Parenteral nutrition (PN) dependence, while life sustaining, carries a significant risk of septic complications associated with epithelial barrier dysfunction and translocation of gut-derived microbiota. Increasing evidence suggests that PN-associated changes in the intestinal microbiota play a central role in the breakdown of the intestinal epithelial barrier. This review outlines the clinical and experimental evidence of epithelial barrier dysfunction with PN, the role of gut inflammatory dysregulation in driving this process, and the role of the intestinal microbiome in modulating inflammation in the gut and systemically. The article summarizes the most current work of our laboratory and others and describes many of the laboratory findings behind our current understanding of the PN enteral environment. Understanding the interaction between nutrient delivery, the intestinal microbiome, and PN-associated complications may lead to the development of novel therapies to enhance safety and quality of life for patients requiring PN.
MartindaleRGMcClaveSATaylorBLawsonCM.Perioperative nutrition: what is the current landscape?JPEN J Parenter Enteral Nutr. 2013;37(5 suppl):5S-20S.
2.
PeterJVMoranJLPhillips-HughesJ.A metaanalysis of treatment outcomes of early enteral versus early parenteral nutrition in hospitalized patients. Crit Care Med. 2005;33(1):213-220; discussion 260-261.
3.
MooreFAFelicianoDVAndrassyRJ. Early enteral feeding, compared with parenteral, reduces postoperative septic complications: the results of a meta-analysis. Ann Surg. 1992;216(2):172-183.
4.
BraunschweigCLLevyPSheeanPMWangX.Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr. 2001;74(4):534-542.
ZalogaGP.Parenteral nutrition in adult inpatients with functioning gastrointestinal tracts: assessment of outcomes. Lancet. 2006;367(9516):1101-1111.
7.
DoigGSHeighesPTSimpsonFSweetmanEADaviesAR.Early enteral nutrition, provided within 24 h of injury or intensive care unit admission, significantly reduces mortality in critically ill patients: a meta-analysis of randomised controlled trials. Intensive Care Med. 2009;35(12):2018-2027.
8.
DoigGSChevrou-SeveracHSimpsonF.Early enteral nutrition in critical illness: a full economic analysis using US costs. Clinicoecon Outcomes Res. 2013;5:429-436.
9.
McClaveSAMartindaleRGVanekVW. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2009;33(3):277-316.
10.
PfuntnerAWierLMStocksC.Most frequent procedures performed in U.S. hospitals, 2010: Statistical Brief #149. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville, MD: Agency for Healthcare Research & Quality; 2006.
11.
DoigGSSimpsonFSweetmanEA. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA. 2013;309(20):2130-2138.
12.
DoigGSSimpsonFEarlyPNTrial Investigators Group. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a full economic analysis of a multicenter randomized controlled trial based on US costs. Clinicoecon Outcomes Res. 2013;5:369-379.
13.
HarveySEParrottFHarrisonDA. Trial of the route of early nutritional support in critically ill adults. N Engl J Med. 2014;371(18):1673-1684.
14.
Perioperative total parenteral nutrition in surgical patients. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group. N Engl J Med. 1991;325(8):525-532.
15.
HeneghanAFPierreJFTandeeK. Parenteral nutrition decreases Paneth cell function and intestinal bactericidal activity while increasing susceptibility to bacterial enteroinvasion. JPEN J Parenter Enteral Nutr. 2014;38(7):817-824.
16.
BuzbyGP.Overview of randomized clinical trials of total parenteral nutrition for malnourished surgical patients. World J Surg. 1993;17(2):173-177.
17.
PeyretBCollardeauSTouzetS. Prevalence of liver complications in children receiving long-term parenteral nutrition. Eur J Clin Nutr. 2011;65(6):743-749.
18.
SquiresRHDugganCTeitelbaumDH. Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium. J Pediatr. 2012;161(4):723-728, e722.
19.
DemehriFRStephensLHerrmanE. Enteral autonomy in pediatric short bowel syndrome: predictive factors one year after diagnosis. J Pediatr Surg. 2015;50(1):131-135.
20.
