Intestinal mucosal atrophy and adaptation

Table 1 Reported regulators of intestinal mucosal adaptation

Cytokines		Intracellular transducers of physical force effects		Nutrients
Stimuli	Ref.	Stimuli	Ref.	Stimuli	Ref.
PDGF-α	Sukhotnik et al[86]	FAK-Tyr 925	Chaturvedi et al[225]	L-arginine	Koppelmann et al[88]
HGF	Katz et al	Integrin-linked Kinase	Yuan et al[243]	Glutamine	Lardy et al[252]
Transforming GF-β	Sukhotnik et al[151]	RhoA	Chaturvedi et al[244]	Ornithine	Lardy et al[252]
IGF-1	Lund et al[92]	ROCK	Chaturvedi et al[244]	Butyrate	Bartholome et al[161]
VEGF	Parvadia et al	mDial	Chaturvedi et al[244]	Short-chain fructooligosaccharide	Barnes et al[163]
EGF	Warner et al[90]	-	-	-	-
GLP-2	Bortvedt et al[93]	-	-	-	-

PDGF: Platelet derived growth factor; HGF: Hepatocyte growth factor; EGF: Epidermal growth factor; IGF-1: Insulin-like growth factor-1; GH: Growth hormone; GLP-2: Glucagon-like peptide-2; ROCK: Rho-associated kinases; mDia: The formin homology protein mDia1; VEGF: Vascular endothelial growth factor.

Table 2 Cellular factors involved in enterocyte differentiation during adaptation

Cellular factors
Wnt/β-catenin
Notch
Hedgehog
PI3K
HNF1 α/β
GATA
ETS
Cdx2
FGF4
NEUROG3
Schlafen-3
Math1

PI3K: Phosphoinositide 3-​kinase; FGF: Fibroblast growth factor; HNF: Hepatocyte nuclear factor.

Table 3 Potential pharmacotherapy targets for intestinal failure

Dose mg/kg per d		Side effects	Structure	Approval
Growth hormone	0.1	Fluid retention, joint pain, hyperglycemia	191-amino acid protein	FDA
EGF	NA1	NA	53-amino acid peptide	Not available commercially
GLP-2	0.1	Abdominal pain/obstructive symptoms	dpp-IV resistant 33-amino acid peptide	Phase III clinical trials available in Europe

¹Dose not specified for human use. FDA: Food and Drug Administration; GLP-2: Glucagon-like peptide-2; EGF: Epidermal growth factor; dpp-IV: Dipeptidyl peptidase IV; NA: Not available.

Table 4 Questions for future study

What is the ideal timing for influence of proliferative and differentiation phases in small bowel adaptation with targeted therapy?

What are useful combination regimens of multimodality therapy?

What dietary supplementation is essential for optimization of adaptation?

What is an appropriate algorithm for advanced medical compared to surgical treatment of small bowel syndrome ?

What is the precise role for glutamine supplementation in facilitating adaptation?

What is the ideal dose of Teduglutide?

Can other agents such as polyamines or retinoic acid be useful?

How can surgical procedures best be combined with multimodal therapy?

How can the role of physical force in adaptation be replaced pharmacologically?

Why is neoplasm more common in the large intestine than in the small intestine?

Why do APC (Min) mice have more common neoplasms in the small bowel?