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Journal of Parenteral and Enteral Nutrition
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Intestinal Polymeric Immunoglobulin Receptor Is Affected by Type and Route of Nutrition

Yoshifumi Sano, MD{ddagger}, F. Enrique Gomez, PhD{ddagger}, Woodae Kang, MD, PhD{ddagger}, Jinggang Lan, PhD{ddagger}, Yoshinori Maeshima, MD{ddagger}, Joshua L. Hermsen, MD{ddagger}, Chikara Ueno, MD{ddagger} and Kenneth A. Kudsk, MD*,{dagger}

From the * Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin; and the {dagger} Department of Surgery, University of Wisconsin–Madison School of Medicine and Public Health, Madison, Wisconsin

Correspondence: Kenneth A. Kudsk, MD, 600 Highland Ave, H4/736 CSC, Madison, WI 53792-7375. Electronic mail may be sent to kudsk{at}surgery.wisc.edu.

Background: Secretory immunoglobulin A (SIgA) prevents adherence of pathogens at mucosal surfaces to prevent invasive infection. Polymeric immunoglobulin receptor (pIgR) is located on the basolateral surface of epithelial cells and binds dimeric immunoglobulin A (IgA) produced by plasma cells in the lamina propria. This IgA-pIgR complex is transported apically, where IgA is exocytosed as SIgA to the mucosal surface. Our prior work shows that mice fed intragastric (IG, an elemental diet model) and IV parenteral nutrition (PN) solution have reduced intestinal T and B cells, SIgA, and interleukin-4 (IL-4) compared with mice fed chow or a complex enteral diet (CED). Prior work also demonstrates a reduction in IgA transport to mucosal surfaces in IV PN–fed mice. Because IL-4 up-regulates pIgR production, this work studies the effects of these diets on intestinal pIgR. Methods: Male Institute of Cancer Research (ICR) mice were randomized to chow (n = 11) with IV catheter, CED (n = 10) or IG PN (n = 11) via gastrostomy and IV PN (n = 12) for 5 days. CED and PN were isocaloric and isonitrogenous. Small intestine was harvested for pIgR and IL-4 assays after mucosal washing for IgA. IgA and IL-4 levels were analyzed by enzyme-linked immunosorbent assay and pIgR by Western blot. Results: Small intestinal pIgR expression, IgA levels, and IL-4 levels decreased significantly in IV PN and IG PN groups. Conclusions: Lack of enteral stimulation affects multiple mechanisms responsible for decreased intestinal SIgA levels, including reduced T and B cells in the lamina propria, reduced Th-2 IgA-stimulating cytokines, and impaired expression of the IgA transport protein, pIgR.

Parenteral nutrition (PN) compared with enteral feeding increases infectious morbidity in severely injured patients.1–4 Increasing evidence suggests that lack of enteral stimulation when PN is administered to avoid malnutrition induces a mucosal immune deficiency, which is largely responsible for this difference in clinical outcome. The common mucosal immune hypothesis links intestinal and extraintestinal mucosal sites together to provide protection from potential pathogens at all mucosal surfaces.

Mucosal-associated lymphoid tissue (MALT) provides the immunologic infrastructure to maintain this system and collectively constitutes one of the largest and most active secondary immune organs. More than 80% of all immunoglobulin-secreting cells are localized in the murine small intestine, and >70% of these cells secrete immunoglobulin A (IgA).5,6 The process of generating mucosal immunity begins as naïve lymphocytes are activated by exposure to antigen in Peyer's patches within the gut-associated lymphoid tissue (GALT). Further maturation and development of memory ensues as the cells migrate to the systemic circulation via lymph nodes and the thoracic duct.7 Mature cells home to the lamina propria underlying mucosal surfaces to produce immunoglobulin (predominantly IgA), which is transported by polymeric immunoglobulin receptor (pIgR) to the mucosal surfaces. Mucosal surfaces are linked via this system as exposure to antigen at one mucosal surface provides specific immunity to that antigen at other mucosal sites.8–10Our previous work demonstrates a PN-induced mucosal immune impairment in an animal model, resulting in reduced IgA levels at intestinal and respiratory mucosal surfaces, as well as changes in GALT phenotype. Specifically, we have described reductions in lamina propria and Peyer's patch lymphocyte mass,11 intestinal Th-2 type cytokines (interleukin [IL]-4 and IL-10),12 and Peyer's patch expression of mucosal addressin cellular adhesion molecule-1 (MAdCAM-1), a molecule critical in attracting naïve T and B cells into the MALT.13,14 This work investigates the effect of route and type of nutrition on pIgR, the molecule that transports IgA to the mucosal surface after production by plasma cells to provide antibody-mediated mucosal immunity.


