Metabolic insights into fibrosis mechanisms in Crohn’s disease
Fibrosis complicates Crohn’s disease and often leads to surgery. Anti fibrotic medical therapies do not exist. One of the reasons is the lack of understanding of fibrosis development in Crohn’s disease. Through multi-omics analyses, we uncovered how fibroblasts and their metabolism contribute to tissue scarring, identifying key pathways that may guide future antifibrotic therapies.
Focus Group: Intestinal Inflammation, Anastomic Healing, and Fibrosis
PD Dr. Philipp-Alexander Neumann (TUM University Hospital Rechts der Isar),
Alumnus Albrecht Struppler Clinician Scientist Fellow (funded as part of the Excellence Strategy of the federal and state governments)
Annalisa Buck (TUM University Hospital Rechts der Isar), Doctoral Candidate
Collaboration Partner: Prof. Dirk Haller (TUM)
Intestinal fibrosis represents one of the most debilitating long-term complications of Crohn’s disease, often leading to intestinal strictures and the need for repeated surgical interventions. Despite major advances in anti-inflammatory therapies, no effective medical treatment is currently available to prevent or reverse intestinal fibrosis. Our TUM-IAS Focus Group addressed this challenge by investigating the molecular mechanisms that drive fibroblast activation and extracellular matrix (ECM) remodeling in fibrotic intestinal tissue. The second goal was to investigate the microbiome as a potential contributor to intestinal fibrosis.
To achieve these goals, we analyzed a dedicated cohort of Crohn’s disease patients (Fig. 1) and, in parallel, developed mouse models of chronic intestinal inflammation and postsurgical fibrosis. This dual approach of truly translational research enabled direct investigation of patient tissue while testing therapeutic interventions in vivo. Comprehensive “omics” analyses of patient samples revealed two key findings: The WNT signaling pathway was strongly upregulated in fibrotic Crohn’s disease tissue, whereas metabolic processes, particularly fatty acid oxidation, were markedly downregulated. These observations led us to hypothesize that metabolic pathways may play a direct role in the development of intestinal fibrosis.
To spatially resolve the heterogeneous fibroblast populations within the fibrotic niche and to characterize their metabolic functions, we applied spatial transcriptomic analyses of human samples (Fig. 2). This analysis revealed highly specific fibroblast subtypes, some predominantly present in fibrotic tissue, others restricted to non-fibrotic regions. These findings led us to identify a key target molecule for further analysis: WISP1, a WNT pathway effector (Fig. 3). We demonstrated that WISP1 not only activates fibroblasts by promoting cytoskeletal remodeling and extracellular matrix (ECM) production but also acts as an adipokine, profoundly altering fibroblast metabolism.
For the first time in Crohn’s disease-associated fibrosis, we were able to establish a direct link between defective fibroblast metabolism and excessive ECM deposition. Restoration of metabolic processes not only could lead to less ECM deposition but also could reverse fibrotic ECM accumulation by inducing ECM degradation. This represents an important step toward the development or repurposing of therapeutic strategies to prevent or reverse intestinal fibrosis in Crohn’s disease.
Figure 1
disease tissue.
Our findings were further validated in translational in vivo models, where therapeutic administration of a neutralizing anti-WISP1 antibody markedly reduced fibrosis following chronic inflammation. These results pave the way for novel antifibrotic therapies targeting WISP1 signaling. The work has been submitted for publication and is currently in revision.
In the future, already approved metabolic drugs should be tested in Crohn’s disease-associated fibrosis. This approach could accelerate clinical approval and make effective therapies available to patients more quickly. Our in vivo models provide an ideal platform for such preclinical evaluation.
Regarding the role of the microbiome in fibrosis, our mouse models further revealed that animals with chronic inflammation and fibrosis exhibited a distinct microbial composition. Fibrosis promoted the expansion of pathogenic taxa while protective species were reduced. These observations suggest that future studies should further explore the interplay between the microbiome and WNT/WISP1 signaling to better understand and prevent postoperative fibrotic recurrence in Crohn’s disease. The Fellowship not only initiated collaborative research at TUM but also led to a prolonged stay of Dr. Neumann at the University of Chicago, USA, to further understand the implications of the microbiome on wound healing following surgery. This exchange is expected to intensify further exchange between TUM and the University of Chicago with initiation of combined projects and grant applications
Selected publications
- S. K. Hyoju, K. Cira, I. McKinley, R. Faazal, D. Mailhiot, A. Ostdiek, P. A. Neumann, J. C. Alverdy, “Feasibility and preliminary results of modeling a clinically meaningful anastomotic leak in pigs.”
Int J Surg. Feb 18, 2026 Feb, doi: 10.1097/JS9.0000000000004959.
- A. Buck, K. Widemann, M. C. Weber., P. A. Neumann, “WISP1 Drives Intestinal Fibrosis in Crohn’s Disease via Metabolic and Rho/ROCK/MRTF-mediated cytoskeletal Remodeling”, in revision for Gastroentrology
- M. C. Weber, Z. Clees, A. Buck, P. A. Neumann, “Role of the serosa in intestinal anastomotic healing: insights from in-depth histological analysis of human and murine anastomoses,” (in eng), BJS Open, vol. 8, no. 5, Sep 3 2024, doi: 10.1093/bjsopen/zrae108.
- M. C. Weber, K. Schmidt, A. Buck, P. A. Neumann, “Fractal analysis of extracellular matrix for observer-independent quantification of intestinal fibrosis in Crohn’s disease,” Sci Rep, vol. 14, no. 1, p. 3988, 2024/02/17 2024, doi: 10.1038/s41598-024-54545-4.