The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer Model

Spaendonk, Hanne Van; Ceuleers, Hannah; Smet, Annemieke; Berg, Maya; Joossens, Jurgen; Veken, Pieter Van der; Francque, Sven; Lambeir, Anne‐Marie; Man, Joris G. De; Meester, Ingrid De; Augustyns, Koen; Winter, Benedicte Y. De

doi:10.3389/fphar.2021.682065

Cited by 6 publications

(4 citation statements)

References 53 publications

(88 reference statements)

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“…The explanation for this increase is not entirely clear but might be explained by 1) the disturbance of the protease–anti-protease balance interfering with inflammatory or anti-inflammatory mediators, 2) an interaction with other luminal components (e.g., the microbiome or its metabolites), or 3) the presence of neutrophil extracellular traps, which could release proteins such as MPO but also neutrophil elastase or cathepsin G ( Drury et al, 2021 ; Hanning et al, 2021 ). Interestingly, we recently demonstrated an amelioration of the inflammatory parameters after a 2-week i. p. treatment with UAMC-00050 in a chronic colitis T cell transfer mouse model ( Van Spaendonk et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Serine Protease Inhibitors on Visceral Pain in Different Rodent Models With an Intestinal Insult

Ceuleers

Hanning²,

bruyn³

et al. 2022

Front. Pharmacol.

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Background: Serine proteases are believed to play a key role in the origin of abdominal pain in IBD and IBS. We previously demonstrated a reduction of visceral pain in a post-inflammatory IBS rat model after a single intraperitoneal or intracolonic administration of a serine protease inhibitor. The aim of this study was to investigate the efficacy of serine protease inhibition on visceral pain in two different animal models involving a colonic insult based either on acute inflammation or on neonatal irritation. Moreover, protease profiling was explored in the acute colitis model.Methods: An acute 2,4,6-trinitrobenzenesulphonic acid (TNBS) colitis rat model and a chronic neonatal acetic acid mouse model were used in this study. Visceral sensitivity was quantified by visceromotor responses (VMRs) to colorectal distension, 30 min after intraperitoneal administration of the serine protease inhibitors nafamostat, UAMC-00050 or their vehicles. Colonic samples from acute colitis rats were used to quantify the mRNA expression of a panel of serine proteases and mast cell tryptase by immunohistochemistry. Finally, proteolytic activities in colonic and fecal samples were characterized using fluorogenic substrates.Key Results: We showed a significant and pressure-dependent increase in visceral hypersensitivity in acute colitis and neonatal acetic acid models. UAMC-00050 and nafamostat significantly reduced VMRs in both animal models. In acute colitis rats, the administration of a serine protease inhibitor did not affect the inflammatory parameters. Protease profiling of these acute colitis animals revealed an increased tryptase immunoreactivity and a downregulation of matriptase at the mRNA level after inflammation. The administration of UAMC-00050 resulted in a decreased elastase-like activity in the colon associated with a significantly increased elastase-like activity in fecal samples of acute colitis animals.Conclusion: In conclusion, our results suggest that serine proteases play an important role in visceral hypersensitivity in an acute TNBS colitis model in rats and a neonatal acetic acid model in mice. Moreover, we hypothesize a potential mechanism of action of UAMC-00050 via the alteration of elastase-like proteolytic activity in acute inflammation. Taken together, we provided fundamental evidence for serine protease inhibitors as a promising new therapeutic strategy for abdominal pain in gastrointestinal diseases.

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Section: Discussionmentioning

confidence: 99%

The Effect of Serine Protease Inhibitors on Visceral Pain in Different Rodent Models With an Intestinal Insult

Ceuleers

Hanning²,

bruyn³

et al. 2022

Front. Pharmacol.

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“…For instance, Van Spaendonk et al. (2021) induced chronic colitis by injecting 100 μL of 1 × 10 6 CD4 + CD25 − CD62L + T cells intraperitoneally into severe combined immunodeficient mice. The symptoms observed included weight loss and an elevated level of pro‐inflammatory cytokines.…”

Section: Adoptive Transfer Model Of Ibdmentioning

confidence: 99%

An evaluation of animal models for using bioactive compounds in the treatment of inflammatory bowel disease

Tie,

Chen,

Tan

2024

Food Frontiers

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Inflammatory bowel disease (IBD) is a prevalent chronic relapsing‐remitting disease that affects the digestive tract and reduces patients’ quality of life. Food bioactive compounds are a promising approach for nutritional intervention of IBD with minimal side effects. To evaluate their potential, researchers have developed various animal models that simulate human IBD, including chemically induced, spontaneous, genetically engineered, and adoptive transfer models. In this work, the main animal models, pathogenesis, symptoms, strengths, and limitations of IBD were discussed. Although these models could not perfectly replicate human IBD, they provided useful tools to study the disease's progression and therapeutic processes. In addition, taking these IBD animals as models, the specific experimental methods, intervention results, and mechanisms of food bioactive compounds to prevent or treat IBD were described in detail. The continuous improvement of animal models is crucial to gain a better understanding of IBD's etiology and pathogenesis and to evaluate the efficacy of food bioactive compounds for the effective control of IBD.

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“…This is because of the high proteolytic activity observed in IBS patients [ 71 ]—the use of anti-proteases to counteract this activity takes relevance. Anti-protease of chemical origin [ 72 ] can be used, as well as bacteria that naturally expresses them. Motta et al [ 73 ] demonstrated the efficacy of a recombinant L. lactis strain expressing human elafin anti-protease activity against inflammation in a mouse model of IBD, with similar protection properties to those of IL-10, also delivered by a recombinant L. lactis strain.…”

Section: Target Screening To Select Bacterial Strains With Probiotic ...mentioning

confidence: 99%

Strategies for the Identification and Assessment of Bacterial Strains with Specific Probiotic Traits

et al. 2022

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Early in the 1900s, it was proposed that health could be improved and senility delayed by manipulating gut microbiota with the host-friendly bacteria found in yogurt. Later, in 1990, the medical community reconsidered this idea and today probiotics represent a developed area of research with a billion-dollar global industry. As a result, in recent decades, increased attention has been paid to the isolation and characterization of novel probiotic bacteria from fermented foods and dairy products. Most of the identified probiotic strains belong to the lactic acid bacteria group and the genus Bifidobacterium. However, current molecular-based knowledge has allowed the identification and culture of obligatory anaerobic commensal bacteria from the human gut, such as Akkermansia spp. and Faecalibacterium spp., among other human symbionts. We are aware that the identification of new strains of these species does not guarantee their probiotic effects and that each effect must be proved through in vitro and in vivo preclinical studies before clinical trials (before even considering it as a probiotic strain). In most cases, the identification and characterization of new probiotic strain candidates may lack the appropriate set of in vitro experiments allowing the next assessment steps. Here, we address some innovative strategies reported in the literature as alternatives to classical characterization: (i) identification of alternatives using whole-metagenome shotgun sequencing, metabolomics, and multi-omics analysis; and (ii) probiotic characterization based on molecular effectors and/or traits to target specific diseases (i.e., inflammatory bowel diseases, colorectal cancer, allergies, among others).

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The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer Model

Cited by 6 publications

References 53 publications

The Effect of Serine Protease Inhibitors on Visceral Pain in Different Rodent Models With an Intestinal Insult

The Effect of Serine Protease Inhibitors on Visceral Pain in Different Rodent Models With an Intestinal Insult

An evaluation of animal models for using bioactive compounds in the treatment of inflammatory bowel disease

Strategies for the Identification and Assessment of Bacterial Strains with Specific Probiotic Traits

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