The long-range goal of our research is to enhance the lives of individuals with intestinal dysfunction.  Efforts focus on understanding the regulation of small intestinal function by various nutrients and intestinal-specific peptides, and our laboratory’s publications demonstrate versatility in testing hypotheses addressing fundamental issues in gastrointestinal physiology.  In addition to our studies conducted in both human subjects and cell culture, our hypotheses surrounding the regulation of gastrointestinal function have led us to establish innovative animal models simulating a spectrum of clinical scenarios involving intestinal adaptation (Figure 1).  A brief discussion of the impact of our research is described on the following pages.

Premature infants are at risk for short bowel syndrome secondary to necrotizing enterocolitis (NEC), whereas adults who are traumatically injured face intestinal resection following non-occlusion small bowel necrosis (NOSBN).  Aggressive enteral nutrition and poor intestinal perfusion are hypothesized to play an important pathogenic role in both NEC and NOSBN.  Our research has tested the novel hypothesis that during intestinal hypoperfusion, or reduced blood flow, enteral nutrients may increase oxygen demand beyond that available, potentially increasing intestinal hypoxia and impairing small intestinal function (Tappenden, 2003).  Our results indicate that hypoperfusion alters the transport of specific nutrients across the intestine and this has important implications for specialized nutrition support provided by neonatologists, intensivists and nutritionists.  Using newly developed models of NEC in the clinically-relevant neonatal piglet, the cellular mechanisms underlying the differential regulation of nutrient transport during hypoperfusion are being examined.  This information is critical for assuring that the composition of enteral nutrients provided to the hypoperfused intestine is optimized to prevent further impairment in GI function.

When NEC develops, massive small bowel resection is typically performed to remove the necrotic intestine.  However, this intervention often results in short bowel syndrome (SBS), rendering the infant with inadequate intestinal surface area for digestion and absorption of orally consumed nutrients.  My laboratory has developed a neonatal piglet model that combines an 80% massive small bowel resection with intravenous nutrition, or total parenteral nutrition TPN (Tappenden et al., 2003), thereby establishing an excellent pre-clinical model for investigating therapeutic modalities for SBS (Bartholome et al., 2004; Albin et al., 2003a; 2003b).  This surgical model has become the focus for a NIH-funded research project aimed at understanding the underlying mechanism(s) whereby short-chain fatty acids (SCFA) modulate intestinal adaptation in neonates receiving TPN.  Work from our laboratory, has determined that the supplementation of parenteral nutrition with SCFA enhances structural and functional adaptation in neonatal piglets (Albin et al., 2003a; 2003b; Bartholome et al., 2004) following massive small bowel resection.  It appears that butyrate is the SCFA responsible for augmenting structural aspects of intestinal adaptations by increasing proliferation and decreasing apoptosis as early as 4 hours post-resection (Bartholome et al., 2004).  Current efforts focus on whether butyrate mediates these effects directly or involves a mechanism relating to induced expression of the intestinotrophic peptide, glucagon-like peptide-2 (GLP-2; Bartholome et al., 2005; Mangian et al., 2006).  The rationale that underlies this research is that if the role and underlying mechanism(s) whereby short-chain fatty acids modulate intestinal adaptation in neonates receiving TPN is understood, nutritional formulas could be optimized to promote intestinal adaptation in children with short-bowel syndrome and reduce their long-term dependence on TPN.Regardless of the experimental model/species studied, we have noted that a very consistent response to SCFA administration is upregulation of the brush-border glucose transporter, SGLT-1, and basolateral hexose transporter, GLUT2.  However, our research indicates that SCFAs appear to utilize different cellular and molecular mechanisms to induce the increase in SGLT-1 or GLUT2 activity (i.e., an increase in mRNA abundance of SGLT-1 is not observed as it is for GLUT2).  To study these acute observations and underlying mechanism(s), we have developed both in situ and ex vivo experimental models with neonatal piglet intestine.  We have recently made thenovel observation that ileal tissue exposed to butyrate for as little as 15 minutes results in a 6-fold increase in glucose transport via SGLT-1 (Chung and Tappenden, 2005)Our laboratory is currently investigating whether the mechanism of the butyrate-mediated response is via facilitating recruitment of intracellular pools of SGLT-1 to the brush-border membrane.  To examine the regulatory mechanism whereby SCFAs increase GLUT2 mRNA abundance, reporter assays are conducted with differentiated Caco-2BBe monolayers transfected with the GLUT2 promoter and indicate that transcription of the GLUT2 promoter is initiated by butyrate (Mangian et al., 2006).  Understanding these mechanisms provides valuable insight into treatment modalities and markers of therapeutic efficiency for use in individuals with intestinal failure.  This work also demonstrates our efforts to support the hypotheses being tested in novel in vivo models with focused, mechanistic in vitro experiments thereby increasing the breadth of experimental data generated.

In addition to our pre-clinical animal models and in vitro studies, we are conducting studies with human subjects with SBS to investigate the therapeutic effectiveness of a new gastrointestinal peptide analog, teduglutide (Jeppesen et al., 2005; Tappenden et al., under review).  These efforts are currently the focus of a Food and Drug Administration Phase III clinical trial wherein samples from clinical investigators around the world send mucosal biopsies from TPN-dependent patients with intestinal failure to my laboratory for assessment of the structural and functional adaptations induced by teduglutide therapy.  The leadership of our research group in the area of intestinal failure has been recognized by the National Institutes of Health (NIH) wherein they invited Dr. Tappenden to chair a 2-day research workshop in 2004 titled ‘Intestinal Failure: Current and Emerging Therapies Including Transplantation’ (Figure 2).  This invitation allowing Dr. Tappenden to assemble a faculty of 24 international experts and drew approximately 300 clinical and basic researchers from 9 countries.  The culmination of these efforts allowed Dr. Tappenden to serve as Associate Editor for Gastroenterology, the leading journal in this field, wherein the proceedings of this symposium were recently published (2006, volume 130).  In conclusion, our numerous efforts in both basic and clinical research, in addition to NIH-sponsored workshops and publications, promise to realize our long-term goal of enhancing the lives of patients with intestinal dysfunction.

Consistent with our overall research focus, we have developed models for both parenteral and enteral (gastrostomy and jejunostomy) nutrient administration, as well as diarrheal diseases (salmonella infection) in neonatal piglets (Correa-Matos et al., 2003; Milo et at., 2004).   Various collaborators have sought this expertise to examine nutrient formulas with a range of characteristics on the function and structure of the gastrointestinal tract.  Findings to date indicate that both parenteral and enteral solutions can be formulated to enhance intestinal function.  Furthermore, because of our commitment to understanding the cellular alterations induced by the optimal administration of specialized nutrition support, our laboratory is currently identifying molecular and functional markers that can be used to assess the efficacy of therapeutic strategies for individuals with intestinal dysfunction.
In summary, by understanding the cellular adaptations, molecular mechanisms and applicability to human populations, work from our research group is impacting the medical nutrition therapy provided to patients with intestinal failure.  Ultimately, we expect to significantly enhance their quality of life by reducing their dependence on long-term TPN.

Innovative models key to novel, clinically-relevant hypotheses