Parenteral Nutrition, Critical Illness, Paneth Cell Function and the Innate Immune Response

  • Xinying Wang
  • Joseph F. Pierre
  • Kenneth A. Kudsk
Reference work entry


Parenteral nutrition, an important mode of nutrition support in patients who have loss absorptive and digestive ability of the intestine, is associated with an increased susceptibility to infection compared to enteral nutrition. One probable cause of this increased infectious risk is impaired acquired and innate mucosal immunity of the gastrointestinal and respiratory tract associated with lack of enteral stimulation. Innate immunity is a teleologically ancient defense system which includes Paneth cells and goblet cells that function as specialized secreting epithelial cells. Each plays critical roles in innate immune function of the gut. Paneth cells contain dense granules abundant in antibiotic proteins and peptides as well as proinflammatory mediators. These biological molecules not only protect the host from enteric pathogens but also affect the composition of the colonizing microbiota. The goblet cells produce a mucin layer that coats the mucosa and concentrates the biologic molecules. Experimentally, lack of enteral stimulation significantly impairs innate mucosal immune function by diminishing Paneth cell antimicrobial proteins (secretory phospholipase A2, lysozyme, and cryptdin 4), reducing goblet cell p-products (mucin2, trefoil peptides, and resistin-like molecule β), shifting the microbiome composition, and decreasing the bactericidal activity of intestinal secretions. Taken in total, these changes impair the antibacterial defenses protecting the mucosa against invasion. This review examines the experimental changes in innate immunity and Paneth cell function that occurs during parenteral nutrition without enteral stimulation.


Parenteral Nutrition Goblet Cell Enteral Nutrition Paneth Cell Mucosal Immunity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

