Scientific Publications
This page provides an overview of scientific publications from the FIBROTARGET project and its partners. Additional resources, including summaries, infographics and plain-language materials, are available for selected publications.
Browse the publications below to explore the latest research from FIBROTARGET!
Jie Su, Dalia A Lartey, Gaia Zanella, Lukas J A C Hawinkels, Gianluca Matteoli, Mark Löwenberg & Marieke C Barnhoorn, Therapeutic potential of Janus kinase inhibitors for the management of fibrosis in inflammatory bowel disease, Journal of Crohn’s and Colitis, 6 June 2025, https://doi.org/10.1093/ecco-jcc/jjaf087
A new review from FIBROTARGET researchers based at KU Leuven alongside collaborator spublished in the Journal of Crohns and Colitis explores the potential of targeting the JAK-STAT signalling pathway in IBD fibrosis.
Half of people with Crohn’s disease develop intestinal fibrosis – thickening and scarring of the bowel tissue. Currently there are no treatments, with surgery the only option to remove fibrotic tissue. In some cases, repeated surgeries are required which can significantly impact individuals’ quality of life.
Moreover, the biological mechanisms which drive the development of fibrosis are not known, making design of new treatments more challenging. One of the key aims of the FIBROTARGET project is to identify new that can prevent or treat IBD fibrosis, based on biomarkers – small molecules which can be a way to identify disease.
Researchers suggest that as the JAK-STAT pathway has been shown to play a key role in various fibrotic diseases including pulmonary fibrosis, liver cirrhosis and systemic sclerosis, the same signalling pathway may also be relevant in the context of intestinal fibrosis. This means that this signalling pathway could be targeted by new drugs for intestinal fibrosis.
The review summarises important results from in vitro (experiments carried out on cells in the lab) and in vivo (experiments carried out in living beings) studies which show how the JAK-STAT pathway contributes to fibrosis.
The JAK-STAT pathway regulates the expression and production of inflammatory molecules and pro-fibrotic signals. Therefore, targeting components of this signalling cascade could help prevent the release of these mediators and the development of intestinal fibrosis.
Current therapeutics already in use for other chronic inflammatory diseases including Rheumatoid arthritis as well as ulcerative colitis and Crohn’s disease are JAK inhibitors – drugs designed to block the JAK enzymes essential for the JAK-STAT signalling pathway.
The next step is to find out if these drugs can help not just with inflammation, but also with fibrosis. If successful, this could pave the way for the first medicines that specifically target fibrosis in Crohn’s disease.
The review concludes that drugs which block the JAK-STAT pathway could offer new hope for people living with IBD fibrosis. As research moves forward, these therapies may become an important part of treating not just inflammation, but the scarring and damage that comes with fibrosis.
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The FIBROTARGET project aims to improve prevention, diagnosis and treatment of fibrosis utilising emerging technologies.
Gianluca Matteoli, DVM, PhD
Professor (Department of Chronic Diseases, Metabolism and Ageing) – Translational Research in GastroIntestinal Disorders
ON1 Herestraat 49 – box 701 3000 Leuven ; Belgium
Victoria Gudiño, Raquel Bartolomé-Casado & Azucena Salas, Single-cell omics in inflammatory bowel disease: recent insights and future clinical applications, Gut, 4 February 2025, https://doi.org/10.1136/gutjnl-2024-334165
A recent review from FIBROTARGET researchers based at Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) at Hospital Clinic Barcelona published in Gut, brings together the latest studies using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to explore inflammatory bowel disease (IBD).
Single-cell technologies, including scRNA-seq, single-cell assay fr transposase-accessible chromatin (scATAC-seq), and spatial transcriptomics, allow researchers to study cells individually in detail. Single-cell technologies are transforming our understanding of disease by revealing previously unknown diversity of cell types and interactions between them.
By applying single-cell techniques, scientists have identified over 60 different cell types or states in the intestinal mucosa, shedding light on key disease mechanisms in Crohn’s disease and ulcerative colitis. These findings could provide important information into how IBD develops and progresses, paving the way for more targeted therapies.