   MATERIALS AND METHODS
Top
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 
Animals
All protocols were approved by the Animal Care and Use Committee of the University of Wisconsin–Madison and the Middleton Veterans Administration Hospital, Madison. Male Institute of Cancer Research (ICR) mice were purchased from Harlan (Indianapolis, IN) and housed in an American Association for Accreditation of Laboratory Animal Care–accredited conventional facility. Mice were housed in an environment controlled for temperature, humidity, and light (12-hour light:dark). Five mice were housed per covered/filtered box and fed ad libitum chow (LabDiet; PMI Nutrition International, St. Louis, MO) and water for 1 week before initiation of study protocol. After entry into study protocol, mice were individually housed in metal cages with wire grid floors to prevent coprophagia.

Experimental Protocol
Forty-four 6- to 8-week-old mice were randomized to diet groups (chow, n = 11; complex enteral diet [CED], n = 10; intragastric [IG] PN, n = 11; IV PN, n = 12), anesthetized, and cannulated via the external jugular vein (chow and IV PN, 0.012-in ID/0.25-in OD; Helix Medical, Inc, Carpinteria, CA) or a posterior gastrostomy (CED and IG PN, 0.02-in ID/0.037-in OD; Helix Medical, Inc). Catheters were tunneled subcutaneously over the back and exited midtail. Mice were immobilized by the tail, which has been shown not to induce significant physical or biochemical stress.15

After catheterization, mice were connected to infusion pumps and recovered for 48 hours while receiving 4 mL of 0.9% saline/d, as well as chow and water ad libitum. After the recovery period, the different diets were initiated. Chow-fed animals received 0.9% saline at 4 mL/d, as well as chow and water ad libitum throughout the study. CED animals received 5 mL/d of Nutren (Nestlé, Chicago, IL) for the first day, with increases to 7 mL/d (day 2) and then to 13 mL/d (days 3–5). Nutren contains 12.7% carbohydrate, 3.8% fat, and 4.0% protein (4186 kJ/L), along with electrolytes and vitamins. The nonprotein calorie/nitrogen ratio of the CED is 549.4 kJ/g of nitrogen. PN-fed (IV and IG) mice received solution at 4 mL/d (day 1), 7 mL/d (day 2) and 10 mL/d (days 3–5). The PN solution contains 6.0% amino acids, 34.9% dextrose (6002 kJ/L), electrolytes, and multivitamins, with a non-protein calorie/nitrogen ratio of 535.8 kJ/g nitrogen. The PN and CED feedings control for equal nutrition intake but not equal volume. These feedings meet the calculated nutrient requirements of mice weighing 25–30 g.

After 5 days of feeding, mice were anesthetized and exsanguinated by cardiac puncture. The small intestine was removed by dissection from mesenteric fat, lymph nodes, and vasculature. Twenty milliliters of Hanks' balanced salt solution (HBSS; Bio Whittaker, Walkersville, MD) was irrigated through the intestinal lumen to obtain intestinal washing specimens.

IgA Antibody Quantitative Analysis
Total IgA in the small intestinal washing specimens was measured using a sandwich enzyme-linked immunosorbent assay (ELISA). Briefly, 96-well plates (BD Biosciences, Bedford, MA) were coated with 50 µL of a 10 µg/mL goat antimouse IgA, {alpha}-chain specific (Sigma-Aldrich, St. Louis, MO) in 0.1 mol/L coating buffer (0.1-M carbonate-bicarbonate, pH 9.6) and incubated overnight at 4°C. Plates were washed 3 times and blocked with 100 µL of 1% bovine serum albumin in Tris-buffered saline with 0.5% Tween-20 solution for 1 hour at room temperature. One hundred microliters of intestinal washing (diluted 1:100) or IgA standards (seven 2-fold dilutions, from 1000 to 7.8 ng/mL, Sigma-Aldrich) were added, and plates were incubated for 1 hour at room temperature. Plates were again washed 3 times, and 100 µL of a 1:500 dilution of the secondary antibody, goat antimouse IgA, {alpha}-chain specific-HRP conjugate (Sigma-Aldrich) was added and incubated for 1 hour at room temperature. Plates were again washed 3 times, and 100 µL of the substrate solution (H2O2 and o-phenylenediamine) was added and incubated for 12 minutes at room temperature. The reaction was stopped by the addition of 50 µL of 2-N H2SO4 and the absorbance read at 490 nm in a Vmax Kinetic Microplate Reader (Molecular Devices, Sunnyvale, CA). Mass amounts of IgA in the samples were calculated by plotting their absorbance values on the IgA standard curve, which was calculated using a 4-parameter logistic fit with SOFTmax PRO software (Molecular Devices).

