# Endoscopic healing in pediatric IBD perpetuates a persistent signature defined by Th17 cells with molecular and microbial drivers of disease

## TL;DR

This study finds that even when the gut looks healed in children with IBD, harmful immune and microbial changes still persist, suggesting deeper treatment is needed.

## Contribution

The study identifies a persistent IBD signature involving Th17 cells and microbial changes that remain despite endoscopic healing.

## Key findings

- A residual IBD signature is defined by Th17 cells and inflammation-related markers like DUOX2, SAA2, and NOS2.
- Microbial diversity remains low in IBD patients, regardless of disease location or activity.
- Persistent mucosal alterations suggest that endoscopic healing does not equate to full disease resolution.

## Abstract

Endoscopic healing (EH) is the major long-term treatment target for inflammatory bowel diseases (IBDs), mainly achieved by immune-suppressive therapies. However, the chronic and relapsing nature of the disease indicates a lifelong persistence of unknown tissue-associated IBD residues. Based on longitudinally collected gastrointestinal biopsies (n = 217) from pediatric patients with IBD (N = 32) and pediatric non-IBD controls (N = 5), we describe cellular, molecular, and microbial drivers of IBD that persist under EH in the terminal ileum and sigmoid colon. Whole biopsy transcriptomics in combination with single T cell analysis (72,026 cells) characterizes an inflammatory bowel residual disease (IBrD) signature, connecting stress- and inflammation-related tissue markers (e.g., DUOX2, SAA2, and NOS2) with pathogenic interleukin-17 (IL-17)-producing T helper cells. 16S rRNA gene sequencing reveals individual microbial composition with persistently low diversity, irrespective of disease location and activity. Overall, our study identifies a persisting IBD signature that reflects ongoing mucosal alterations despite EH. These markers may provide targets for future or sequential therapies.

•Multiple features with the potential to drive IBD persist despite endoscopic healing•These changes vary among patients with IBD but are absent in non-IBD controls•Residual IBD signature reflects persistently disturbed microbiome-host interaction•Individual mucosal microbiota and TCRs can generate universal IBD mucosal response

Multiple features with the potential to drive IBD persist despite endoscopic healing

These changes vary among patients with IBD but are absent in non-IBD controls

Residual IBD signature reflects persistently disturbed microbiome-host interaction

Individual mucosal microbiota and TCRs can generate universal IBD mucosal response

Persistent inflammation compromises long-lasting remission in patients with inflammatory bowel disease (IBD). Siebert et al. identify a transcriptomic signature of residual disease in intestinal biopsies from pediatric patients, even when endoscopic examinations suggest mucosal healing. These findings emphasize the need for more comprehensive healing beyond endoscopic appearance.