One of the major challenges in IBD is fibrosis, a complication for which there are no available treatments, which can lead to strictures potentially requiring surgery. By offering a detailed view of cells and their differences, single-cell technologies have helped uncover new cell types and states associated with fibrosis.
Looking ahead, researchers plan to use these technologies to map out signalling networks between cells and molecules that drive fibrosis, with the aim of identifying new therapeutic targets. This could open the door to the development of innovative anti-fibrotic treatments that address the underlying mechanisms of fibrosis in IBD, one of the key goals of the FIBROTARGET project.
More generally, by providing a detailed picture of how cellular composition changes across disease states, single cell technologies can help identify biomarkers (cells or molecules associated with disease) for early diagnosis, predict treatment responses, and support the development of personalised therapies tailored to individual patients.
"We are uncovering the cellular heterogeneity of the intestinal mucosa at an unprecedent resolution, and we now need to functionally understand the role of these pathogenic cell types/states during complicated IBD phenotypes like fibrosis" – Victoria Gudiño, First Author & Postdoctoral Researcher at IDIBAPS
As research in this field continues to advance, single-cell and spatial transcriptomics could play an important role in improving our understanding of IBD and fibrosis.
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The FIBROTARGET project aims to improve prevention, diagnosis and treatment of fibrosis utilising emerging technologies.
Michael Beck, Torsten Kuwert, Armin Atzinger, Maximilian Gerner, Arndt Hartmann, Marc Saake, Michael Uder, Markus Friedrich Neurath & Raja Atreya, Discrimination between Inflammatory and Fibrotic Activity in Crohn’s Disease-Associated Ileal-Colonic Anastomotic Strictures by Combined Ga-68-FAPI-46 and F-18-FDG-PET/CT Imaging, Visceral Medicine., 20 December 2024, https://doi.org/10.1172/JCI173835
A new paper published by the team at FIBROTARGET partner institution Erlangen University Hospital has developed a new imaging method to identify fibrotic-specific cells in the intestines of individuals with Crohn’s Disease.
Fibrosis, formation of hard tissue and scarring in the bowel, is common in individuals with Crohn’s Disease. Fibrosis can worsen over time, leading to the development of strictures (narrowing of the bowel). Strictures can even lead to full obstruction in the bowel if left untreated. This complication associated with the disease can result in dramatic effects on individuals’ quality of life and general health.
Currently, there are no approved treatments for fibrosis presenting a serious unmet clinical need. If we can design diagnostic tools which can assess the level of inflammation and fibrosis in the intestines of Crohn’s Disease patients, then we could more effectively monitor and manage disease.
Michael Beck, Raja Atreya and the team at Erlangen University Hospital aimed to distinguish cells associated with inflammation and cells associated with fibrosis making use of a common diagnostic imaging technique, a type of PET scan.
The team used two different fluorescent labels which would attach to 1. Inflammatory areas (to identify cells associated with inflammation) and 2. Fibrotic areas (to identify fibrotic fibroblast cells). These labels have been created based on known biomarkers (proteins on the surface of cells) of inflammation and fibrosis: FAP (prolyl endopeptidase fibroblast activating protein).
Researchers found that different levels of these fluorescent labels were seen within strictures of a small number of Crohn’s disease patients. Further analysis revealed that there was a link between the amount of fluorescence seen and the severity of either fibrosis or inflammation in the intestines of these patients.
These results suggest that we can use imaging techniques that already exist in the clinic and combine these with fluorescent labelling techniques to 1. Identify specific areas of inflammation and fibrosis separately in Crohn’s disease patients and 2. Use this information to guide treatment and disease management.
“The combination with F-18-FDG PET/CT represents a promising imaging modality to distinguish intestinal inflammation from fibrosis, warranting further studies.” – Prof. Raja Atreya
Researchers plan to investigate this new imaging technique further with more patients to see if these results can be repeated with different types of IBD-related inflammation.
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From advancing scientific knowledge to possibly improving patient care and driving economic and societal benefits, FIBROTARGET is helping to change the status quo in inflammatory bowel disease care once again.
