Box 1 Model for survival/adaptation against diarrhea/malnutrition endowed by the apoE-cholesterol phenotype
Subject	Hypotheses
Intestinal maturation	(a) APOE4 by increasing cholesterol absorption may improve intestinal cell maturation and polarity and adhesiveness by maintaining the integrity of tight junctions [93,94,48]
	(b) ApoE-cholesterol may influence cholesterol:phospholipid molar ratios in the enterocyte brush border [95–97]
	(c) APOE4 may enhance the corticosterone-IGF-1 system during weaning, thus improving intestinal maturation and responsiveness to infection [98,99]
Brain plasticity	(a) Increasing arginine transport to the brain and increasing NO traffic to neurons during development. NO is critical for synapses [100–103]
	(b) Increasing cholesterol availability to the developing brain, cholesterol as a glial synaptogenic factor and indirect trigger for myelination in the brain [34,104,28,105,27]
Infection	(a) ApoE4 by downregulating LDL receptors may starve enteric pathogens from cholesterol and block proliferation. The LDL-receptor pathway is also highly conserved across the animal kingdom [106–110]
	(b) ApoE is secreted in a polarized manner by enterocytes, increased by 25-OH-cholesterol and decreased by LPS through an LXRα/RXR independent signaling pathway [47].