BackhedFLeyRESonnenburgJLPetersonDAGordonJI.Host-bacterial mutualism in the human intestine. Science. 2005;307(5717):1915-1920.
21.
KoethRAWangZLevisonBS. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576-585.
FengYRallsMWXiaoWMiyasakaEHermanRSTeitelbaumDH.Loss of enteral nutrition in a mouse model results in intestinal epithelial barrier dysfunction. Ann N Y Acad Sci. 2012;1258:71-77.
24.
DeitchEA.Gut-origin sepsis: evolution of a concept. Surgeon. 2012;10(6):350-356.
25.
AlverdyJCAoysEMossGS.Total parenteral nutrition promotes bacterial translocation from the gut. Surgery. 1988;104(2):185-190.
26.
SakamotoKMoriYTakagiH. Translocation of Salmonella typhimurium in rats on total parenteral nutrition correlates with changes in intestinal morphology and mucus gel. Nutrition. 2004;20(4):372-376.
27.
NakasakiHMitomiTTajimaTOhnishiNFujiiK.Gut bacterial translocation during total parenteral nutrition in experimental rats and its countermeasure. Am J Surg. 1998;175(1):38-43.
28.
DemehriFRBarrettMRallsMWMiyasakaEAFengYTeitelbaumDH.Intestinal epithelial cell apoptosis and loss of barrier function in the setting of altered microbiota with enteral nutrient deprivation. Front Cell Infect Microbiol. 2013;3:105.
29.
RallsMWDemehriFRFengYWoods IgnatoskiKMTeitelbaumDH.Enteral nutrient deprivation in patients leads to a loss of intestinal epithelial barrier function. Surgery. 2015;157(4):732-742.
30.
CruzNLuQAlvarezXDeitchEA.Bacterial translocation is bacterial species dependent: results using the human Caco-2 intestinal cell line. J Trauma. 1994;36(5):612-616.
31.
DeitchEA.Bacterial translocation: the influence of dietary variables. Gut. 1994;35(1 suppl):S23-S27.
32.
YangHKiristiogluIFanY. Interferon-gamma expression by intraepithelial lymphocytes results in a loss of epithelial barrier function in a mouse model of total parenteral nutrition. Ann Surg. 2002;236(2):226-234.
33.
BischoffSCBarbaraGBuurmanW. Intestinal permeability—a new target for disease prevention and therapy. BMC Gastroenterol. 2014;14:189.
34.
MarchiandoAMShenLGrahamWV. The epithelial barrier is maintained by in vivo tight junction expansion during pathologic intestinal epithelial shedding. Gastroenterology. 2011;140(4):1208-1218, e1201-e1202.
ShroffKEMeslinKCebraJJ.Commensal enteric bacteria engender a self-limiting humoral mucosal immune response while permanently colonizing the gut. Infect Immun. 1995;63(10):3904-3913.
43.
UlluwishewaDAndersonRCMcNabbWCMoughanPJWellsJMRoyNC.Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr. 2011;141(5):769-776.
44.
EwaschukJBDiazHMeddingsL. Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am J Physiol Gastrointest Liver Physiol. 2008;295(5):G1025-G1034.
45.
LeslieJLHuangSOppJS. Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect Immun. 2015;83(1):138-145.
46.
PierreJFHeneghanAFTsaoFH. Route and type of nutrition and surgical stress influence secretory phospholipase A2 secretion of the murine small intestine. JPEN J Parenter Enteral Nutr. 2011;35(6):748-756.
47.
OmataJPierreJFHeneghanAF. Parenteral nutrition suppresses the bactericidal response of the small intestine. Surgery. 2013;153(1):17-24.
48.
ConourJEGanessunkerDTappendenKADonovanSMGaskinsHR.Acidomucin goblet cell expansion induced by parenteral nutrition in the small intestine of piglets. Am J Physiol Gastrointest Liver Physiol. 2002;283(5):G1185-G1196.
49.
SunXYangHNoseK. Decline in intestinal mucosal IL-10 expression and decreased intestinal barrier function in a mouse model of total parenteral nutrition. Am J Physiol Gastrointest Liver Physiol. 2008;294(1):G139-G147.
