Anatomical and functional maturation of the mid-gestation human intestine

Gastrointestinal (GI) maturation is a key determinant of survival for extremely preterm infants. The enteric nervous system (ENS) controls GI motility, and immature GI motility limits enteral feeding and causes severe health complications.1 Due to the significant challenges in obtaining and studying human fetal tissue, little is known about when the human ENS becomes mature enough to carry out vital functions. Here we define the progressive anatomical maturation of the human fetal ENS and analyze GI motility in the second trimester of in utero development. We identify substantial structural changes in the ENS including the emergence of striped neuronal cytoarchitecture and a shift in the representation of excitatory and inhibitory neurons. We further analyze and pharmacologically manipulate GI motility in freshly collected human fetal intestines, which, to our knowledge, is a first functional analysis of intact human fetal organs ex vivo. We find that the ENS influences GI motility beginning at 21 postconceptional weeks (PCW), the earliest reported evidence of neurogenic GI motility. Our study provides unprecedented insight into human fetal ENS development, foundational knowledge which facilitates comparisons with common animal models to advance translational disease investigations and testing of pharmacological agents to enhance GI motility in prematurity.