1/10
We profiled the entire colon epithelium at single-cell resolution in mice.
-> The colon is highly regionalized—proximal, mid, and distal zones each have unique gene signatures.

2/10
Depleting microbes erased that pattern.
Colonocytes lost their regional gene expression, becoming uniform. Recolonization restored it.
-> The microbiome is an important part of establishing and maintaining colon regionalization.

3/ 10
Organoids from different colon regions couldn’t maintain distinct identities in culture.
So the pattern isn’t intrinsic to stem cells—it’s driven by external (microbial) cues.

4/10
We found the transcription factor PPARα as a key regulator of proximal colon identity.
Activating PPARα boosted expression of lipid metabolism genes like Hmgcs2 and Abcb1a, mirroring in vivo proximal expression.

5/10
Metabolomics pointed to a key signal: nicotinic acid (niacin).
It’s enriched in the proximal colon, lost with antibiotics, and sufficient to induce proximal genes when added to organoids.

6/10
Nicotinic acid acts partly through PPARα, but not entirely—it also triggers some genes independently.
Feeding NA to mice shifted the colon toward a proximal-like identity throughout.

7/10
That identity protects tissue.
In DSS colitis, loss of microbiome increased proximal injury.
NA treatment restored protection, even without microbes, by strengthening the epithelial barrier.

8/10
In humans, similar regionalization exists—lipid metabolism in ascending colon, mucus genes in descending.
And in Crohn’s disease, proximal identity genes like HMGCS2 are lost at inflamed sites.

9/10
In short:
🦠 The microbiome shapes regional identity in the colon.
💊 Nicotinic acid promotes a protective proximal state.
🤕 Proximal identity is lost in Crohn’s disease, suggesting potential new paths for IBD treatment.

Microbes don’t just live in the gut—they shape it.

10/10
Huge thanks to everyone who contributed to this work in the Klein Lab and to our fantastic collaborators in the Ken Lau and @hausmannannika.bsky.social Labs. Special thanks to Ophir for outstanding mentorship and for creating such a supportive and stimulating lab environment.

Microbiome-produced nicotinic acid controls colon regional identity and injury susceptibility The gut epithelium is regionally patterned to support digestive functions. In the colon, this regionalization, which is extrinsically dictated by microbiome-derived signals rather than through intrins...

Ever wondered how different regions of the gut are established? 🤔
Stem cells, right?
Turns out, not in the colon ❌.

The microbiome 🦠 — via region-specific metabolism — is an important regulator of colonocyte identity.

📄 New paper out in Cell
www.cell.com/cell/fulltex...

🧵 Thread below 👇

Microbiome-produced nicotinic acid controls colon regional identity and injury susceptibility The gut epithelium is regionally patterned to support digestive functions. In the colon, this regionalization, which is extrinsically dictated by microbiome-derived signals rather than through intrinsic stem cell programs, impacts tissue susceptibility to injury.

Now online! Microbiome-produced nicotinic acid controls colon regional identity and injury susceptibility

Join Us at the 6th In't Conference on #StemCells few registration slots still available. www.aegeanconferences.org/src/App/conf... #Crete #Greece #Heraklion Oct 1-6, 2025 Program Available Online!

Check out our latest study now on bioRxiv!
Huge thanks to our collaborators @pkeukeleire.bsky.social, Martin Kircher & all co-authors

🔬 6th International Aegean Conference on Stem Cells 📢
Join us Oct 1–6, 2025 in Crete, for talks on stem cell biology, regenerative medicine, genome editing & aging.

📅 Abstracts & Early Reg: Due June 1, 2025
🔗 Register now: www.aegeanconferences.org/src/App/conf...

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