Total parenteral nutrition (TPN) is frequently used for surgical and trauma patients who cannot tolerate enteral feedings. A number of alterations occur in the intestinal mucosa with TPN, including loss of mucosal barrier function and villus atrophy, which may contribute to increased septic complications, commonly seen in patients on TPN. TPN leads to a number of changes in the intestinal intraepithelial lymphocytes (IEL) - which reside in the epithelial layer of the gut. This includes an increased IEL expression of interferon gamma (IFN-gamma), which mediates a loss of epithelial barrier function, and up-regulates epithelial cell (EC) apoptosis. TPN also results in a significant decline in IEL-derived keratinocyte growth factor (KGF) expression, which contributes to the development of mucosal atrophy with TPN. The causative factors leading to these IEL changes are unknown. An important factor for IEL development and function is EC expression of interleukin 7 (IL-7). EC-derived IL- 7 is significantly decreased with TPN administration, and this may contribute to the observed changes in IEL phenotype and function. The overlying aim of this proposal is to further understand how TPN-associated IEL changes affect alterations in epithelial physiology, and to understand the mechanisms which lead to these changes. The following aims are proposed: 1) Examine the mechanisms by which IEL-derived cytokines mediate the TPN-associated loss of epithelial barrier function, using Ussing chamber measurements. 2) Determine if the decline in EC-derived IL-7, with TPN, leads to IEL phenotype and functional changes. This will be approached by both the removal of IL-7, as well as the creation of IL-7 over-expressing mice. 3) Test the hypothesis that alterations in IEL-derived cytokine and KGF expression, with TPN administration, lead to changes in EC-derived IL-7. 4) Investigate the contributions of nutritional substrates and gut peptides in the development of TPN-associated changes in IEL phenotype and function. Factors will include glutamine, arginine, epidermal growth factor and gastrin-releasing peptide. These experiments will both advance understanding of IEL/EC interactions, as well as explain the observed findings of mucosal atrophy and epithelial barrier leak that occur during TPN. This may lead to methods to prevent such problems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI044076-06
Application #
6824498
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Rothermel, Annette L
Project Start
1999-07-01
Project End
2009-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$293,810
Indirect Cost
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
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Ralls, Matthew W; Demehri, Farokh R; Feng, Yongjia et al. (2016) Bacterial nutrient foraging in a mouse model of enteral nutrient deprivation: insight into the gut origin of sepsis. Am J Physiol Gastrointest Liver Physiol 311:G734-G743
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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
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
Demehri, Farokh R; Krug, Susanne M; Feng, Yongjia et al. (2016) Tight Junction Ultrastructure Alterations in a Mouse Model of Enteral Nutrient Deprivation. Dig Dis Sci 61:1524-33
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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

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