List of Abbreviations


Antimicrobial peptides




Colony-forming units


Complex enteral diet


Enteral nutrition


Fc-γ-binding protein


Gut-associated lymphoid tissue


Intensive care unit


Mucosal addressin cellular adhesion molecule-1


Nucleotide oligomerization domain 2


Parenteral nutrition


Pathogen-associated molecular patterns


Polymeric immunoglobulin receptor


Resistin-like molecule β


Secretory immunoglobulin-A


Secretory phospholipase A2


Toll-like receptors


Trefoil peptides


  1. Abreu MT. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol. 2010;10:131–44. doi:10.1038/nri2707.CrossRefPubMedGoogle Scholar
  2. Ayabe T, Satchell DP, Wilson CL, et al. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol. 2000;1:113–8. doi:10.1038/77783.CrossRefPubMedGoogle Scholar
  3. Bevins CL, Salzman NH. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat Rev Microbiol. 2011;9:356–68. doi:10.1038/nrmicro2546.CrossRefPubMedGoogle Scholar
  4. Braunschweig CL, Levy P, Sheean PM, et al. Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr. 2001;74:534–42.PubMedGoogle Scholar
  5. Cheng H, Leblond CP. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am J Anat. 1974;141:537–61. doi:10.1002/aja.1001410407.CrossRefPubMedGoogle Scholar
  6. Coutinho HB, da Mota HC, Coutinho VB, et al. Absence of lysozyme (muramidase) in the intestinal Paneth cells of newborn infants with necrotising enterocolitis. J Clin Pathol. 1998;51:512–4.CrossRefPubMedPubMedCentralGoogle Scholar
  7. DeWitt RC, Wu Y, Renegar KB, et al. Glutamine-enriched total parenteral nutrition preserves respiratory immunity and improves survival to a Pseudomonas pneumonia. J Surg Res. 1999;84:13–8. doi:10.1006/jsre.1999.5592.CrossRefPubMedGoogle Scholar
  8. DeWitt R, Wu Y, Renegar K, et al. Bombesin recovers gut-associated lymphoid tissue and preserves immunity to bacterial pneumonia in mice receiving total parenteral nutrition. Ann Surg. 2000;231:1–8.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Fre S, Huyghe M, Mourikis P, et al. Notch signals control the fate of immature progenitor cells in the intestine. Nature. 2005;435:964–8. doi:10.1038/nature03589.CrossRefPubMedGoogle Scholar
  10. Ganz T. Defensins: antimicrobial peptides of vertebrates. C R Biol. 2004;327:539–49.CrossRefPubMedGoogle Scholar
  11. Ganz T, Selsted ME, Szklarek D, et al. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985;76:1427–35. doi:10.1172/JCI112120.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Genton L, Kudsk KA. Interactions between the enteric nervous system and the immune system: role of neuropeptides and nutrition. Am J Surg. 2003;186:253–8.CrossRefPubMedGoogle Scholar
  13. Gramlich L, Kichian K, Pinilla J, et al. Does enteral nutrition compared to parenteral nutrition result in better outcomes in critically ill adult patients? A systematic review of the literature. Nutrition. 2004;20:843–8. doi:10.1016/j.nut.2004.06.003.CrossRefPubMedGoogle Scholar
  14. Hadfield JI. Preoperative and postoperative intravenous fat therapy. Br J Surg. 1965;52:291–8.CrossRefPubMedGoogle Scholar
  15. Harwig SS, Tan L, Qu XD, et al. Bactericidal properties of murine intestinal phospholipase A2. J Clin Invest. 1995;95:603–10. doi:10.1172/JCI117704.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Heneghan AF, Pierre JF, Gosain A, et al. IL-25 Improves luminal innate immunity and barrier function during parenteral nutrition. Ann Surg. 2013. doi:10.1097/SLA.0b013e318284f510.PubMedCentralGoogle Scholar
  17. Hermsen JL, Gomez FE, Sano Y, et al. Parenteral feeding depletes pulmonary lymphocyte populations. J Parenter Enter Nutr. 2009;33:535–40. doi:10.1177/0148607109332909.CrossRefGoogle Scholar
  18. Hodin CM, Lenaerts K, Grootjans J, et al. Starvation compromises Paneth cells. Am J Pathol. 2011;179:2885–93. doi:10.1016/j.ajpath.2011.08.030.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Janu P, Li J, Renegar K, et al. Recovery of gut-associated lymphoid tissue and upper respiratory tract immunity after parenteral nutrition. Ann Surg. 1997;225:707–15. discussion 715-7.CrossRefPubMedPubMedCentralGoogle Scholar
  20. King BK, Li J, Kudsk KA. A temporal study of TPN-induced changes in gut-associated lymphoid tissue and mucosal immunity. Arch Surg. 1997;132:1303–9.CrossRefPubMedGoogle Scholar
  21. King BK, Kudsk KA, Li J, et al. Route and type of nutrition influence mucosal immunity to bacterial pneumonia. Ann Surg. 1999;229:272–8.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kobayashi KS, Chamaillard M, Ogura Y, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307:731–4. doi:10.1126/science.1104911.CrossRefPubMedGoogle Scholar
  23. Krimi RB, Kotelevets L, Dubuquoy L, et al. Resistin-like molecule beta regulates intestinal mucous secretion and curtails TNBS-induced colitis in mice. Inflamm Bowel Dis. 2008;14:931–41. doi:10.1002/ibd.20420.CrossRefPubMedGoogle Scholar
  24. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding. Effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg. 1992;215:503–11. discussion 511-3.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Kudsk KA, Li J, Renegar KB. Loss of upper respiratory tract immunity with parenteral feeding. Ann Surg. 1996;223:629–35. discussion 635-8.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kudsk KA, Wu Y, Fukatsu K, et al. Glutamine-enriched total parenteral nutrition maintains intestinal interleukin-4 and mucosal immunoglobulin A levels. J Parenter Enter Nutr. 2000;24:270–4. discussion 274-5.CrossRefGoogle Scholar
