Surgical patients who cannot tolerate enteral feedings are critically dependent on total parenteral nutrition (TPN). However, TPN is associated with a loss of epithelial barrier function (EBF), which can lead to intestinal dysfunction and the transit of luminal pathogens and toxins into the host. Using a mouse TPN model, our laboratory has demonstrated that the intestinal intraepithelial lymphocytes (IEL) population undergoes a number of significant changes in phenotype and function, including an increase in interferon gamma (IFN-g), decrease in interleukin-10 (IL-10), and increase in epithelial cell (EC)-membrane-bound TNF-a. These cytokine changes may well be key mechanisms leading to the loss of EBF, and appears to be regulated via the PI3K/p-Akt signaling pathway. TPN resulted in a loss in the phosphorylation of Akt (p-Akt), an ubiquination in b-catenin, and loss of EBF. Interestingly, preliminary data also shows that the addition of glutamine to TPN, exogenous epidermal growth factor (EGF) or the removal of pro-inflammatory cytokines can prevent many of these TPN-associated changes. The overlying hypothesis for this proposal is the TPN administration leads to altered cytokine expression with resultant decline in PI3K/p-Akt signaling that results in loss of EBF. To address this, the following specific aims are proposed. 1. To determine the influence of IEL-derived cytokine expression on the alterations in the EC PI3k/p-Akt signaling pathway.
This aim will determine the relevance of the presence or absence of pro-inflammatory cytokines within the mucosa to the abundance of p-Akt. Using novel promoters of this signaling pathway, the aim then proposes to determine the relation of p-Akt expression to the maintenance of EC proliferation and EBF. 2. Examine whether the loss of EGF-receptor expression with TPN results in the loss of p-AKT abundance.
The aim will also examine whether improved barrier function with glutamine supplemented TPN is dependent on EGF/EGF-R signaling. Finally, this aim will examine if the TPN- associated decline in EGF signaling can be prevented by manipulation of IEL-derived cytokine expression. 3. Determine how alteration in TNF-a receptor abundance during TPN administration alters EBF.
This aim will examine changes in the abundance of TNF-a and its receptors in the formation of TPN-associated decline in EBF. As EGF signaling can be dependent on TNF-a, the interdependence of these factors will also be examined. Finally, a disintegrin and metalloproteinase 17 (ADAM17) can shed the active ligands for EGF-R, and TNF-a receptors. The relation of ADAM17 and the loss of EBF will be explored. 4.
This aim will measure changes in intestinal mucosal immunocyte phenotype and function during pediatric and adult administration of TPN, and correlate these with associated loss of epithelial barrier function. These experiments will elucidate many of the mechanisms driving loss of EBF associated with TPN. Beyond this goal, the information derived from this proposal will augment our basic understanding of lymphoid / EC interactions, which may have relevance to a number of other gastrointestinal disease processes.

Public Health Relevance

Surgical patients who cannot tolerate enteral feedings are critically dependent on total parenteral nutrition (TPN), or intravenous nutrition. However, TPN is associated with a loss of epithelial barrier function (EBF), which can lead to the transit of luminal pathogens and toxins into the host. Using a mouse model of TPN and novel transgenic mice and promoters and inhibitors of intracellular signaling this proposal will examine the mechanisms which lead to this loss of EBF. Beyond this goal, the information derived from this proposal will augment our basic understanding of a number of other gastrointestinal disease processes where barrier function is lost, including inflammatory bowel disease and infectious disorders of the intestine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044076-13
Application #
8213497
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Rothermel, Annette L
Project Start
1999-07-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
13
Fiscal Year
2012
Total Cost
$351,993
Indirect Cost
$120,461
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ochi, Takanori; Feng, Yongjia; Kitamoto, Sho et al. (2016) Diet-dependent, microbiota-independent regulation of IL-10-producing lamina propria macrophages in the small intestine. Sci Rep 6:27634
Feng, Yongjia; Barrett, Meredith; Hou, Yue et al. (2016) Homeostasis alteration within small intestinal mucosa after acute enteral refeeding in total parenteral nutrition mouse model. Am J Physiol Gastrointest Liver Physiol 310:G273-84
Demehri, Farokh R; Utter, Brent; Freeman, Jennifer J et al. (2016) Development of an endoluminal intestinal attachment for a clinically applicable distraction enterogenesis device. J Pediatr Surg 51:101-6
Ralls, Matthew W; Demehri, Farokh R; Feng, Yongjia et al. (2015) Enteral nutrient deprivation in patients leads to a loss of intestinal epithelial barrier function. Surgery 157:732-42
Barrett, Meredith; Demehri, Farokh R; Teitelbaum, Daniel H (2015) Intestine, immunity, and parenteral nutrition in an era of preferred enteral feeding. Curr Opin Clin Nutr Metab Care 18:496-500
Feng, Yongjia; Tsai, Yu-Hwai; Xiao, Weidong et al. (2015) Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition. Mol Cell Biol 35:3604-21
Freeman, Jennifer J; Feng, Yongjia; Demehri, Farokh R et al. (2015) TPN-associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways. FASEB J 29:2943-58
Ralls, Matthew W; Miyasaka, Eiichi; Teitelbaum, Daniel H (2014) Intestinal microbial diversity and perioperative complications. JPEN J Parenter Enteral Nutr 38:392-9
Sueyoshi, Ryo; Woods Ignatoski, Kathleen M; Okawada, Manabu et al. (2014) Distraction-induced intestinal growth: the role of mechanotransduction mechanisms in a mouse model of short bowel syndrome. Tissue Eng Part A 20:830-41
Xiao, Weidong; Feng, Yongjia; Holst, Jens J et al. (2014) Glutamate prevents intestinal atrophy via luminal nutrient sensing in a mouse model of total parenteral nutrition. FASEB J 28:2073-87

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