Loss of upper respiratory tract immunity with parenteral feeding.

OBJECTIVE: The authors examine the effect of route and type of nutrition on an established upper respiratory tract immunity and investigate potential mechanisms for increased pneumonia rates in critically injured patients fed parenterally. SUMMARY BACKGROUND DATA: The primary immunologic defense against many mucosal infections is IgA. Prior work shows that mice fed total parenteral nutrition (TPN) solutions either intravenously or intragastrically had small intestinal gut-associated lymphoid tissue (GALT) atrophy along with decreased intestinal IgA compared with animals fed complex enteral diets. The small intestine is postulated to be the origin of most mucosal immunity, both intraintestinal and extraintestinal. The impact of diets affecting GALT, small intestine IgA, and upper respiratory tract immunity is studied. METHODS: Male Institute of Cancer Research mice underwent intranasal inoculation with a mouse-specific influenza virus to establish immunity. Three weeks later, the mice were randomized to chow, intragastric Nutren (Clintec, Chicago, IL), intravenous TPN, or intragastric TPN. After 5 days of feeding, mice were challenged with intranasal virus and killed at 40 hours to determine viral shedding from the upper respiratory tract. RESULTS: Despite similar body weights, there was significant atrophy in the Peyer's patch cells from animals fed the TPN solution intravenously or intragastrically. There was no viral shedding in any animal fed via the gastrointestinal tract, whereas 5 of 10 animals fed intravenous TPN had continued viral shedding. CONCLUSIONS: The IgA-dependent upper respiratory tract immunity was preserved with enteral feeding but not with intravenous feeding. Upper respiratory tract immunity is not dependent on intestinal GALT mass but is influenced by route of nutrition. The underlying mechanisms may explain the higher pneumonia rate in critically injured patients fed parenterally.     

Recovery of gut-associated lymphoid tissue and upper respiratory tract immunity after parenteral nutrition.

OBJECTIVE: The authors characterize the recovery of parenteral nutrition-induced changes in gut-associated lymphoid tissue (GALT) and upper respiratory tract immunity with enteral nutrition and provide further information defining the effects of enteral feeding on mucosal immunity. SUMMARY BACKGROUND DATA: The small intestine plays a prominent role in development and maintenance of mucosal immunity, both intestinal and extraintestinal, primarily through immunoglobulin A (IgA)-mediated mechanisms. Prior research has shown that mice fed total parenteral nutrition (TPN) have reduced GALT T and B cells, the cells responsible for IgA production, as well as impaired upper respiratory tract immunity to viral challenge of previously immunized animals. The recovery of TPN-induced changes in GALT and upper respiratory tract immunity after enteral refeeding is studied. METHODS: Male institute of Cancer Research mice received 5 days of TPN followed by 0 to 4 days of chow. Small intestinal GALT was characterized by flow cytometry. In a second experiment, animals were immunized intranasally with moused-adapted influenza virus. Three weeks later, one group received a 5-day course of TPN followed by enteral refeeding for 5 days. A second group received TPN alone. Both groups were challenged with intranasal virus and killed 40 hours postchallenge to determine viral shedding from the upper respiratory tract. RESULTS: Animals fed TPN only had significantly fewer GALT lymphocytes compared with those chow-fed control subjects. Peyer's patch counts increased after a single day of refeeding, returning to normal levels by 48 hours. Lamina propria counts remained significantly depressed after 24 hours of refeeding, but also returned to normal after 48 hours of refeeding. The T-cell and B-cell populations mimicked total cell patterns. Lamina propria CD4+/CD8+ ratio returned to normal only after 72 hours of refeeding. None of the 9 animals refed enterally for 5 days were positive for viral shedding, compared with 8 of 12 matched TPN-fed animals. CONCLUSIONS: Enteral refeeding after TPN is associated with rapid repletion of GALT cellularity, initially within Peyer's patches and subsequently within the lamina propria. Refeeding corrects the impairment of IgA-mediated upper respiratory tract antiviral immunity occurring with TPN administration. This work further enhances the authors' knowledge of the underlying immunologic differences influenced by routes of nutrition.     

