# Intestinal epithelial Smad7 drives purine metabolic dysregulation and ileal inflammation

## TL;DR

This study shows that overexpression of Smad7 in gut epithelial cells causes ileal inflammation and mucus depletion by disrupting purine metabolism, particularly adenosine production.

## Contribution

The study reveals a novel role for epithelial Smad7 in driving ileal inflammation through purine metabolic dysregulation.

## Key findings

- Smad7TgCre+ mice developed spontaneous terminal ileitis with mucus depletion and CD8+ T cell infiltration.
- Smad7 overexpression reduced adenosine levels, and oral adenosine reversed ileal pathology and mucus depletion.
- Elevated Smad7 in CD patients correlated with reduced CD73 expression in inflamed ileum.

## Abstract

Defects of the gut epithelial barrier and counter-regulatory mechanisms are a prerequisite for the onset of intestinal inflammation in patients with inflammatory bowel diseases (IBD). Elevated levels of Smad7, an inhibitor of TGF-β1, in both epithelial and immune cells have been associated with the pathological processes observed in IBD. We aim to determine the relevance of Smad7 expression in the epithelial compartment.

We generated mice overexpressing Smad7 in the gut epithelium (Smad7TgCre+) and monitored pathology development. Inflammatory cell infiltration was assessed using multiplex immunofluorescence and flow cytometry. To investigate the molecular mechanisms underlying ileal damage, we performed spatial transcriptomics on frozen ileal samples and metabolomics on intestinal epithelial cells (IECs) from Smad7TgCre+ and control mice. The impact of adenosine on Mucin-2 expression was evaluated through both in vitro and in vivo approaches. Finally, we evaluated the protein expression of CD73 and Smad7 in ileal tissue from Crohn’s disease (CD) patients.

Smad7TgCre+ mice developed spontaneous terminal ileitis, which was characterized by villus shortening and widening, mucus depletion, increased intestinal permeability, and infiltration of CD8 + T cells. By integrating spatial transcriptomics and metabolomics data, we demonstrated that Smad7TgCre+ mice exhibited altered expression of enzymes involved in purine metabolism, particularly CD73, the key enzyme responsible for adenosine production. Consequently, these mice produced lower levels of adenosine, and oral adenosine administration restored mucus production and alleviated the ileal pathology. Lastly, we observed that in the inflamed ileum of CD patients, elevated Smad7 levels were correlated with decreased CD73 expression.

Our data indicate that Smad7 overexpression in IECs is sufficient to promote ileal mucosal damage, which is linked to the impairment of purine metabolism.

The online version contains supplementary material available at 10.1186/s12929-026-01224-3.