E. histolytica adaptive ability mediates nutrient extraction and survival in the fluctuating colonic environment. (a) Colonic nutrient sources include dietary polysaccharides, microbiota, and human cellular molecules including mucin. Microbial glycosidases degrade complex polysaccharides into fatty acids absorbed by intestinal epithelial cells (IECs) and sugars for their own metabolism. An intact mucous layer provides plentiful nutrients from mucin and microbiota, inducing a parasite program for colonization. (b) Upon mucus depletion, nutrient starvation induces virulence and activates the transcriptional regulator URE3-BP. Starvation responses include decreased adherence and enhanced motility and oxidative stress resistance. Upon adherence to host cells, virulence factors are induced to enable extraction of cell-associated nutrients. Abbreviations: CP, cysteine protease; CRD, carbohydrate-recognition domain; Gal, galactose; GalNAc, N-acetyl-d-galactosamine; HGL, heavy lectin subunit; IGL, intermediate lectin subunit; LGL, light lectin subunit.