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Symposium: Glucagon-Like Peptide 2: Function and Clinical Applications

Glucagon-Like Peptide-2 and Short-Chain Fatty Acids: A New Twist to an Old Story^1,2

Kelly A. Tappenden^*,,3, David M. Albin, Anne L. Bartholome and Heather Fottler Mangian^*

^* Department of Food Science and Human Nutrition, Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801

³To whom correspondence should be addressed. E-mail: tappende{at}uiuc.edu.

	ABSTRACT

TOP ABSTRACT Intestinal adaptation Dietary carbohydrate and SCFA SCFA and intestinal adaptation SCFA and the neonatal... Butyrate, GLP-2 and GLUT2... CONCLUSION LITERATURE CITED

 
The nutritional regulation of intestinal adaptation extends beyond the route of nutrient administration as specific nutrients are known to mediate the adaptive response. Dietary carbohydrates are known to enhance intestinal adaptation in patients with short-bowel syndrome. This review discusses SCFA-induced adaptation in intestinal structure and function in adult rat and neonatal piglet models. Potential mechanisms relate to the salvage of energy as SCFA in the colon, direct mediation of intestinal adaptation by SCFA and stimulated release of glucagon-like peptide-2 (GLP-2) from enteroendocrine L cells by SCFA. Among the produced SCFA, butyrate appears to be responsible for increasing plasma GLP-2 concentration, in addition to the enterotrophic effects. Emerging evidence reveals that physiological concentrations of butyrate acutely upregulate the expression of key enterocyte-associated nutrient transporters. Focused experiments are needed to carefully identify the critical components of intestinal adaptation and yield conclusions regarding the relative contributions of SCFA and GLP-2 during the various phases of this process.

KEY WORDS: • intestinal adaptation • short-bowel syndrome • nutrient transport • butyrate • piglet

The small intestine is a remarkable organ with a distinct structure aimed at meeting the digestive and absorptive demands of the host. The length of the adult small intestine is 20 ft. However, this absorptive surface area is further amplified by numerous mucosal folds of Kerckring, containing finger-like villi, lined by a polar epithelium displaying a brush border membrane adjacent to the intestinal lumen. This structural configuration results in a surface epithelium estimated to be 600-fold greater than if a simple smooth cylinder (1). As a result, the normal healthy intestine is estimated to greatly exceed the digestive and absorptive requirement of the host, wherein the majority of nutrients are absorbed within the jejunum.

	Intestinal adaptation

TOP ABSTRACT Intestinal adaptation Dietary carbohydrate and SCFA SCFA and intestinal adaptation SCFA and the neonatal... Butyrate, GLP-2 and GLUT2... CONCLUSION LITERATURE CITED

 
Short-bowel syndrome (SBS) typically follows resection of 50% or more of the small intestine and is associated with diarrhea, dehydration, electrolyte disturbances, malabsorption and progressive malnutrition (2). In adults, Crohn’s disease necessitates 60% of massive small bowel resections, whereas neonatal disorders, such as necrotizing enterocolitis, are among the underlying conditions afflicting the pediatric population (3,4). Severity of malabsorption is determined by the amount and location of intestine resected, with a special acknowledgment for nutrients such as vitamin B-12 that are absorbed in distinct regions of the small intestine.

Due to the prevention of dehydration and malnutrition, total parenteral nutrition (TPN) has improved the prognosis that patients with SBS would have received 25 y ago (5–7). However, the administration of nutrients intravenously inhibits the process of intestinal adaptation (8,9), a key phenomena wherein the residual intestine undergoes structural (i.e., dilation, lengthening and thickening) and functional (i.e., digestive and absorptive) enhancements (10–12). The nutritional regulation of intestinal adaptation extends beyond the route of nutrient administration because specific nutrients are known to mediate the adaptive response. Whereas the other contributors to this symposium have demonstrated that glucagon-like peptide-2 (GLP-2) is intestinotrophic (13–16), the focus of this paper is to examine the evidence supporting the hypothesis that SCFA, indeed butyrate alone, enhance structural and functional adaptations following massive small bowel resection by means of the indirect actions of GLP-2 (Fig. 1).

View larger version (13K): [in this window] [in a new window]   FIGURE 1 Proposed mechanism for butyrate-induced intestinal adaptation. Butyrate enhances structural and functional adaptations following massive small bowel resection and is associated with increased plasma concentrations of GLP-2. Additional data are needed to discern the relative contributions of butyrate and GLP-2 during the various phases of intestinal adaptation.

