Amniotic fluid: Source of trophic factors for the developing intestine

Table 1 Phases of mammalian gastrointestinal development (adapted from reference 1)

Phase	Development
Phase 1	Embryonic phase of organogenesis
	Forms primitive GIT
Phase 2	Entrance and exit sites of GIT form
	Formation of rudimentary primitive GIT
	Formation of mouth and anus
	Fetal swallowing of amniotic fluid begins
Phase 3	Active differentiation
	Increase in cell number in crypts
	Cells from crypts start migrating up to the villi
	GIT growth is more rapid than the fetal body as a whole
	Growth accompanied by selective apoptosis
Phase 4	After birth, exposure to enteral nutrition
	Breast milk feeding – rapid mucosal differentiation and development
	Infancy – mucosal growth continues with deepening crypts, increasing villi (increasing width and number) and appearance of sub-mucosal folds
	Development of GIT mucosal immunity due to exposure to dietary antigens
	Mucosal immune system can distinguish between foreign pathogens and safe nutrient proteins and commensal organisms
Phase 5 (Weaning)	Late infancy – early childhood. Transition from milk feeding to solid foods. This is second phase of mucosal immunity with epithelial hyperplasia with maturation of gut functions similar to older children.

GIT: Gastrointestinal tract.

Table 2 Important nutritional components of amniotic fluid

Component	Most important examples
Amino acids	Glutamine, arginine
Proteins	Lactoferrin
Minerals	Zinc, iron
Hormones	Growth hormone, prolactin
Growth factors	IGF-1, EGF

IGF-1: Insulin like growth factor-1; EGF: Epidermal growth factor.

Table 3 Amniotic fluid volume changes with increasing gestational age

Gestational Age	Volume of AF
10 wk	25 mL
20 wk	400 mL
28 wk	800 mL
Term gestation	Plateau in volume of AF
42 wk	400 mL

AF: Amniotic fluid.

Table 4 Roles of various trophic factors found in amniotic fluid in intestinal development and the location of their receptors

Trophic factor	Location of receptors	Role in intestinal growth
EGF	Basolateral intestinal membrane	Stimulates cell mitosis and differentiation
		Stimulates intestinal epithelial cell proliferation
HGF	Intestinal crypt epithelial cells and in the muscle layers of the intestine	Intestinal cell proliferation in vitro and has been demonstrated to induce intestinal growth in rats
TGF-α and TGF-β	Basolateral intestinal membrane	Primary role may be intestinal mucosal repair
IGF-1	Crypt cells, basolateral membrane and in the distal intestine	Primary mediator of both intrauterine and postnatal growth in mammals
		May be important for growth of muscle growth of distal small intestine
EPO	Apical surface of intestinal epithelial cells	Increased villus height, villus area, crypt depth and crypt epithelia cell proliferation in rat pups. In vitro, recombinant EPO has been shown to protect cells against mucosal injury
G-CSF	Apical regions of the intestine	Role in epithelial cell maintenance
IL family	Intestinal epithelial cells	Enhances intestinal epithelial cell restitution. Enhances the integrity of the intestinal epithelial cell junctions. Intestinal epithelial cell proliferation and increased nutrient uptake

IGF-1: Insulin like growth factor-1; EGF: Epidermal growth factor; TGF: Transforming growth factor; HGF: Hepatocyte growth factor; EPO: Erythropoietin; G-CSF: Granulocyte colony stimulating factor; IL: Interleukin.

Table 5 Effects of epidermal growth factor on the gastrointestinal tract

Increased effect on	Possible secondary message
Proliferation	-
Bicarbonate secretion	Prostaglandins
NaCl and glucose uptake	Na+- glucose cotransporter, lipids
Mucus secretion	Prostaglandins
GI blood flow	Beta-adrenergic NO prostaglandins
Longitudinal smooth muscle contraction	Prostaglandins
Circular smooth muscle contraction	Desensitizes (not prostaglandins)
Restitution	Cell-migration prostaglandins
Permeability	-
Mucosal protection	Proliferation, polyamines, mucus, trefoil peptides
Decreased effect on	Possible secondary message
Gastric acid secretion	Protein kinase C, cAMP
Gastric emptying	-
Increased and decreased effect on	Possible secondary message
Chloride secretion	Phosphatidylinositol 3-kinase
Pancreatic amylase (3.2.1.1) secretion	cAMP phospholipase C

GI: Gastrointestinal; NaCl: Sodium chloride; cAMP: Cyclic adenosine monophosphate.

Table 6 Important trophic factors involved in gut development and the most relevant reference articles

Trophic factor	Ref.	n of references cited
EGF	Maheshwari (2004)[24]	36
	Underwood (2005)[18]	63
	Playford (1996)[29]	23
	Cummins (2002)[15]	108
HGF	Maheshwari (2004)[24]	36
	Underwood (2005)[18]	63
	Cummins (2002)[15]	108
TGF-α and TGF-β	Maheshwari (2004)[24]	36
	Seare (1998)[56]	32
	Underwood (2005)[18]	63
	Cummins (2002)[15]	108
IGF-1	Maheshwari (2004)[24]	36
	Underwood (2005)[18]	63
	Seare (1998)[56]	32
	Cummins (2002)[15]	108
Cytokines	Maheshwari (2004)[24]	36
	Seare (1998)[56]	32

IGF-1: Insulin like growth factor-1; TGF: Transforming growth factor; EGF: Epidermal growth factor; HGF: Hepatocyte growth factor.