The shutdown of food digestion due to endoplasmic reticulum homeostasis disruption acts as a protective mechanism in C. elegans

Food digestion is essential for nutrient absorption, supporting protein synthesis and maintaining endoplasmic reticulum (ER) homeostasis. However, whether animals can sense ER stress and suppress digestion to reduce ER overload remains unclear. Here, we show that Caenorhabditis elegans can sense ER stress and shut down digestion as a protective response. Food intake activates the unfolded protein response in the ER, and loss of its central regulator, XBP-1, impairs digestion, highlighting the importance of ER homeostasis in food digestion. We identify FDR-1, a food-induced protein, as a key factor that promotes digestion by preserving ER balance through its interaction with DPY-11. Disruption of FDR-1 triggers the innate immune p38/PMK-1 pathway, leading to a protective shutdown of digestion to mitigate ER stress. These findings reveal an adaptive mechanism by which animals limit digestion under ER stress and suggest that modulating nutrient intake may offer therapeutic strategies for diseases related to ER dysfunction.