	Dietary carbohydrate and SCFA

TOP ABSTRACT Intestinal adaptation Dietary carbohydrate and SCFA SCFA and intestinal adaptation SCFA and the neonatal... Butyrate, GLP-2 and GLUT2... CONCLUSION LITERATURE CITED

	SCFA and intestinal adaptation

TOP ABSTRACT Intestinal adaptation Dietary carbohydrate and SCFA SCFA and intestinal adaptation SCFA and the neonatal... Butyrate, GLP-2 and GLUT2... CONCLUSION LITERATURE CITED

 
The addition of SCFA to TPN has been shown to prevent TPN-associated mucosal atrophy (21) and enhance structural markers of adaptation to small bowel resection in adult rats (22,23). In addition to determining that these structural adaptations occur as early as 3 d following intestinal resection (23), we examined functional adaptations augmented by the SCFA, acetate, propionate and butyrate. Ileal uptake of D-glucose is increased by systemic SCFA administration both 3 and 7 d following intestinal resection by increasing the maximal transport rate without altering the apparent Michaelis affinity constant or passive permeability coefficient (24).

Because SCFA were found to increase the functional capacity of the residual small bowel in adult rats, we examined the mRNA abundance of nutrient transporters within the enterocytes to provide potential cellular mechanisms underlying this increase in functional capacity (24). The results indicate that SCFA increased mRNA abundance of the facilitative glucose transporter, GLUT2, and tended to increase the mRNA abundance of the brush-border sodium/glucose cotransporter, SGLT-1 (Fig. 2). Subsequent acute studies in adult rats with healthy unresected intestine receiving TPN indicated that systemic SCFA markedly increase both mRNA and protein abundance of GLUT2 within 6 h of administration (25). These results are unique because they indicate that a specific nutrient (i.e., SCFA) may modulate the gene expression and transport capacity of other nutrients (i.e., glucose, galactose and fructose). Furthermore, the observed increase in nutrient uptake indicates that systemic nutrients (i.e., those provided to the basolateral pole of the enterocyte, as in TPN) can increase the transport of luminal substrates (via brush-border transporters) provided by oral or enteral nutrition. The concept that SCFA can be provided intravenously to prepare the intestinal brush-border for effective digestion and absorption of enteral nutrients is particularly attractive for patients with SBS.

View larger version (20K): [in this window] [in a new window]   FIGURE 2 SCFA and functional adaptation. SCFA-supplementation of total parenteral nutrition in following massive small bowel resection increases glucose uptake and is associated with upregulated enterocyte expression of the monosaccharide transporters, SGLT-1 and GLUT2.

	SCFA and the neonatal piglet

TOP ABSTRACT Intestinal adaptation Dietary carbohydrate and SCFA SCFA and intestinal adaptation SCFA and the neonatal... Butyrate, GLP-2 and GLUT2... CONCLUSION LITERATURE CITED

 
Although the adult rat model allowed initial examination of the role of SCFA in intestinal adaptation, a major limitation of this model is its applicability to the growing population of human infants with SBS. Similarities in nutritional requirements, gastrointestinal physiology and metabolism make the neonatal piglet an appropriate model for the parenterally supported human infant with SBS (27,28) that accurately resembles the complications of SBS in human infants (29). Therefore, recent efforts have turned to parenterally supported neonatal piglets with SBS for additional investigations aimed at characterizing SCFA-induced intestinal adaptation and identifying the mechanisms underlying these responses (30–32). Littermate piglets were randomized to one of four treatment groups: standard TPN (control); standard TPN plus 60 mmol/L SCFA [36 mmol/L acetate, 15 mmol/L propionate and 9 mmol/L butyrate (SCFA)]; standard TPN plus 9 mmol/L butyrate (9Bu); or standard TPN plus 60 mmol/L butyrate (60Bu). Within each diet group, animals were further randomized (n = 6 per group) to receive infusions for various time points following surgery to allow for examination of acute (4, 12, 24 h) and chronic (3 or 7 d) adaptations. Morphometry revealed increased jejunal and ileal villus height and surface area in the SCFA, 9Bu and 60Bu groups compared with the control group, at all time points including the 4 h group (30). Protein abundance of proliferating cell nuclear antigen was lowest, whereas prohormone caspase-3 protein abundance was highest in the control group (30). These results indicate that the SCFA butyrate increases epithelial surface area by enhancing proliferation and inhibiting apoptosis. Similar to the response of adult rat intestine, mucosal transport of glucose is upregulated at various time points following systemic SCFA administration, as is dipeptide, glutamine and arginine transport (31,32). Unpublished data from our lab indicate that these structural and functional adaptations are associated with increased plasma GLP-2 concentration in response to systemic butyrate, regardless of time point studied.

