Keratinocyte growth factor (KGF) is a paracrine growth factor whose mRNA has been detected in human adult and rodent gut tissues together with its associated receptor. Our objectives were to assess the presence of immunoreactive KGF ligand and receptor proteins in human fetal gastrointestinal (GI) tract segments and to evaluate the role of exogenous KGF on cell proliferation and intestinal digestive functions. KGF (26-28 kD doublet) was identified in esophagus, stomach, small intestine, and colon by Western blot. Its receptor (135 kD) was ubiquitously detected in proliferative and differentiated epithelial cells of each GI segment by use of indirect immunofluorescence (anti-bek, anti-K-sam). The addition of KGF to explants cultured in serum-free conditions greatly stimulated DNA synthesis in all GI tract tissues. The growth factor up-regulated intestinal sucrase-isomaltase and gamma-glutamyl-transpeptidase activities in jejunal explants, whereas it down-regulated these activities in colon explants. It is suggested that the KGF system likely represents an important paracrine pathway that is able to stimulate cell proliferation in all segments of the human fetal GI tract and to differentially regulate intestinal digestive functions.