Route and type of nutrition influence mucosal immunity to bacterial pneumonia

OBJECTIVE: To develop a model of established respiratory immunity against Pseudomonas aeruginosa pneumonia and to investigate the effects of route and type of nutrition on this immunity. SUMMARY BACKGROUND DATA: Diet influences the ability of gut-associated lymphoid tissue (GALT) to maintain mucosal immunity. Complex enteral diets and chow maintain normal GALT populations against established IgA-mediated antiviral respiratory immunity. Both intravenous and intragastric total parenteral nutrition (TPN) produce GALT atrophy, but only intragastric TPN preserves established antiviral immunity. The authors hypothesized that both GALT-depleting diets (intragastric and intravenous TPN) would impair immunity against bacterial pneumonia. METHODS: P. aeruginosa was administered intratracheally to determine the mortality rate at increasing doses, and liposomes containing P. aeruginosa antigens were used to generate effective respiratory immunization. In the final experiment, mice received liposomes containing P. aeruginosa antigens to establish immunity and then were randomized to chow, complex enteral diets, intragastric TPN, or intravenous TPN. After 5 days of diet, mice received live intratracheal P. aeruginosa, and the death rate was recorded at 24 and 48 hours. RESULTS: The LD50 and LD100 were 9 x 10(7) and 12 x 10(7), respectively. Immunization reduced the mortality rate from 66% to 12%. This immunization was maintained in mice fed chow or a complex enteral diet and was lost in animals receiving intravenous TPN. Intragastric TPN partially preserved this respiratory immunity. CONCLUSIONS: Protection against bacterial pneumonia can be induced by prior antigenic immunization. This protection is lost with intravenous TPN, partially preserved with a chemically defined enteral diet, and completely preserved with chow or complex enteral diets. Both route and type of nutrition influence antibacterial respiratory tract immunity.     

Impairment of mucosal immunity by parenteral nutrition: depressed nasotracheal influenza-specific secretory IgA levels and transport in parenterally fed mice

OBJECTIVE: To examine the effects on mucosal selective transport of polymeric IgA (pIgA) and the ability of exogenous pIgA to provide protection despite altered mucosal transport. SUMMARY BACKGROUND DATA: Parenteral nutrition significantly impairs established antipseudomonal immunity and IgA-mediated antiviral immunity in association with gut-associated lymphoid tissue mass atrophy. Lack of enteral feeding also induces mucosal effects. METHODS: After immunization, nasotracheal levels of influenza-specific IgA were measured in cannulated mice randomized to chow feeding or parenteral nutrition. Nonimmune animals were randomized to chow or total parenteral nutrition, and after 5 days of diet were given a mixture of two antiinfluenza monoclonal antibodies, pIgA and IgG. Four hours after injection, nasal washes were collected and influenza-specific antibody levels were determined by enzyme-linked immunosorbent assay to calculate the selective transport index of IgA relative to IgG. In the final experiment, immunized animals were randomized to chow or parenteral feeding, and after 5 days, parenterally fed animals received either normal mouse serum or antiviral pIgA before viral challenge. Viral shedding was measured at 42 hours after challenge. RESULTS: Parenteral nutrition significantly reduced virus-specific IgA in nasotracheal washes. Parenteral nutrition depressed the selective transport index, demonstrating impaired mucosal transport of pIgA. Parenterally fed animals given specific antiviral pIgA but not normal mouse serum eliminated virus from the airway and regained mucosal protection, demonstrating adequate residual transport for immunity if adequate pIgA is present. CONCLUSION: Although both decreased IgA production due to gut-associated lymphoid tissue atrophy and impaired mucosal transport occur when enteral feeding is not provided, residual transport can provide antiviral protection if exogenous antiviral pIgA is available. Production, rather than transport, may be the most important factor in maintaining established respiratory tract IgA-mediated immunity.     