	Butyrate, GLP-2 and GLUT2 transcriptional initiation

TOP ABSTRACT Intestinal adaptation Dietary carbohydrate and SCFA SCFA and intestinal adaptation SCFA and the neonatal... Butyrate, GLP-2 and GLUT2... CONCLUSION LITERATURE CITED

 
Regardless of the experimental model or species studied, a very marked and acute in vivo response to SCFA administration is increased mRNA and protein abundance of the facilitative hexose transporter, GLUT2. To test the hypothesis that butyrate and/or GLP-2 increase GLUT2 mRNA abundance by activation of the GLUT2 promoter, the pGL3 reporter plasmid containing 1800 bases of the human GLUT2 promoter was cotransfected with renilla (a transfection efficiency control) into differentiated Caco-2BBe cells. In parallel experiments, both GLP-2 (unpublished data) and butyrate (33) activated the GLUT2 promoter in a dose-dependent manner. Consistent with the in vivo piglet data, studies conducted with a cocktail of SCFA including acetate, propionate and butyrate indicate that butyrate is indeed the stimulatory SCFA because acetate and propionate treatments did not differ from control (33). Additional studies are underway regarding the intriguing observation that both butyrate and GLP-2 independently activate the GLUT2 promoter. In addition to their independent effects, trials are focusing on potential synergistic effects that may exist between butyrate and GLP-2 and determining if each of these stimuli initiate GLUT2 transcription through activation of distinct regions of the promoter.

	CONCLUSION

TOP ABSTRACT Intestinal adaptation Dietary carbohydrate and SCFA SCFA and intestinal adaptation SCFA and the neonatal... Butyrate, GLP-2 and GLUT2... CONCLUSION LITERATURE CITED

 
Historical clinical reports with human subjects and recent data obtained from adult rat and neonatal piglet SBS models support the hypothesis that the mechanism whereby SCFA-supplemented TPN enhances structural and functional aspects of intestinal adaptation is via upregulation of the intestinal trophic peptide, GLP-2. However, current data reveal only positive associations and definitive trials await specific GLP-2 antagonists, immunoneutralizing GLP-2 antibodies or GLP-2 receptor knockout models. It is very possible that butyrate directly induces adaptive alterations, or alternatively that there is a synergism between GLP-2 and butyrate with each of these potential signals regulating different aspects of this complex process. Finally, it also remains possible that butyrate initiates adaptation directly; however, it is more likely involved in a cascade of adaptive mediators, of which GLP-2 is a strong candidate. Acute regulation of nutrient transporter expression by butyrate, in a GLP-2 independent manner, leads us to speculate that GLP-2 may have an important role in the chronic changes aimed at increasing steady-state levels of small intestinal function. Indeed, experimental evidence indicates that there are likely separate signals for acute versus chronic adaptations, as there are for structural versus functional adaptations (34). Therefore, focused experiments are needed to carefully identify the critical components of intestinal adaptation and to yield conclusions regarding the relative contributions of butyrate and GLP-2 during the various phases of this process.

	FOOTNOTES

 
¹ Presented at the Experimental Biology meeting, April 11–15 2003, San Diego, CA. The symposium was sponsored by The American Society for Nutritional Sciences and supported in part by the USDA-Human Nutrition Program, NPS Pharmaceuticals, NIH-Office of Dietary Supplements and Wyeth Nutritionals. The proceedings are published as a supplement to The Journal of Nutrition. This supplement is the responsibility of the guest editors to whom the Editor of The Journal of Nutrition has delegated supervision of both technical conformity to the published regulations of The Journal of Nutrition and general oversight of the scientific merit of each article. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, editor or editorial board of The Journal of Nutrition. Guest Editors for the symposium publication are Doug Burrin, USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas and Kelly Tappenden, Department of Food Science and Human Nutrition/Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois.

² This work was supported, in part, by federal funds from the National Institutes of Health, NIDDK 1 R01 DK 57682 (K.A.T.).

	LITERATURE CITED

TOP ABSTRACT Intestinal adaptation Dietary carbohydrate and SCFA SCFA and intestinal adaptation SCFA and the neonatal... Butyrate, GLP-2 and GLUT2... CONCLUSION LITERATURE CITED

 

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