IL-4 Immunoassays
Small intestinal tissues were homogenized in RIPA lysis buffer (Upstate, Lake Placid, NY) containing 1% of a protease inhibitor cocktail (Sigma-Aldrich). The homogenates were incubated 30 minutes on ice and centrifuged at 16,000 x g for 10 minutes at 4°C, and the supernatants were stored at –20°C until assayed. Protein concentration of each preparation was determined by the Coomassie dye-binding method using bovine serum albumin as standard. The amount of IL-4 in the supernatant was measured using a BD OptEIA ELISA (BD Biosciences Pharmingen, San Diego, CA). Briefly, 96-well plates were coated with capture antibody and incubated overnight at 4°C in a humid chamber. After 3 washes and inhibition of nonspecific binding with Assay Diluent (BD Biosciences Pharmingen), prediluted IL-4 standard and experimental samples were added to the plate and incubated for 2 hours at room temperature. Plates were then washed 5 times, and working detector (detection antibody + streptavidin–horseradish peroxidase conjugate) was added to the plate and incubated for 1 hour at room temperature. Color was developed with the substrate reagent set (tetramethyl benzidine plus H2O2; BD Biosciences) for 30 minutes and stopped with 2-N H2SO4. Absorbance was read at 450 nm. Mass values of IL-4 were determined from plotting the absorbances on the standard curve and expressed as pg/mg protein.

Western Blot for pIgR Expression
Solubilized protein obtained from the small intestine was denatured at 95°C for 10 minutes with sodium dodecylsulfate and β-mercaptoethanol, and 15 µg of protein was separated in a denaturing 10% polyacrylamide gel by electrophoresis at 150 V for 1 hour at room temperature. The proteins were transferred to a polyvinylidene fluoride membrane using a Tris-glycine buffer plus 20% methanol at 80 V for 50 minutes at 4°C. The membrane was blocked with 5% nonfat dry milk prepared in TBS-Tween for 1 hour at room temperature with constant agitation. Membranes were incubated with the primary antibody, rabbit antimouse secretory component (SC) IgG diluted 1:20,000 for 3 hours at room temperature with constant agitation. Membranes were washed and incubated with stabilized goat antirabbit-IgG HRP conjugate (Pierce Biotechnology, Rockford, IL) diluted 1:5000 for 1.5 hours at room temperature with agitation. After the last wash, the membrane was incubated for 5 minutes with the substrate for HRP (Super Signal West Femto maximum sensitivity substrate; Pierce) and bands were detected using photographic film. Densitometric measurements of protein bands were analyzed and quantified with the National Institutes of Health (NIH) Image J software. The combined value of the ~120-kDa and ~94-kDa bands was determined for the quantitation of the pIgR protein expression in each case.16–18 pIgR values are expressed as a percentage of the chow case with the strongest band (100%) on each gel.

Statistical Analysis
All values (including pIgR percentages) are expressed as mean ± SE. Statistical analysis was performed by ANOVA, followed by the Fisher's protected least significant difference post hoc test. Pearson's correlation coefficients were estimated to quantify relationships between pIgR expression, IgA levels, and IL-4 levels.


   RESULTS
Top
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 
There were no significant differences in initial body weights between groups. CED, IG PN, and IV PN mice lost significantly more weight during the feeding than chow mice (Table I). Prior work shows that chow-fed mice typically have 1.5 g of residual feces, whereas the gastrointestinal tracts of IG PN and IV PN mice are empty. CED results in <0.5 g of feces.