The effect of glutamine-enriched TPN on gut immune cellularity.

Prolonged parenteral feeding with standard nutrient solutions results in significant alteration in the structural, hormonal, and immunological composition of the intestinal tract. The purpose of the following study was to evaluate the effect of glutamine-supplemented parenteral nutrition on the immune cellularity of the gut. Twenty-one Fischer rats were randomized to three groups of seven animals each. Group I was fed rat chow and water ad lib, Group II was fed a standard solution of total parenteral nutrition (TPN) (D25/4.25% amino acids) via a central venous catheter, and Group III was fed the standard solution of TPN with 2% glutamine which was isonitrogenous and isocaloric to Group II. Animals were fed their respective diets for 1 week and bile was collected and assayed for secretory IgA (s-IgA) and IgM. The terminal ileum was stained and assayed for IgA+, IgM+, IgG+, CD4+, and CD8+ plasma cells and lymphocytes. Results indicate that the feeding of a standard parenteral diet results in a significant decrease in biliary s-IgA and IgA+ plasma cells in the gut lamina propria compared to chow-fed animals (S-IgA: chow, 858 +/- 23 micrograms/ml; TPN, 494 +/- 41 micrograms/ml; IgA cells: chow, 35.7 +/- 1.8; TPN, 8.6 +/- 0.9 cells/hpf). In addition a marked depletion of CD4+ and CD8+ lymphocytes was observed with standard solutions of parenteral nutrition compared to chow (CD4+: chow, 36.8 +/- 6.6; TPN, 14.9 +/- 6.0; CD8+: chow, 18.8 +/- 5.6; TPN, 5.7 +/- 2.7 cells/hpf). The addition of glutamine to the standard TPN solution maintained both B and T cell populations at levels similar to chow-fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enteral feeding preserves mucosal immunity despite in vivo MAdCAM-1 blockade of lymphocyte homing

OBJECTIVE: To determine the influence of route of nutrition on gut mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) expression and the effect of MAdCAM-1 blockade on gut-associated lymphoid tissue (GALT) lymphocyte populations and established respiratory antibacterial immunity. SUMMARY BACKGROUND DATA: Lymphocytes, sensitized to antigens in Peyer's patches, migrate via mesenteric lymph nodes and home to intestinal lamina propria. MAdCAM-1 located on endothelial cells regulates this trafficking. Experimentally, parenteral nutrition (PN) decreases GALT cell mass and mucosal immunity when compared with enteral feeding. METHODS: In experiment 1, MAdCAM-1 expression was quantified in 32 mice after 4 days of feeding chow, a complex diet, intragastric (IG)-PN, or PN. In experiment 2, MAdCAM-1 was measured in 102 mice 0, 4, 8, 12, 24, 48, or 72 hours after starting PN and at 0, 4, 8, 12, 24, or 48 hours after reinstituting chow following 5 days of PN. In experiment 3, 56 mice received chow, PN, chow + MECA-367 (anti-MAdCAM-1 mAb), or chow + Isotype control Ab (IsoAb) for 5 days, followed by Peyer's patches, lamina propria, and intraepithelial lymphocyte yield with respiratory and intestinal IgA levels. In experiment 4, 10 days after Pseudomonas immunization, mice received chow + MECA-367 or chow + IsoAb for 4 days followed by 1.2 x 108 Pseudomonas intratracheally. RESULTS: Diet and route affect MAdCAM-1 expression (chow > complex diet > IG-PN > PN). Decreased MAdCAM-1 expression occurred within hours of starting PN in Peyer's patches, but not mesenteric lymph nodes or the intestine, and recovered quickly with enteral refeeding. MAdCAM-1 blockade reduced all GALT populations. Blockade had little effect on IgA levels and partially impaired the late response of established respiratory immunity. CONCLUSIONS: Enteral feeding affects MAdCAM-1 expression. Complete MAdCAM-1 blockade reduces GALT lymphocytes to PN levels, but the chow feeding stimulus preserves IgA and early antibacterial resistance, implying the existence of non-MAdCAM-1 mechanisms to preserve mucosal immunity.     