50.
FengYTeitelbaumDH.Tumour necrosis factor–induced loss of intestinal barrier function requires TNFR1 and TNFR2 signalling in a mouse model of total parenteral nutrition. J Physiol. 2013;591(pt 15):3709-3723.
51.
WildhaberBELynnKNYangHTeitelbaumDH.Total parenteral nutrition-induced apoptosis in mouse intestinal epithelium: regulation by the Bcl-2 protein family. Pediatr Surg Int. 2002;18(7):570-575.
52.
ClayburghDRShenLTurnerJR. A porous defense: the leaky epithelial barrier in intestinal disease. Lab Invest. 2004;84(3):282-291.
53.
YangHFinalyRTeitelbaumDH.Alteration in epithelial permeability and ion transport in a mouse model of total parenteral nutrition. Crit Care Med. 2003;31(4):1118-1125.
54.
WildhaberBEYangHSpencerAUDrongowskiRATeitelbaumDH.Lack of enteral nutrition—effects on the intestinal immune system. J Surg Res. 2005;123(1):8-16.
55.
MadaraJLStaffordJ.Interferon-gamma directly affects barrier function of cultured intestinal epithelial monolayers. J Clin Invest. 1989;83(2):724-727.
56.
YangHFanYTeitelbaumDH.Intraepithelial lymphocyte-derived interferon-gamma evokes enterocyte apoptosis with parenteral nutrition in mice. Am J Physiol Gastrointest Liver Physiol. 2003;284(4):G629-G637.
57.
FengYTeitelbaumDH.Epidermal growth factor/TNF-alpha transactivation modulates epithelial cell proliferation and apoptosis in a mouse model of parenteral nutrition. Am J Physiol Gastrointest Liver Physiol. 2012;302(2):G236-G249.
58.
MiyasakaEAFengYPoroykoV. Total parenteral nutrition-associated lamina propria inflammation in mice is mediated by a MyD88-dependent mechanism. J Immunol. 2013;190(12):6607-6615.
59.
BarnesPJKarinM.Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997;336(15):1066-1071.
60.
MadsenKLMalfairDGrayDDoyleJSJewellLDFedorakRN.Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. Inflamm Bowel Dis. 1999;5(4):262-270.
61.
BergDJZhangJWeinstockJV. Rapid development of colitis in NSAID-treated IL-10-deficient mice. Gastroenterology. 2002;123(5):1527-1542.
62.
FreemanJJFengYDemehriFRDempseyPJTeitelbaumDH.TPN-associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways. FASEB J. 2015;29(7):2943-2958.
63.
McElroySJFreyMRYanF. Tumor necrosis factor inhibits ligand-stimulated EGF receptor activation through a TNF receptor 1-dependent mechanism. Am J Physiol Gastrointest Liver Physiol. 2008;295(2):G285-G293.
64.
HodinCMVisschersRGRensenSS. Total parenteral nutrition induces a shift in the Firmicutes to Bacteroidetes ratio in association with Paneth cell activation in rats. J Nutr. 2012;142(12):2141-2147.
65.
HarveyRBAndrewsKDroleskeyRE. Qualitative and quantitative comparison of gut bacterial colonization in enterally and parenterally fed neonatal pigs. Curr Issues Intest Microbiol. 2006;7(2):61-64.
66.
BentleyDWNicholsRLCondonREGorbachSL.The microflora of the human ileum and intra-abdominal colon: results of direct needle aspiration at surgery and evaluation of the technique. J Lab Clin Med. 1972;79(3):421-429.
67.
MarteauPPochartPDoréJBéra-MailletCBernalierACorthierG.Comparative study of bacterial groups within the human cecal and fecal microbiota. Appl Environ Microbiol. 2001;67(10):4939-4942.
68.
ShigaHKajiuraTShinozakiJ. Changes of faecal microbiota in patients with Crohn’s disease treated with an elemental diet and total parenteral nutrition. Dig Liver Dis. 2012;44(9):736-742.
69.
Engstrand LiljaHWeferHNystromNFinkelYEngstrandL. Intestinal dysbiosis in children with short bowel syndrome is associated with impaired outcome. Microbiome. 2015;3:18.