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  		Table I Mice body weight and weight gain

 

IV PN significantly decreased small intestinal IgA levels (91.9 ± 6.9 µg) compared with both chow (206 ± 28.7 µg; p < .05) and CED (162.4 ± 19.6 µg; p < .05). IG PN mice had significantly lower small intestinal IgA than chow mice (134.6 ± 19.8 µg vs 206 ± 28.7 µg; p < .05; Figure 1). IV PN significantly decreased intestinal IL-4 levels compared with chow and CED groups, whereas IG PN IL-4 was significantly decreased compared with chow feeding (Figure 2).


Figure 1
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  		FIGURE 1. Small intestinal IgA levels. IV PN (parenteral nutrition) and intragastric (IG) PN mice significantly decreased IgA levels compared with chow mice. IV PN mice significantly decreased compared with a complex enteral diet (CED) also. Values are mean ± SE. *p < .05 vs chow; {dagger}p < .05 vs CED.

 

Figure 2
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  		FIGURE 2. Small intestinal IL-4 levels. IV PN (parenteral nutrition) and intragastric (IG) PN mice significantly dropped IL-4 levels compared with chow mice. IV PN mice also significantly dropped compared with complex enteral diet (CED). Values are mean ± SE. *p < .05 vs chow; {dagger}p < .05 vs CED.

 
The Western blot from the small intestine samples detected bands at ~120 kDa and ~94 kDa, representing the pIgR and the SC, respectively. Intestinal expression of pIgR was significantly reduced in both IG PN and IV PN groups compared with both chow and CED (Figure 3).


Figure 3
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  		FIGURE 3. Small intestinal polymeric immunoglobulin receptor (pIgR) expression. Western blot detected bands at ~120 (pIgR) and ~94 (secretory component) kDa. pIgR expression (measured by combining bands) significantly dropped in IV PN (parenteral nutrition) and intragastric (IG) PN. Values are mean ± SE. *p < .05 vs chow; {dagger}p < .05 vs CED.

 

All groups were combined and correlation analysis was performed to discern relationships between IgA and IL-4 with pIgR. There were significant correlations between pIgR and IgA and between IL-4 and pIgR (Figures 4 and 5).


Figure 4
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  		FIGURE 4. Correlation of intestinal polymeric immunoglobulin receptor (pIgR) expression and IgA levels in the small intestine. There was a significant correlation between pIgR expression and IgA levels.

 

Figure 5
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  		FIGURE 5. Correlation of intestinal IL-4 levels and polymeric immunoglobulin receptor (pIgR) expression in the small intestine. There was a significant correlation between IL-4 levels and pIgR expression.

 

   DISCUSSION
Top
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 
There are significant amounts of clinical and experimental evidence showing that enteral feeding significantly affects resistance to infections compared with parenteral feeding. In studies of severely injured trauma patients, the patient group randomized to enteral feeding sustained significantly fewer cases of pneumonia and intra-abdominal abscesses than a comparably injured group fed parenterally.1–4 Experimentally, our work and the work of others show that route and type of nutrition influence established mucosal immunologic defenses,19,20 intraperitoneal cytokine and immunologic responses,21 and systemic inflammatory responses to injury.22–24

In our mouse model, we have found that route and type of nutrition significantly alter MALT and GALT, with direct effects on the main antigen-specific mucosal immune defense, IgA. The effects are influenced by the degree of enteral stimulation. Our work consistently shows that chow feeding maintains normal mucosal defenses. A CED consisting of complex proteins, carbohydrates, and fat almost completely maintains these defenses as well. PN with no enteral stimulation is associated with significantly reduced intestinal and respiratory defenses by decreasing levels of molecules responsible for directing T and B cells into and through the mucosal immune network, resulting in impaired mucosal immune function and integrity.13,14 Administration of this parenteral formula intragastrically, an elemental diet of sorts, produces alterations midway between the complex diet and parenteral feeding. Thus, route, complexity, and possibly intermittency of feeding (because chow feeding is intermittent rather that continuous as in all other groups25) seem to be important variables that affect mucosal defenses. The present work confirms that these same variables affect pIgR, an integral component of mucosal immunity that facilitates the final transport of IgA to mucosal surfaces.

pIgR is a 7-domain (5 extracellular, 1 transmembrane, and 1 cytoplasmic) transmembrane protein found on nonapical epithelial cell surfaces.26,27 It binds dimeric IgA after production by plasma cells in the underlying lamina propria.

