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Intestinal epithelial expression of human TNF is sufficient to induce small bowel inflammation and sacroiliitis, mimicking human spondyloarthritis

Karlijn Debusschere (UGent) , Donald Souza, Gerald H. Nabozny, Emilie Dumas (UGent) , Eveline Verheugen (UGent) , Julie Coudenys (UGent) , Teddy Manuello (UGent) , Flore Stappers (UGent) , Tine Decruy (UGent) , Margaux Maelegheer (UGent) , et al.
(2025) RHEUMATOLOGY. 64(5). p.3116-3124
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Abstract
Objectives: Gut and joint disease commonly co-occur in SpA. Up to 50% of patients with SpA show signs of subclinical gut inflammation, of which 10% develops IBD. However, the mechanisms underlying this gut-joint axis are still unclear. Here we investigated the hypothesis that restricted expression of a pro-inflammatory cytokine in the intestine may trigger the onset of combined gut and joint inflammation. Methods: Intestinal expression of human TNF (hTNF) was achieved by driving hTNF gene expression using the rat FAPB2 promoter, creating a new animal model, TNFgut mice, that expresses hTNF in the proximal intestinal tract. Intestinal-specific TNFgut mice were examined for pathological changes in the intestine and extra-intestinal tissues by means of histology, reverse transcription PCR (RT-PCR) and flow cytometry, along with 16S sequencing on stools. Results: Local expression of hTNF in the epithelium of the small intestine induces a pro-inflammatory state of the proximal intestinal tract, with epithelial alterations and induction of members of the S100 family, as well as local upregulation of Th17 and Treg, but no obvious signs of dysbiosis. Curiously, TNFgut mice develop sacroiliitis (P <0.05) in addition to small bowel inflammation (P <0.05). However, no signs of peripheral arthritis or enthesitis could be documented. Conclusion: Intestinal expression of hTNF is sufficient to initiate a pro-inflammatory cascade culminating in small bowel inflammation and sacroiliitis. Thus, gut-derived cytokines are sufficient to induce SpA.
Keywords
spondyloarthritis, IBD, TNF, TUMOR-NECROSIS-FACTOR, CROHNS-DISEASE, RHEUMATOID-ARTHRITIS, FACTOR RECEPTORS, TRANSGENIC MICE, FACTOR-ALPHA, GUT, TRAFFICKING, PREVALENCE, CLONING

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MLA
Debusschere, Karlijn, et al. “Intestinal Epithelial Expression of Human TNF Is Sufficient to Induce Small Bowel Inflammation and Sacroiliitis, Mimicking Human Spondyloarthritis.” RHEUMATOLOGY, vol. 64, no. 5, 2025, pp. 3116–24, doi:10.1093/rheumatology/keae507.
APA
Debusschere, K., Souza, D., Nabozny, G. H., Dumas, E., Verheugen, E., Coudenys, J., … Elewaut, D. (2025). Intestinal epithelial expression of human TNF is sufficient to induce small bowel inflammation and sacroiliitis, mimicking human spondyloarthritis. RHEUMATOLOGY, 64(5), 3116–3124. https://doi.org/10.1093/rheumatology/keae507
Chicago author-date
Debusschere, Karlijn, Donald Souza, Gerald H. Nabozny, Emilie Dumas, Eveline Verheugen, Julie Coudenys, Teddy Manuello, et al. 2025. “Intestinal Epithelial Expression of Human TNF Is Sufficient to Induce Small Bowel Inflammation and Sacroiliitis, Mimicking Human Spondyloarthritis.” RHEUMATOLOGY 64 (5): 3116–24. https://doi.org/10.1093/rheumatology/keae507.
Chicago author-date (all authors)
Debusschere, Karlijn, Donald Souza, Gerald H. Nabozny, Emilie Dumas, Eveline Verheugen, Julie Coudenys, Teddy Manuello, Flore Stappers, Tine Decruy, Margaux Maelegheer, Nadia Schryvers, Elisabeth Gilis, and Dirk Elewaut. 2025. “Intestinal Epithelial Expression of Human TNF Is Sufficient to Induce Small Bowel Inflammation and Sacroiliitis, Mimicking Human Spondyloarthritis.” RHEUMATOLOGY 64 (5): 3116–3124. doi:10.1093/rheumatology/keae507.
Vancouver
1.
Debusschere K, Souza D, Nabozny GH, Dumas E, Verheugen E, Coudenys J, et al. Intestinal epithelial expression of human TNF is sufficient to induce small bowel inflammation and sacroiliitis, mimicking human spondyloarthritis. RHEUMATOLOGY. 2025;64(5):3116–24.
IEEE
[1]
K. Debusschere et al., “Intestinal epithelial expression of human TNF is sufficient to induce small bowel inflammation and sacroiliitis, mimicking human spondyloarthritis,” RHEUMATOLOGY, vol. 64, no. 5, pp. 3116–3124, 2025.
@article{01JRWWQW9NFKHEQAPYRHKXQK7X,
  abstract     = {{Objectives: Gut and joint disease commonly co-occur in SpA. Up to 50% of patients with SpA show signs of subclinical gut inflammation, of which 10% develops IBD. However, the mechanisms underlying this gut-joint axis are still unclear. Here we investigated the hypothesis that restricted expression of a pro-inflammatory cytokine in the intestine may trigger the onset of combined gut and joint inflammation. Methods: Intestinal expression of human TNF (hTNF) was achieved by driving hTNF gene expression using the rat FAPB2 promoter, creating a new animal model, TNFgut mice, that expresses hTNF in the proximal intestinal tract. Intestinal-specific TNFgut mice were examined for pathological changes in the intestine and extra-intestinal tissues by means of histology, reverse transcription PCR (RT-PCR) and flow cytometry, along with 16S sequencing on stools. Results: Local expression of hTNF in the epithelium of the small intestine induces a pro-inflammatory state of the proximal intestinal tract, with epithelial alterations and induction of members of the S100 family, as well as local upregulation of Th17 and Treg, but no obvious signs of dysbiosis. Curiously, TNFgut mice develop sacroiliitis (P <0.05) in addition to small bowel inflammation (P <0.05). However, no signs of peripheral arthritis or enthesitis could be documented. Conclusion: Intestinal expression of hTNF is sufficient to initiate a pro-inflammatory cascade culminating in small bowel inflammation and sacroiliitis. Thus, gut-derived cytokines are sufficient to induce SpA.}},
  author       = {{Debusschere, Karlijn and Souza, Donald and Nabozny, Gerald H. and Dumas, Emilie and Verheugen, Eveline and Coudenys, Julie and Manuello, Teddy and Stappers, Flore and Decruy, Tine and Maelegheer, Margaux and Schryvers, Nadia and Gilis, Elisabeth and Elewaut, Dirk}},
  issn         = {{1462-0324}},
  journal      = {{RHEUMATOLOGY}},
  keywords     = {{spondyloarthritis,IBD,TNF,TUMOR-NECROSIS-FACTOR,CROHNS-DISEASE,RHEUMATOID-ARTHRITIS,FACTOR RECEPTORS,TRANSGENIC MICE,FACTOR-ALPHA,GUT,TRAFFICKING,PREVALENCE,CLONING}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{3116--3124}},
  title        = {{Intestinal epithelial expression of human TNF is sufficient to induce small bowel inflammation and sacroiliitis, mimicking human spondyloarthritis}},
  url          = {{http://doi.org/10.1093/rheumatology/keae507}},
  volume       = {{64}},
  year         = {{2025}},
}
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