Metabolic divergence in intestinal lineages. Credit: Nature (2025). DOI: 10.1038/s41586-025-09097-6

Memorial Sloan Kettering Cancer Center researchers have identified a metabolic switch that determines whether intestinal stem cells become absorptive or secretory cells. Manipulating the enzyme OGDH either fuels cell expansion or redirects fate, with potential consequences for colitis recovery and regenerative therapy.

Stem cells in the intestine maintain a delicate balance between self-renewal and differentiation, continuously replenishing the epithelial lining of the gut.

As they divide, some daughter cells become absorptive enterocytes that expand the surface for nutrient uptake, while others branch into secretory cells that manufacture mucus, antimicrobial peptides, and hormones essential for gut immunity. Injury and inflammation can tip this balance, depleting secretory lineages and disrupting tissue integrity.

Previous work has mapped this differentiation to transcription factors and signaling pathways like WNT, BMP, and Notch. How this biochemical interplay shapes regenerative responses in complex tissues has remained unresolved, particularly in the context of diseases such as Crohn's and ulcerative colitis, where regenerative imbalance is evident.

In the study, "Metabolic adaptations direct cell fate during tissue regeneration, " published in Nature, researchers engineered inducible mouse models and intestinal organoids to determine how metabolic pathways influence lineage specification in the gut epithelium.

Organoids were generated from crypts pooled from five mice per replicate, and each pool was plated and cultured in triplicate wells. Tissue sections and RNA-sequencing samples were drawn from experiments performed at Memorial Sloan Kettering Cancer Center.

Metabolomic profiling of progenitor organoids identified 299 metabolites with differential abundance. Absorptive progenitors showed elevated ATP and biosynthetic intermediates, while secretory progenitors displayed increased citrate, aconitate and α-ketoglutarate (αKG), all intermediates in the tricarboxylic acid (TCA) cycle, but diminished downstream TCA-cycle intermediates.

Suppressing OGDH in intestinal stem cells increased αKG levels and drove commitment toward the secretory lineage without causing cell death.

Supplementation with a cell-permeable αKG analog produced similar effects. Secretory progenitors accumulated αKG, exhibited reduced expression of downstream TCA-cycle enzymes, and showed elevated DNA hydroxymethylation at loci associated with secretory fate.

Depleting OGDH in absorptive progenitors impaired proliferation, triggered cell death, and depleted mitochondrial metabolites such as fumarate and malate.

In vivo, αKG supplementation and OGDH suppression both increased the number of goblet and Paneth cells and raised intestinal 5-hydroxymethylcytosine (5hmC) levels. During colitis, OGDH expression rose and αKG declined. Suppression of OGDH or α-ketoglutarate supplementation reversed these trends and improved epithelial recovery.

The findings reveal that OGDH functions as a lineage-specific metabolic switch, sustaining the metabolic needs of absorptive cells while limiting αKG accumulation in secretory progenitors.

By modulating this enzyme, they redirected intestinal stem cell fate and enhanced secretory cell output. During colitis, interventions targeting OGDH or supplementing αKG improved tissue regeneration.

The authors suggest that metabolism functions not only as a consequence of cell fate but as a driver, raising the possibility that metabolic tuning could support recovery in disorders marked by inflammation and epithelial imbalance.

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More information: Almudena Chaves-Perez et al, Metabolic adaptations direct cell fate during tissue regeneration, Nature (2025). DOI: 10.1038/s41586-025-09097-6 Ram P. Chakrabarty et al, Mitochondrial molecule has unexpected role in tissue healing, Nature (2025). DOI: 10.1038/d41586-025-01583-1  Journal information: Nature

Ram P. Chakrabarty et al, Mitochondrial molecule has unexpected role in tissue healing, Nature (2025). DOI: 10.1038/d41586-025-01583-1

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