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Macroautophagy/autophagy defects are a risk factor for inflamatory bowel disease (IBD), but the mechanism remains unclear. We previously demonstrated that conditional whole-body deletion of the essential  Atg7  (autophagy related 7) gene in adult mice ( atg7 Δ/Δ) causes specific tissue damage and shortens lifespan to three months primarily due to neurodegeneration with surprisingly no disturbing effects on the intestine. In contrast, we recently found that conditional whole-body deletion of other essential autophagy genes,  Atg5  or  Rb1cc1/Fip200  ( atg5 Δ/Δ  or rb1cc1 Δ/Δ), cause death within five days due to rapid inhibition of autophagy, elimination of intestinal stem cells, and loss of barrier function in the ileum.  atg5 Δ/Δmice lose PDGFRA/PDGFRα +  mesenchymal cells (PMCs) and WNT signaling essential for stem cell renewal. Depletion of aspartate and nucleotides in  atg5 Δ/Δileum was revealed by novel mass-spectrometry imaging (MALDI-MSI), consistent with metabolic insufficiency underlying PMCs loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss because gradual whole-body  atg5  deletion extends lifespan, phenocopying deletion of  Atg7  or  Atg12 . Therefore, we established that autophagy is required for ileum PMC metabolism, stem cell maintenance and mammalian survival. PMC loss caused by autophagy deficiency may therefore contribute to IBD.

Autophagy in PDGFRA + mesenchymal cells is required for intestinal homeostasis and mammalian survival