the mechanisms and mediators of intestinal adaptation are multifactorial and include intraluminal nutrients , gastrointestinal secretions , as well as hormones10 , 11 ( figure  1 ) . in general , most research has focused on various growth factors and how they affect rates of enterocyte proliferation as the primary driver of resection - induced mucosal growth . it should be considered , however , that enhanced rates of enterocyte proliferation actually may occur secondary to growth of subepithelial structures . enteral nutrients appear to stimulate intestinal adaptation via several mechanisms including direct contact with epithelial cells as well as stimulated secretion of trophic gastrointestinal hormones and pancreaticobiliary secretions . the contributions of luminal nutrients to the adaptive response of the intestine is underscored by the observations that gut mucosal atrophy is associated with starvation and is reversed by refeeding . furthermore , surgical transposition of a segment of the ileum into the more proximal intestinal stream results in structural and functional  jejunalization  of the transposed ileum.13 , 14 not only is the presence of luminal nutrition important for adaptation , but so is the nutritional composition . more complex nutrients requiring more metabolic energy to absorb and digest have been suggested to induce the greatest adaptation response , presumably by virtue of an increased functional workload of the enterocyte . more specifically , longer - chain and more polyunsaturated fats as present in fish oil may provide an even greater adaptive stimulus.16 , 17 , 18 multiple experimental observations have contributed to the notion that endogenous gastrointestinal secretions are important for adaptation . experimental models in which the ampulla of vater is transposed surgically to areas more distal in the gastrointestinal tract induces villus hyperplasia beyond the transposed segment.19 , 20 bile alone has been shown to stimulate intestinal rna and dna content when delivered directly to the mid  small bowel , but the effect seems to be more profound when combined with pancreatic secretions . in other studies , pancreatic secretions seem to be more trophic to the intestinal mucosa when compared with bile . further evidence that pancreaticobiliary secretions are important for postresection adaptation is the observation that somatostatin , an agent that dramatically diminishes the output of endogenous gastrointestinal secretions , also is associated with an inhibited adaptation response . a surgical model of vascular parabiosis in which 2 rats share a common circulation has provided one of the most compelling studies endorsing the contributions of hormones to resection - induced adaptation . in that report , intestinal resection in one animal was associated with adaptive changes in the intestine of the other unoperated animal . multiple endogenous humoral factors that have been suggested to play a role in intestinal adaptation including growth hormone , insulin - like growth factor , glucagon - like peptide-2 , epidermal growth factor ( egf ) , leptin , thyroxine , and corticosteroids , to name but a few . many of these factors either have been found to be increased in the serum of patients who have undergone sbr , or exogenous administration of these agents after sbr has resulted in enhanced parameters of adaptation . growth hormone ( gh ) is a 191amino acid , single - chain protein produced in the anterior pituitary gland . this growth factor is known to be a major regulator of postnatal growth in mammals as well as play an important role in the regulation of lipid and carbohydrate metabolism.24 , 25 because gh has been shown to induce growth and proliferation in many different tissues and cell lines , its role in the setting of short - gut syndrome has been studied extensively . the receptor for gh has been found throughout the intestine : in cells of the muscularis propria , submucosa , muscularis mucosa , lamina propria , and intestinal epithelium . because of the widespread distribution for this receptor in the gut , gh has been proposed to stimulate intestinal growth directly . in addition to stimulating growth of the intestinal layers directly , gh is a major stimulus for the production of insulin - like growth factor-1 ( igf-1 ) , another intestinotrophic hormone , whose role in intestinal adaptation will be discussed in later . in animal studies , exogenous gh has resulted in significantly increased small - bowel length , mucosal height , jejunal villus height , and/or glutamine and leucine transport in animals that had undergone intestinal resection.27 , 28 , 29 in contrast , other reports have failed to show an effect of gh on postresection mucosal growth.30 , 31 gh appears to be more effective in combination with glutamine , an enterocyte - preferred fuel . several , but not all , animal studies evaluating gh plus glutamine have shown improvements in structural measures of intestinal adaptation.32 , 33 , 34 , 35 in a clinical trial , byrne et  al showed clinical benet by administering gh and glutamine in 10 patients with short - bowel syndrome who had been on long - term parenteral nutrition . this study inspired multiple subsequent clinical trials with mixed results . in a 2010 cochrane review , wales et  al analyzed 5 clinical trials of gh with or without glutamine and suggested a positive effect of gh on weight gain and energy absorption . in the majority of trials , the effects were short - lived and returned to baseline shortly after cessation of therapy . the evidence to recommend this therapy therefore was inconclusive and the clinical utility of this treatment was questioned . somatropin is a recombinant form of human gh and recently has been shown to enhance fat - free mass through the stimulation of protein synthesis and to decrease proteolysis in response to feeding . in that study , improvements in de novo synthesis and intestinal absorption increased glutamine availability over the physiologic range , suggesting that beneficial effects of gh may not require supplemental glutamine . igf-1 is a hormone produced chiefly in the liver and to a lesser degree in the gastrointestinal tract and has commanded much attention as an enterotrophic hormone . similar to gh , these observations , along with the localization of igf-1 production , its receptor , and regulatory binding proteins in the intestine , make igf-1 an attractive target for modulating adaptation responses.40 , 41 it has been considered that igf-1 is the mediator of the effects attributed to gh.32 , 42 both functional and structural parameters of adaptation have been shown to be amplified by igf-1 . vanderhoof et  al found an increase in the activity of the ileal digestive enzymes sucrase , maltase , and leucine aminopeptidase when igf-1 was given after sbr . in rats with short - bowel syndrome , igf-1 treatment allowed the rats to be weaned from parenteral nutrition . in that study , igf-1treated short - bowel rats also were found to have greater body weights and increased lean body mass . in addition to the effects of igf-1 on enterocytes , our laboratory has shown a possible effect of igf-1 on the smooth muscle of the intestine . we performed sbr procedures on transgenic mice who overexpressed igf-1 specifically in smooth muscle cells . we found that these mice increased the length of their remnant intestine far more ( approximately 2-fold ) than nontransgenic control mice that also underwent sbr . of note , these transgenic mice did not show the normal adaptive response of increasing villus height and crypt depth in the early phases of adaptation . the intestinal lengthening response preceded villus growth , which was noted at later postoperative time points . these experiments suggest that the igf-1stimulated muscular lengthening might be an important trigger for enhanced villus and crypt growth . as such , it is plausible to consider that enterocyte proliferation occurs secondary to growth of the underlying mesenchyme , as opposed to being the primary stimulus for villus lengthening . in contrast with the positive findings described earlier , adaptation responses appear to be preserved after sbr in both igf-1-null mice as well as in a strain of mice in whom igf-1receptor expression was disrupted specifically in enterocytes . first , they suggest that enterocytes are not a major cell compartment for igf-1receptor signaling during adaptation . thus , the beneficial effects of exogenous igf-1 may involve igf-1 receptors in other cells within the bowel wall . this notion would be supported by the magnified intestinal lengthening shown after sbr in mesenchymal igf-1 transgenic mice as described earlier . in addition , these findings would offer the possibility that other ligands ( such as insulin or igf-2 ) for the igf receptor may be able to compensate for the lack of igf-1 expression . despite the significant preclinical work that has been performed , no human clinical trials with igf-1 have been reported . glucagon - like peptide-2 ( glp-2 ) is an enterotrophic hormone and a member of the pituitary adenylate cyclase activating peptide glucagon superfamily . glp-2 is synthesized in enteroendocrine l cells of the distal ileum and proximal colon.46 , 47 within this 33amino acid protein , the second amino acid in the sequence is alanine , which makes the hormone sensitive to degradation by the exopeptidase dipeptidyl peptidase-4.48 , 49 substitution of glycine for alanine at position 2 makes a synthetic analog of glp-2 ( teduglutide ) that is resistant to enzymatic degradation and significantly extends its half - life . glp 2 exerts its effects through the glp-2 receptor , which has been identified on intestinal enteroendocrine cells , enteric neurons , and subepithelial myofibroblasts.51 , 52 , 53 secretion of glp-2 by intestinal l cells is driven by both direct stimulation of nutrients in the distal bowel and vagally mediated pathways , which are activated