• Inflammatory Bowel Diseases/microbiology
• Intestinal Mucosa/immunology
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/microbiology
• Intestines/immunology
• Intestines/microbiology
• Symbiosis/immunology
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/microbiology

• CIHR

• IL-22
• lactobacilus
• probiotic
• secretion
• therapeutic delivery

• P01 CA039542 NCI NIH HHS
• T32 DK007664 NIDDK NIH HHS

Proteases play an essential role in the pathophysiology of inflammatory bowel disease (IBD), contributing to the intestinal mucosal lesions through the degradation of the extracellular matrix and alteration of the barrier function. Ulcerative colitis (UC) is characterized by an extensive infiltrate of neutrophils into the mucosa and hence, increased proteolytic activity. Human neutrophil elastase (HNE) is a serine protease that has been reported to be increased in UC patients’ intestinal mucosa. Based on our previous studies, we hypothesized that HNE might induce proteolytic degradation and loss of function of therapeutic monoclonal antibodies in IBD patients.

Elastase expression and elastinolytic activity were determined in mucosal explants from ulcerative colitis patients (n=6) and cultured ex vivo in the presence or absence of recombinant elafin. Enzymatic digestions of therapeutic monoclonal antibodies were performed using recombinant HNE and elafin. The integrity of the therapeutic antibodies was evaluated by immunoblotting and protein G binding assay, whereas their TNF-neutralizing activity was assessed with a reporter cell line.

We found that HNE and its elastinolytic activity were increased in the gut mucosa of UC patients. We also demonstrated that HNE cleaved biological drugs, impairing the TNF-α neutralizing capacity of anti-TNF monoclonal antibodies. This proteolytic degradation was inhibited by the addition of the specific inhibitor, elafin.

Our results suggest that the high level of proteolytic degradation by mucosal neutrophil elastase, along with a potential imbalance with elafin, contributes to the loss of function of biologic agents, which are currently used in patients with IBD. These findings might explain the non-responsiveness of UC patients to therapeutic monoclonal antibodies and suggest the potential beneficial concomitant use of elafin in this treatment.

• anti-TNF
• biological drugs
• elafin
• elastinolytic activity
• inflammatory bowel disease