Microbes and diet reshape the Drosophila intestine via distinct cellular dynamics

The intestine adapts to environmental challenges by changing size, but whether such remodeling reflects fixed homeostatic restoration or context-dependent adaptation remains unclear. Here, using Drosophila melanogaster, we combine defined diets with oral bacterial infection to quantify midgut size, cell number, cell size, and epithelial turnover. We show that diet and infection reshape the midgut through distinct cellular programs. Infection causes rapid shrinkage only when the organ was initially large, whereas post-infection regrowth requires dietary nutrients and converges toward a diet-defined state rather than a fixed pre-injury size. Diet-driven expansion occurs primarily through enterocyte hypertrophy and persists after stem cell ablation, whereas infection-induced recovery requires intestinal stem cell/progenitor activity. Microbes also have context-dependent effects, acting as damaging stressors in nutrient-rich conditions but promoting growth and survival under nutrient-poor conditions. These findings reveal modular cellular strategies through which diet and microbes jointly shape epithelial plasticity. Quantifying how diet and infection reshape the Drosophila midgut reveals distinct cellular strategies underlying epithelial remodeling and organ size control.