by the presence of nutrients in the proximal bowel . ingestion of nutrients , particularly long - chain fatty acids , plays a major role in glp-2 secretion . in patients with short - bowel syndrome , the presence of a colon in continuity with the small intestine is important for nutrient - stimulated increases in glp-2.56 , 57 this finding may help explain why the presence of the colon reduces the likelihood that a patient with short - bowel syndrome will require parenteral nutrition . the intestinal effects of glp-2 have been studied both in animal models and in human clinical trials . when given to rodents , glp-2 stimulates intestinal mucosal growth.58 , 59 in addition to elongated intestinal villi and crypts , glp-2 administration augments rates of crypt cell proliferation and attenuates rates of apoptosis . other effects mediated by glp-2 include reduced gastric motility , inhibited gastric acid secretion , and increased mesenteric blood flow.60 , 61 , 62 glp-2 also acts on the enteric nervous system , which may play a key role in its ability to stimulate mucosal growth . after administration of glp-2 , cellular changes have been detected in enteric neurons before affecting the intestinal crypts , suggesting that many of the effects of glp-2 may be mediated by the enteric nervous system . along this line , a potential role for the enteric nervous system was suggested by studies of ret - heterozygous mutant mice who show enhanced adaptation responses to sbr . in several studies , adult patients with short - bowel syndrome treated with teduglutide showed increases in villus height and decreases in parenteral nutrition and fluid requirements.64 , 65 , 66 teduglutide is now approved for clinical use in parenteral nutrition human egf is a 53amino acid protein found in platelets , macrophages , urine , saliva , breast milk , and plasma . egf is a member of a family of ligands sharing a common egf receptor , which also includes transforming growth factor , heparin - binding egf - like growth factor , amphiregulin , epiregulin , epigen , betacellulin , and neuregulins 14 . this growth factor has been shown to induce growth in the epithelia of multiple tissues to include skin , lung , tracheal , corneal , and gastrointestinal tract . an important role for egf as a mediator of adaptation initially was suggested by a study in which egf was administered to rats after sbr and showed significant increases in weight gain as well as other parameters of adaptation . through several subsequent experimental paradigms , enhanced resection - induced adaptation responses have been verified after stimulation of the egf receptor either by exogenous egf,71 , 72 in egf transgenic mice , or administration of another egf - receptor ligand ( transforming growth factor- ) . alternatively , inhibiting egf - receptor signaling by removing the submandibular glands , a major source of endogenous egf in the mouse , performing sbr procedures in waved-2 mice with diminished egf - receptor activity , or administration of a pharmacologic egf - receptor inhibitor all resulted in attenuated adaptation responses . because the intestinal mucosa is a very dynamic organ containing some of the most rapidly proliferating cells in the body , the relationship between rates of cell production and cell death must be precise . any imbalance may result in either intestinal mucosal atrophy or neoplasia . in studies focused on mechanisms for egf - receptor regulation of proliferation showed that expression of the cell - cycle inhibitor p21 ( p21 ) was increased and paradoxically required for egf - directed proliferation of enterocytes in  vitro . in this study , a critical region of the p21 promoter was found to be activated by egf - receptor stimulation . this promoter activity required activated extracellular signal - regulated kinase 1/2 and contained a putative binding site for the transcription factor sp1 . the requirement for this cell - cycle regulatory protein was verified in earlier experiments in which p21-null mice showed no induction of enterocyte proliferation after the stimulus of sbr . in seeking potential mechanisms for how p21 regulates adaptation , we initially expanded upon the observation that p21 affects stem cell populations within bone marrow . we therefore sought to determine the effect of p21 deficiency on intestinal stem cells . in these studies , we were unable to show differences in the expression of several stem cell markers or numbers of crypt - base columnar cells in p21-null vs control mice . however , we did identify increased expression of another cell - cycle inhibitor retinoblastoma protein ( rb ) within the crypt cells of the p21-deficient mice . the significance of rb expression was established by genetically inactivating a single rb allele in the p21-null animals , which restored enterocyte proliferation and adaptation responses . in another study , rates of enterocyte proliferation and villus growth were magnified when rb expression was