Endocytosis and transcellular transport occur after formation of a pIgR-IgA complex. On reaching the apical cell surface, cleavage of pIgR between its extracellular and transmembrane domains releases the complex as SIgA. Structurally, this molecule consists of dimeric IgA plus the cleaved extracellular portion of pIgR, known as SC, so that SIgA equals dimeric IgA + SC. pIgR makes this transcellular voyage constitutively even when no IgA is present, and, as a result, some free SC is detectable at mucosal surfaces, accounting for the ~94-kDa band seen on the Western blots.

Just as our previous work has showed with other molecules involved in mucosal immunity, pIgR levels are maximally expressed with chow feeding and proportionately decrease as the amount of enteral stimulation decreases (chow > CED > IG PN > IV PN). We also reconfirmed our previous observations that IL-4, a Th type 2 cytokine, also decreases with decreased enteral stimulation.12 IL-4 promotes growth and differentiation of IgA-producing cells and is a stimulus for pIgR expression.28–31

Intact mucosal immunity consists of 5 basic components: migration, sensitization, distribution, IgA switching and production, and IgA transport. Migration is dictated by the presence of {alpha}4β7 on the surfaces of T and B cells destined for mucosal immunity and several adhesion molecules distributed throughout the mucosal immune system, which guide cells into and through MALT for ultimate localization to effector sites within the lamina propria. One of the first molecules involved in attraction of {alpha}4β +7/L-selectin+ naïve B and T cells is MAdCAM-1, located on the high endothelial venules of the Peyer's patches.32–34 Initial attachment between L-selectin and MAdCAM-1 results in attraction of the cells into the Peyer's patches, where they are sensitized to antigens processed by resident dendritic cells and others.8

Our work showed that the expression of MAdCAM-1 is directly proportional to the amount of enteral stimulation and that within hours of instituting PN, levels of MAdCAM-1 drop dramatically.13,14 The overall effect is reduced entry of T and B cells into the mucosal immune system. This results in decreased Peyer's patches, lamina propria, and intraepithelial lymphocytes in proportion to the degree of enteral stimulation.11 Because of altered T-cell populations, IL-4 levels also drop in proportion to the degree of enteral stimulation.12 IL-4 plays several roles, including stimulation for MAdCAM-1 production in Peyer's patches,35 IgA production by plasma cells,28,29 and with this work, production of the primary IgA transport protein, pIgR.

Functionally, impairment of established antiviral and antibacterial defenses is also proportional to the degree of enteral stimulation.19,20 Parenteral feeding results in complete loss of established antiviral and antibacterial immune defenses, with gradual improvement from PN to IG PN to CED to chow. Previous experiments indicated this might be due in part to decreased transport of IgA to mucosal surfaces, and present work implicates diminished levels of pIgR in this phenomenon.36

Our overriding hypothesis is that lack of enteral stimulation with PN administered to avoid malnutrition induces a mucosal immune deficiency, which explains the difference in clinical outcome between enterally and parenterally fed trauma patients. Our work is limited by the fact that this work is performed in mice and not humans, for obvious reasons. However, there are points at which human markers of mucosal immunity are accessible for measurement such as the respiratory tract. This experimental work provides a context and framework in which to design relevant clinical experiments to confirm the effects of nutrition on human mucosal immunity.

By combining all of these individual observations, a basic stepwise explanation of how decreased enteral stimulation with PN induces mucosal immune deficiency via multiple "hits" gains clarity. The sequence of decreased MAdCAM-114 expression, reduced MALT/GALT cell entry,13 and reduced lymphocyte mass,37 together with reductions in Th-2 IgA-stimulating cytokines, pIgR production, IgA production, and IgA transport, is dependent on the degree of enteral stimulation. The result of decreasing enteral stimulation is an increased vulnerability to external pathogens. This appears to be clinically reflected in increased pneumonia and increased intra-abdominal abscess formation in patients who are critically injured.

The authors thank the Yakult Central Institute for Microbiological Research for providing the antibody SC.

Supported by NIH grant R01 GM53439.

Received for publication December 12, 2006. Accepted for publication January 22, 2007.