Raja Atreya – Professor of Translational Immunology in IBD
University Hospital Erlangen
Email: raja.atreya@uk-erlangen.de
Bo-Jun Ke, Gabriele Dragoni & Gianluca Matteoli, Fibroblast Heterogeneity in Inflammatory Bowel Disease, International Journal of Molecular Sciences., 3 December 2024, https://doi.org/10.3390/ijms252313008
Sara Deleu, Inge Jacobs, Jorge F. Vazquez Castellanos, Sare Verstockt, Bruna Trindade de Carvalho, Ana Suboti, Bram Verstockt, Kaline Arnauts, Lowie Deprez, Eva Vissers, Matthias Lenfant, Greet Vandermeulen, Gert De Hertogh, Kristin Verbeke, Gianluca Matteoli, Geert R. B. Huys, Johan M. Thevelein, Jeroen Raes & Séverine Vermeire, Effect of Mutant and Engineered High-Acetate-Producing Saccharomyces cerevisiae var. boulardii Strains in Dextran Sodium Sulphate-Induced Colitis, Nutrients., 13 August 2024, https://doi.org/10.3390/nu16162668
Gabriele Dragoni, Bo-Jun Ke, Lucia Picariello, Saeed Abdurahiman, Elisabetta Ceni, Francesca Biscu, Tommaso Mello, Simone Polvani, Tommaso Innocenti, Valérie Spalart, Stefano Milani, André D’Hoore, Gabriele Bislenghi, Stefano Scaringi, Bram Verstockt, Gert De Hertogh, Kimberly Martinod, Andrea Galli, Gianluca Matteoli & Séverine Vermeire, The Impact of Peptidyl Arginine Deiminase 4-Dependent Neutrophil Extracellular Trap Formation on the Early Development of Intestinal Fibrosis in Crohn’s Disease Journal of Crohn’s and Colitis., 10 August 2024, https://doi.org/10.1093/ecco-jcc/jjae121
This study explored how neutrophil extracellular traps, known as NETs, may contribute to the early development of intestinal fibrosis in Crohn’s disease. NETs are web-like structures released by activated neutrophils, a type of immune cell involved in inflammation.
The publication focused on PAD4-dependent NET formation and how these structures may activate intestinal fibroblasts, encouraging collagen production and fibrotic tissue remodelling.
The researchers combined analysis of human Crohn’s disease tissue with experimental models. NETs and activated fibroblasts were labelled in resected ileal tissue using multiplex immunofluorescence. Human primary intestinal fibroblasts were then treated with NETs and analysed using bulk RNA sequencing and high-throughput imaging to assess signalling pathways, collagen production and cell behaviour.
The study also investigated the TLR2/NF-κB signalling pathway and used a chronic DSS mouse model with neutrophil-specific Pad4 deletion to examine the role of PAD4-dependent NET formation in intestinal fibrosis.
NETs were found in close proximity to activated fibroblasts in ileal ulcerations from Crohn’s disease patients. When fibroblasts were exposed to NETs, they showed increased pro-fibrotic gene expression, greater collagen release, increased proliferation and reduced migratory capacity.
The findings suggest that NETs can activate fibroblasts through the TLR2/NF-κB pathway. In the mouse model, neutrophil-specific Pad4 deletion was associated with reduced collagen content in the colon during chronic DSS colitis.
This study points to NET formation as a potential early trigger of intestinal fibrosis in Crohn’s disease. By identifying PAD4-dependent NET formation and TLR2/NF-κB signalling as part of this process, the research highlights pathways that could be further explored for future anti-fibrotic treatment strategies.