completely disrupted within the intestinal epithelium of unoperated mice . independent of p21 , egf - receptor stimulation has been shown to inactivate rb directly by phosphorylation in cultured enterocytes . one simple explanation for how rb deficiency results in enterocyte proliferation is the fact that the activity of this cell - cycle inhibitor is attenuated . alternatively , enhanced igf-2 expression has been shown to be associated with rb deficiency in enterocytes . in this study , genetic disruption of igf-2 expression in intestinal rb - deficient mice prevented the mucosal hyperplasia associated with rb deficiency . because acute disruption of intestinal rb expression after intestinal resection results in amplified adaptation responses , future experiments focused on illuminating this previously unrecognized role for rb as a critical player in the molecular mechanism of resection - induced enterocyte proliferation and adaptation appear justified . similar to proliferation , rates of enterocyte apoptosis also are increased after sbr.87 , 88 , 89 , 90 because rates of enterocyte production must be matched perfectly by rates of enterocyte loss , these findings made biological sense . it appears that the proaptotic bcl-2 family member bax is a major mediator of resection - induced enterocyte apoptosis . bax expression is increased in the intestine after sbr,88 , 91 and coincides with reduced expression of the anti - apoptotic bcl-2 family member bcl - w . indeed , the proliferative crypt compartment is the site for the greatest changes in bax and bcl - w expression . when intestinal resections were performed in bax - null mice , the expected increase in enterocyte apoptosis did not occur , despite normal induction of enterocyte proliferation . in the setting of intestinal resection , apoptotic and adaptive responses are preserved in both tumor necrosis factor - receptor 1-null and fas - null mice . these results suggest that the mechanism for increased enterocyte apoptosis after massive sbr does not appear to involve the extrinsic , death receptor  mediated pathway . furthermore , the apoptosis response to sbr is not a simple passive response to increased rates of enterocyte proliferation . the ultimate utility of focusing on both the rates of proliferation and apoptosis is that future growth factor and/or pharmacologic therapy targeted to stimulate proliferation while at the same time inhibit apoptosis may result in an even greater expanded mucosal surface area than either intervention alone . the benefits of this dual therapeutic approach was suggested by co - administration of egf ( to inhibit apoptosis and stimulate proliferation ) and a pharmacologic apoptosis ( pan - caspase ) inhibitor after sbr , resulting in greater mucosal growth a summary of key signaling events that have been established to be involved with egf - directed enhanced enterocyte proliferation and attenuated rates of apoptosis is presented in figure  2 . it presently is unclear whether this angiogenic response occurs as a result of stimulated enterocyte production or whether this angiogenic response is a primary signal to induce enterocyte proliferation . photoacoustic microscopy applied to live mice immediately after intestinal resection showed that both blood flow and arterial oxygen saturation were reduced and oxygen extraction was increased within the remnant intestine . this immediate response was associated with increased expression of hypoxia - inducing factor-1. it therefore is possible that the immediate response to sbr results in a hypoxic milieu that may initiate a series of hypoxia - regulated genes capable of signaling for enterocyte proliferation . this notion is supported by a study that reported rescued adaptation responses in the intestine of vascular endothelial growth factor one proangiogenic chemokine is cxcl-5 , which has been shown to be increased in the adapting intestine after sbr . indeed , genetic disruption of cxcl-5 expression prevents adaptive angiogenesis after sbr . in this study , it was surprising that villus growth occurred despite the lack of an angiogenic response . in a subsequent series of experiments , it therefore is plausible to conclude that the angiogenic response to intestinal resection is more important for functional , rather than structural , adaptation . small - bowel bacterial overgrowth ( sbbo ) and catheter - related bloodstream infections are 2 of the most common complications in patients with intestinal failure and directly impact morbidity and mortality.103 , 104 sbbo generally results from the development of dilated loops of intestine with impaired peristalsis . this anatomic alteration sets the stage for stasis , disruption of the enteric flora , secretory diarrhea , malabsorption , gut mucosal inflammation , d - lactic acid production , and bacterial translocation into either the portal circulation or mesenteric lymph nodes . despite these well - known events , data supporting the occurrence of