  27. Lehrer RI, Barton A, Daher KA, et al. Interaction of human defensins with Escherichia coli. Mechanism of bactericidal activity. J Clin Invest. 1989;84:553–61. doi:10.1172/JCI114198.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Li J, Kudsk KA, Gocinski B, et al. Effects of parenteral and enteral nutrition on gut-associated lymphoid tissue. J Trauma. 1995;39:44–51. discussion 51-2.CrossRefPubMedGoogle Scholar
  29. Li J, King BK, Janu PG, et al. Glycyl-l-glutamine-enriched total parenteral nutrition maintains small intestine gut-associated lymphoid tissue and upper respiratory tract immunity. J Parenter Enter Nutr. 1998;22:31–6.CrossRefGoogle Scholar
  30. Mazaki T, Ebisawa K. Enteral versus parenteral nutrition after gastrointestinal surgery: a systematic review and meta-analysis of randomized controlled trials in the English literature. J Gastrointest Surg. 2008;12:739–55. doi:10.1007/s11605-007-0362-1.CrossRefPubMedGoogle Scholar
  31. Moore FA, Moore EE, Haenel JB, et al. Post-traumatic pulmonary pseudocyst in the adult: pathophysiology, recognition, and selective management. J Trauma. 1989;29:1380–5.CrossRefPubMedGoogle Scholar
  32. Nevalainen TJ, Grönroos JM, Kallajoki M. Expression of group II phospholipase A2 in the human gastrointestinal tract. Lab Invest. 1995;72:201–8.PubMedGoogle Scholar
  33. Omata J, Pierre JF, Heneghan AF, et al. Parenteral nutrition suppresses the bactericidal response of the small intestine. Surgery. 2012. doi:10.1016/j.surg.2012.04.001. S0039-6060(12)00167-5 [pii].PubMedPubMedCentralGoogle Scholar
  34. Ouellette AJ. Paneth cells and innate immunity in the crypt microenvironment. Gastroenterology. 1997;113:1779–84.CrossRefPubMedGoogle Scholar
  35. Pierre JF, Heneghan AF, Tsao FH, et al. Route and type of nutrition and surgical stress influence secretory phospholipase A2 secretion of the murine small intestine. J Parenter Enter Nutr. 2011;35:748–56. doi:10.1177/0148607111414025.CrossRefGoogle Scholar
  36. Porter EM, Bevins CL, Ghosh D, et al. The multifaceted Paneth cell. Cell Mol Life Sci. 2002;59:156–70.CrossRefPubMedGoogle Scholar
  37. Qu XD, Lloyd KC, Walsh JH, et al. Secretion of type II phospholipase A2 and cryptdin by rat small intestinal Paneth cells. Infect Immun. 1996;64:5161–5.PubMedPubMedCentralGoogle Scholar
  38. Reese SR, Kudsk KA, Genton L, et al. l-selectin and alpha4beta7 integrin, but not ICAM-1, regulate lymphocyte distribution in gut-associated lymphoid tissue of mice. Surgery. 2005;137:209–15. doi:10.1016/j.surg.2004.08.003.CrossRefPubMedGoogle Scholar
  39. Santaolalla R, Fukata M, Abreu MT. Innate immunity in the small intestine. Curr Opin Gastroenterol. 2011;27:125–31. doi:10.1097/MOG.0b013e3283438dea.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459:262–5. doi:10.1038/nature07935.CrossRefPubMedGoogle Scholar
  41. Schmitt P, Wilmes M, Pugnière M, et al. Insight into invertebrate defensin mechanism of action: oyster defensins inhibit peptidoglycan biosynthesis by binding to lipid II. J Biol Chem. 2010;285:29208–16.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Selsted ME, Ouellette AJ. Mammalian defensins in the antimicrobial immune response. Nat Immunol. 2005;6:551–7. doi:10.1074/jbc.M110.143388.CrossRefPubMedGoogle Scholar
  43. Stappenbeck TS. Paneth cell development, differentiation, and function: new molecular cues. Gastroenterology. 2009;137:30–3. doi:10.1038/ni1206.CrossRefPubMedGoogle Scholar
  44. Taupin D, Podolsky DK. Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol. 2003;4:721–32. doi:10.1038/nrm1203.CrossRefPubMedGoogle Scholar
  45. Thim L. Trefoil peptides: from structure to function. Cell Mol Life Sci. 1997;53:888–903.CrossRefPubMedGoogle Scholar
  46. Van Klinken BJ, Tytgat KM, Büller HA, et al. Biosynthesis of intestinal mucins: MUC1, MUC2, MUC3 and more. Biochem Soc Trans. 1995a;23:814–8.CrossRefPubMedGoogle Scholar
  47. Van Klinken BJ, Dekker J, Büller HA, et al. Mucin gene structure and expression: protection vs. adhesion. Am J Physiol. 1995b;269:G613–27.PubMedGoogle Scholar
  48. Weiss J, Inada M, Elsbach P, et al. Structural determinants of the action against Escherichia coli of a human inflammatory fluid phospholipase A2 in concert with polymorphonuclear leukocytes. J Biol Chem. 1994;269:26331–7.PubMedGoogle Scholar
  49. Wilmore DW, Dudrick SJ. Growth and development of an infant receiving all nutrients exclusively by vein. JAMA. 1968;203:860–4.CrossRefPubMedGoogle Scholar
  50. Wu Y, Kudsk KA, DeWitt RC, et al. Route and type of nutrition influence IgA-mediating intestinal cytokines. Ann Surg. 1999;229:662–7. discussion 667-8.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Xinying Wang
    • 1
  • Joseph F. Pierre
    • 2
  • Kenneth A. Kudsk
    • 2
  1. 1.Department of SurgerySchool of Medicine, Jinling Hospital, Nanjing UniversityNanjingChina
  2. 2.Department of SurgeryG5/341 Clinical Sciences Center, University of Wisconsin- MadisonMadisonUSA

Personalised recommendations