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Discussant

Mary Hise, PhD, RD, CNSD
University of Kansas Medical Center

Dr Sano and his collaborators are to be congratulated on contributing an interesting paper that examines the effect(s) of parenteral nutrition (PN), whether delivered parenterally or enterally, on the capacity of IgA to enter the lumen of the intestinal tract as secretory IgA. The work specifically examines the effect of PN formula on expression of the polyimmunoglobulin receptor (poly-IgR) at the basolateral surface of mucosal tissue. The Kudsk laboratory has previously published findings showing when nutrition is delivered parenterally, a reduction occurs in (a) the amount of IgA at respiratory and intestinal mucosal surfaces, (b) lamina propria and Peyer's patch lymphocyte mass, (c) intestinal Th-2 type cytokines IL-4 and interleukin-10 (IL-10), and (d) expression of the mucosal adressin cellular adhesion molecule-1 (MadCAM-1), the molecule that allows homing of naïve T and B lymphocytes to the lamina propria. Consequently, the information presented by Sano and coworkers continues to significantly contribute to the growing body of literature that examines the impact of PN and lack of enteral stimulation in alterations and impairment of immune function.

My questions are:

  1. Your paper demonstrated that molecules involved in mucosal immunity are maximally expressed with chow feeding and proportionately decrease as the amount of enteral stimulation decreases. Could you speculate or do you plan to examine what threshold level of enteral stimulation may be necessary to maintain antiviral and antibacterial immune defenses?
  2. You have demonstrated that pIgR may be involved in the decreased transport of IgA to mucosal surfaces. What factors other than the lower level of IL-4 do you plan to examine in the future in order to elucidate the mechanism(s) associated with the reduction in pIgR expression?
  3. It seems that an important question involves the impact of PN per se. Does PN play a detrimental role in immune function independent of the lack of gut stimulation? Do you think that the lack of complex nutrition to the gut is the sole reason for immune impairment, or is there perhaps some component within the PN solution that may contribute to the reduction of entry of T and B cells into the mucosal immune system?
  4. Have you considered using lipids with your PN solutions, and do you think that the lack of lipids in the PN formula provided contributed to the reduction in pIgR and secretory IgA in the gut?

 

Author's Response

There are 2 answers to your first question, depending on how it is interpreted.

If threshold is defined by diet composition or level of enteral stimulation needed, we previously showed that any enteral diet (chow, CED, or the parenteral formula given enterally) preserves antiviral defenses in our models. In the bacterial pneumonia model, chow and CED completely preserve this defense and IG PN partially does.

If threshold is defined as percentage of calories/nutrients delivered enterally (as opposed to parenterally), we do not have data and do not plan, at this time, to pursue this. However, Drs Alexander and Teitelbaum have generated these types of data. In both a burned guinea pig model studying bacterial translocation and in a mouse model studying GALT, somewhere between 25% and 50% of calories/nutrients need to be delivered via the gut to maintain a normal state.

We will examine IL-4 more specifically by investigating the JAK/STAT signaling pathway that is activated by IL-4. We have also started to examine the roles of TNF-{alpha} and lymphotoxin β receptor (LTβR) stimulation on pIgR and the mucosal IgA response.

In regard to your third question, this is an important point. We do not believe that the PN solution itself is detrimental. Several observations support this view. Our laboratory has previously published work showing that addition of the neuropeptide bombesin or of glutamine to the parenteral solution reverses many of the negative effects of PN without enteral stimulation. Also, administration of an antibody that activates LTβR signaling in PN-fed animals also reverses many of the changes that occur with PN. LTβR is the molecular trigger for IL-4 and MAdCAM-1. In addition, we have also done acute fasting experiments (without PN) that show that MAdCAM-1 mRNA levels are decreased without enteral stimulation. Finally, Dr Teitelbaum's laboratory has shown that mice given PN + ad libitum chow or PN + 25% of normal chow amounts display a relatively normal GALT cell phenotype.

I would summarize by saying that we attempt to study the effects of decreased enteral stimulation. PN is a necessary treatment variable because fasted mice do not survive >3 days. PN allows us to eliminate malnutrition as an explanation for the immune changes we see.

Finally, we considered adding fat early as we developed our mouse model. Because there is experimental evidence to suggest that IV lipid preparations have deleterious immune effects, we did not want to tease out whether the changes were due to a lack of enteral stimulation or to the addition of IV lipids. Basically, we wanted to limit our variables.

Our focus clinically is on the acutely injured trauma patient and not chronic PN patients where it is necessary to give lipids. We felt that a lipid-free preparation was the most appropriate model to study.

Journal of Parenteral and Enteral Nutrition, Vol. 31, No. 5, 351-357 (2007)
DOI: 10.1177/0148607107031005351
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