Gianluca Matteoli, DVM, PhD
Professor (Department of Chronic Diseases, Metabolism and Ageing) – Translational Research in GastroIntestinal Disorders
ON1 Herestraat 49 – box 701 3000 Leuven ; Belgium
Email: gianluca.matteoli@kuleuven.be
Bo-Jun Ke, Saeed Abdurahiman, Francesca Biscu, Gaia Zanella, Gabriele Dragoni, Sneha Santhosh, Veronica De Simone, Anissa Zouzaf, Lies van Baarle, Michelle Stakenborg, Veronika Bosáková, Yentl Van Rymenant, Emile Verhulst, Sare Verstockt,1 Elliott Klein, Gabriele Bislenghi, Albert M. Wolthuis, Jan Frič, Christine Breynaert, Andre D’Hoore, Pieter Van der Veken, Ingrid De Meester, Sara Lovisa, Lukas J.A.C. Hawinkels, Bram Verstockt, Gert De Hertogh, Séverine Vermeire, and Gianluca Matteoli, Intercellular interaction between FAP+ fibroblasts and CD150+ inflammatory monocytes mediates fibro-stenosis in Crohn’s disease, J Clin Invest., 23 July 2024, https://doi.org/10.1172/JCI173835
Simone Weber, Selina Sitte, Anna-Lena Voegele, Ludmilla Sologub, Angelika Wilfer, Timo Rath, Andreas Nägel, Sebastian Zundler, Luigi Franchi, Anthony W Opipari, Sophia Sonnewald, Stephen Reid, Arndt Hartmann, Philip Eichhorn, Claudia Handtrack, Klaus Weber, Robert Grützmann, Clemens Neufert, Vera S Schellerer, Elisabeth Naschberger, Arif B Ekici, Christian Büttner, Markus F Neurath, Raja Atreya, NLRP3 Inhibition Leads to Impaired Mucosal Fibroblast Function in Patients with Inflammatory Bowel Diseases, Journal of Crohn’s and Colitis, Volume 18, Issue 3, March 2024, Pages 446–461, https://doi.org/10.1093/ecco-jcc/jjad164
Led by the First Department of Medicine and Deutsches Zentrum Immuntherapie at Friedrich-Alexander-Universität Erlangen-Nürnberg, this article delves into the role of NLRP3 inhibition in individuals living with inflammatory bowel disease (IBD). A multiprotein complex, NLRP3 influences how the body regulates the innate immune system and inflammatory signalling.
In cases of IBD, individuals with the disease can experience mucosal inflammation and fibrosis formation. Whilst NLRP3 could contribute to these processes, investigators remain unsure of its exact expression and function within this context.
“Currently, there is no anti-fibrotic drug that can address the issue of fibrosis in inflammatory bowel disease.”
Investigators examined intestinal NLRP3 expression in mucosal immune cells and fibroblasts from individuals living with IBD. Using single-cell RNA sequencing and microarray analyses, they also looked at NLRP3-associated gene expression.
The study further explored the role of two other physiologic processes:
- Cytokine secretion—a type of protein that helps control inflammation—of NLRP3 inhibitor in treating blood and mucosal cells
- Proliferation, collagen production and cell death of NLRP3 inhibitor in treating intestinal fibroblast samples
- An identified set of monocytes and macrophages as the main cell type involved in the NLRP3 signalling pathway
- Expression of the NLRP3 inflammasome was observed in the intestinal fibroblasts
- A significant reduction in proliferation of intestinal fibroblasts after NLRP3 was inhibited
- This was associated with a marked decrease in collage type I and type VI production
- NLRP3 inhibition in intestinal fibroblasts also induced autophagy, a cellular process involved in collagen degradation
NLRP3 activation has been well established as being crucial in regulating innate immune system processes. There are studies that suggest that overactivation of NLRP3 forms part of the immunopathogenesis of many immune-related diseases, like IBD. Yet, because investigators have not completely understood the exact role of NLRP3 in IBD, this current study adds much needed value to the field!
In fact, the findings imply that NLRP3 inhibition could serve as a pharmacologic target for IBD treatment. This could be exciting news for those living with the disease, given that no anti-fibrotic exists on the market. It could also pique the interests of industry and academia due to the still-to-be explored anti-inflammatory and anti-fibrotic properties of NLRP3 inhibition.
Indeed, NLRP3 inhibition as an eventual targeted treatment could translate into the possible prevention of fibrosis, intestinal structure remodelling, and intestinal stenosis formation—all health conditions that continue to arise during IBD.
Raja Atreya – Professor of Translational Immunology in IBD
University Hospital Erlangen
Email: raja.atreya@uk-erlangen.de
Raja Atreya & Markus F. Neurath, Biomarkers for Personalizing IBD Therapy: The Quest Continues, Clinical Gastroenterology and Hepatology., 3 February 2024, https://doi.org/10.1016/j.cgh.2024.01.026.