bacterial translocation and microbiologic features of sbbo in human beings prior studies have used cultures of duodenal aspirate , absorption of various sugar markers as a surrogate for intestinal permeability , or hydrogen and/or c - d - xylose breath testing . reliance on culturable organisms alone is restricted by the fact that less than 50% of bacterial species in the gut can not be cultured . recent advances in high - throughput sequencing of the 16s ribosomal rna gene of luminal gut bacteria have established a significant association between the intestinal microbiome and various intestinal epithelial and metabolic responses to a wide spectrum of diseases and conditions . by using 16s sequencing , massive sbr has been shown in several animal models ( mouse , piglet ) to be associated with significant alterations in the gut microbiome.105 , 106 , 107 there have been limited pediatric clinical studies involving the gut microbiome in the context of short - bowel syndrome . in one report , the gut microbiota in 11 children with short - bowel syndrome was studied and a reduced bacterial diversity was found to be associated with an increased relative abundance of proteobacteria . a confounding variable of this study was that the majority of patients on parenteral nutrition ( pn ) were receiving antibiotics at the time of stool sampling . in another study of 23 children with intestinal failure , there also was reduced bacterial diversity associated with an increased relative abundance of proteobacteria in patients who required pn , although there was an overabundance of lactobacilli in patients who already had been weaned from pn . in the pn patients , these data offer the possibility that the gut microbiome may be a major contributor in the pathogenesis of cholestasis and hepatic injury in patients with intestinal failure . mayeur et  al studied 16 patients with short - gut syndrome and showed a marked dysbiosis in fecal microbiota , with a predominance of the lactobacillus / leuconostoc group , whereas clostridium and bacteroides were under - represented . the presence of fecal lactate ( 56% of patients ) was used to define a lactate - accumulator ( la ) group , whereas an absence of fecal lactate ( 44% of patients ) defined a non  lactate - accumulator group . the la group had lower serum hc03- levels and were at risk of d - encephalopathic reactions . furthermore , all patients in the non  lactate - accumulator group and those accumulating preferentially l isoform in the la group had never developed d - acidosis . the d / l fecal lactate ratio therefore may be  a relevant index to predict the risk for d - lactate encephalopathy . there was a recent case report of a child with d - lactic acidosis and short - bowel syndrome who was managed successfully by fecal transplantation . through metagenomic and biochemical analysis , the intestinal microbiota of genetically obese mice have been shown to have an increased capacity for energy harvest from the diet . in that study , transfer of stool into the gastrointestinal tract of germ - free mice resulted in a significant increase in body fat . stool from obese mice show a proportional increase in fermicutes phyla ( which includes the genus lactobacilli ) in their intestinal lumen . it therefore is plausible to investigate whether the altered intestinal microbiota in patients with intestinal failure adapts to provide greater energy harvest for the host . the paucity of published data regarding direct interrogation of the microbiota in the setting of intestinal failure represents a significant gap in our understanding of this important morbidity . these data will direct a more informed scientific rationale for current therapeutic interventions such as antibiotic administration , prebiotics , probiotics , surgical reduction in small - bowel caliber , or even future interventions such as microbiota manipulation via fecal transplantation . , roughly half will have a complete adaptation response and be weaned completely from parenteral nutrition . within the other half of patients , an equal proportion will either die or require a small - bowel transplant . current 5-year graft survival rates after intestinal transplantation are roughly 50% , with significant patient morbidity associated with significant immunosuppression . basic research designed to elucidate specific mechanisms for resection - induced adaptation responses therefore are critical for the future design of more targeted , innovative therapies to enhance this important response .
after massive small - bowel resection , the remnant bowel compensates by a process termed adaptation . 
 adaptation is characterized by villus elongation and crypt deepening , which increases the capacity for absorption and digestion per unit length . the mechanisms / mediators of this important response are multiple . 
 the purpose of this review is to highlight the major basic contributions in elucidating a more comprehensive understanding of this process .