Parenteral nutrition impairs gut-associated lymphoid tissue and mucosal immunity by reducing lymphotoxin Beta receptor expression

OBJECTIVE: To determine the effects of parenteral nutrition (PN) on LTbetaR in gut-associated lymphoid tissue (GALT), particularly the intestine and Peyer's patches (PP). SUMMARY BACKGROUND DATA: Lack of enteral stimulation with PN impairs mucosal immunity and reduces IgA levels through depression of GALT cytokines (IL-4 and IL-10) and GALT specific adhesion molecules. We have shown that each is critical to intact mucosal immunity through effects on lymphocyte homing, IgA production, and resistance to antibacterial and antiviral immunity. IgA is the principal specific immunologic mucosal defense. LTbetaR stimulation controls production of IL-4, the adhesion molecule MAdCAM-1, and other key components of GALT, all of which are important in increasing IgA levels and maintaining mucosal defenses. METHODS: Experiment 1: LTbetaR expression in intestine and PP was analyzed by Western blot after 5 days of chow, a complex enteral diet (CED), or PN. Diets were isocaloric and isonitrogenous except for chow. Experiment 2: After completing pilot experiments to determine the appropriate dose of the LTbetaR agonistic antibody, mice received chow, PN + 5 mug of anti-LTbetaR mAb (2 times/d, i.v.) or PN + isotype control antibody. PP lymphocytes and intestinal IgA levels were measured after 2 days. RESULTS: Lack of enteral stimulation with PN significantly decreased LTbetaR expression in intestine and PP compared with chow and CED. LTbetaR stimulation with an agonistic anti-LTbetaR mAb significantly increased PP lymphocyte counts and intestinal IgA in PN fed-mice. CONCLUSIONS: LTbetaR expression is critical for GALT control mechanisms and intact mucosal immunity. PN reduces LTbetaR expression, PP lymphocytes, and intestinal IgA production. Exogenous LTbetaR stimulation reverses PN-induced depression of gut mucosal immunity.     

Route of nutrition influences generation of antibody-forming cells and initial defense to an active viral infection in the upper respiratory tract

OBJECTIVE: To assess whether lack of enteral feeding significantly impairs generation of specific immune responses to an acute viral infection. SUMMARY BACKGROUND DATA: Parenteral feeding provides adequate nutrients to meet metabolic needs, but lack of enteral stimulation creates a defect in mucosal immunity characterized by loss of IgA-mediated defenses in the respiratory tract. METHODS: The enzyme-linked Immunospot (ELISPOT) assay was used to determine accumulation of immunologic cells in the nasal passages after diet manipulation. Viral shedding and nasal IgA levels were measured in additional groups of mice. RESULTS: After determining the time course of antibody-forming cells (AFCs) via ELISPOT to an active infection with the A/PR8 influenza virus, a significant reduction was found in total AFCs, IgA-producing AFCs, and IgG-producing AFCs over the course of a 13-day experiment with significant depression in viral-specific respiratory IgA levels. Eight days following an active infection, seven of nine total parenteral nutrition-fed animals continued to have viral shedding in the nasal passages compared to one of nine chow-fed mice and one of six animals fed a complex enteral diet. CONCLUSIONS: Lack of enteral stimulation significantly impairs the generation of IgA-mediated mucosal immunity.     