70.
DavidLAMauriceCFCarmodyRN. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559-563.
71.
WuGDCompherCChenEZ. Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production [published online November 26, 2014]. Gut. doi:10.1136/gutjnl-2014-308209.
72.
WongJMEsfahaniASinghN. Gut microbiota, diet, and heart disease. J AOAC Int. 2012;95(1):24-30.
73.
SinclairJLAlexanderM.Role of resistance to starvation in bacterial survival in sewage and lake water. Appl Environ Microbiol. 1984;48(2):410-415.
74.
CostelloEKGordonJISecorSMKnightR.Postprandial remodeling of the gut microbiota in Burmese pythons. ISME J. 2010;4(11):1375-1385.
75.
DeplanckeBVidalOGanessunkerDDonovanSMMackieRIGaskinsHR.Selective growth of mucolytic bacteria including Clostridium perfringens in a neonatal piglet model of total parenteral nutrition. Am J Clin Nutr. 2002;76(5):1117-1125.
76.
NovakNBieberT. 2. Dendritic cells as regulators of immunity and tolerance. J Allergy Clin Immunol. 2008;121(2 suppl):S370-S374; quiz S413.
77.
ChichlowskiMHaleLP.Bacterial-mucosal interactions in inflammatory bowel disease: an alliance gone bad. Am J Physiol Gastrointest Liver Physiol. 2008;295(6):G1139-G1149.
78.
AbreuMT.Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nature Rev Immunol. 2010;10(2):131-144.
79.
KarraschTJobinC.NF-kappaB and the intestine: friend or foe?Inflamm Bowel Dis. 2008;14(1):114-124.
80.
LacailleFGupteGColombV. Intestinal failure-associated liver disease: a position paper of the ESPGHAN Working Group of Intestinal Failure and Intestinal Transplantation. J Pediatr Gastroenterol Nutr. 2015;60(2):272-283.
81.
MutanenALohiJHeikkilaPKoivusaloAIRintalaRJPakarinenMP.Persistent abnormal liver fibrosis after weaning off parenteral nutrition in pediatric intestinal failure. Hepatology. 2013;58(2):729-738.
82.
El KasmiKCAndersonALDevereauxMW. Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury. Hepatology. 2012;55(5):1518-1528.
83.
HarrisJKEl KasmiKCAndersonAL. Specific microbiome changes in a mouse model of parenteral nutrition associated liver injury and intestinal inflammation. PloS One. 2014;9(10):e110396.
84.
KorpelaKMutanenASalonenASavilahtiEde VosWMPakarinenMP. Intestinal microbiota signatures associated with histological liver steatosis in pediatric-onset intestinal failure [published online May 1, 2015]. JPEN J Parenter Enteral Nutr. pii:0148607115584388.
85.
KubotaAOkadaAImuraK. The effect of metronidazole on TPN-associated liver dysfunction in neonates. J Pediatr Surg. 1990;25(6):618-621.
86.
KellyDA.Intestinal failure-associated liver disease: what do we know today?Gastroenterology. 2006;130(2 suppl 1):S70-S77.
87.
RenZGLiuHJiangJW. Protective effect of probiotics on intestinal barrier function in malnourished rats after liver transplantation. Hepatobiliary Pancreat Dis Int. 2011;10(5):489-496.
88.
SegawaSWakitaYHirataHWatariJ.Oral administration of heat-killed Lactobacillus brevis SBC8803 ameliorates alcoholic liver disease in ethanol-containing diet-fed C57BL/6N mice. Int J Food Microbiol. 2008;128(2):371-377.
89.
VanderhoofJAYoungRJMurrayNKaufmanSS.Treatment strategies for small bowel bacterial overgrowth in short bowel syndrome. J Pediatr Gastroenterol Nutr. 1998;27(2):155-160.
90.
KanamoriYSugiyamaMHashizumeKYukiNMorotomiMTanakaR.Experience of long-term synbiotic therapy in seven short bowel patients with refractory enterocolitis. J Pediatr Surg. 2004;39(11):1686-1692.