Nutritional route affects ERK phosphorylation and cytokine production in hepatic mononuclear cells

OBJECTIVE: To clarify the influence of nutritional route on hepatic immunity in a murine model. SUMMARY BACKGROUND DATA: Parenteral nutrition is disadvantageous for preventing infectious complications in critically ill and/or severely injured patients as compared with enteral nutrition. To date, lack of enteral nutrition has been demonstrated to impair mucosal immunity, gut barrier function, and the peritoneal defense system. However, influences of nutritional route on hepatic immunity, another important defense system against infection, have not been well studied. METHODS: Male ICR mice were randomized to 3 groups: ad libitum chow (chow), intravenous (IV)-TPN and intragastric (IG)-TPN groups. The TPN groups were given isocaloric and isonitrogenous TPN solutions. After the mice had been fed for 5 days, hepatic mononuclear cells (MNCs) were isolated. Hepatic MNC numbers and functions (cytokine production, intracellular signaling, and LPS receptor expression) were determined. Moreover, 1.0 x 10 Pseudomonas aeruginosa were delivered by intraportal injection. Survival and histology were examined. RESULTS: Hepatic MNC numbers were significantly lower in the IV-TPN group than in the chow and IG-TPN groups, without subpopulation changes. As compared with enterally fed mice, cytokine production (TNF-alpha, IFN-gamma, and IL-10) by hepatic MNCs in response to LPS was impaired in parenterally fed mice in association with blunted phosphorylation of ERK1/2, a MAPK. Hepatic MNCs from IV-TPN mice showed decreased expressions of CD14 and TLR4/MD2, as compared with enterally fed mice. Survival times were reduced in the IV-TPN group as compared with the chow and IG-TPN groups. CONCLUSION: Preservation of hepatic immunity with enteral feeding is important for prevention of infectious complications in severely injured and/or critically ill patients.     

Inducible nitric oxide synthase knockout mice are resistant to diet-induced loss of gut barrier function and intestinal injury

Loss of gut barrier function has been documented to occur in animals receiving total parenteral nutrition (TPN) and certain liquid diets. However, the mechanisms responsible for diet-induced gut barrier dysfunction remain to be fully determined. Thus we tested the hypothesis that increased intestinal nitric oxide production contributes to this phenomenon. To test this hypothesis, iNO S-deficient (iNOS -/-) mice and their wild-type littermates (iNOS +/+) were fed either chow or TPN solution for 14 days. Subsequently they were killed and gut barrier function was assessed by measuring bacterial translocation to the mesenteric lymph node (MLN) complex. Additionally, intestinal bacterial population levels, gut morphology, plasma and intestinal nitric oxide levels, as well as intestinal levels of the nitric oxide synthase (NOS) enzymes cNOS and iNOS, were measured. Bacterial translocation occurred in the iNOS +/+ but not the iNOS -/- mice receiving oral TPN solution. Oral TPN-induced bacterial translocation was associated with increased intestinal bacterial population levels as well as morphologic evidence of intestinal injury. Plasma and intestinal levels of the nitric oxide products, nitrite/nitrate, were increased in the iNOS +/+ mice fed the TPN solution but not in the chow-fed groups or the iNOS -/- mice receiving TPN solution. Last, intestinal iNOS, but not cNOS, activity was increased in the iNOS +/+ oral TPN-fed mice. These results implicate a role for increased intestinal nitric oxide production, through iNOS, in the pathogenesis of oral TPN-induced gut barrier dysfunction and injury.     

Role of bombesin on gut mucosal growth.

OBJECTIVE: The authors examined the effects of exogenous bombesin (BBS) on gut mucosal growth in chow-fed rats and the mucosal regeneration after gut atrophy brought about by feeding an elemental diet and after intestinal injury produced by methotrexate (MTX). SUMMARY BACKGROUND DATA: Bombesin is one of many gastrointestinal peptides implicated in the regulation of gut mucosal growth. Although BBS is known to stimulate growth of normal pancreatic tissue, the trophic effect of BBS on gut mucosa is less clear and its exact role in gut mucosal regeneration and repair is not known. METHODS: Rats were fed a regular chow diet (control) or an elemental diet plus either saline or BBS (10 micrograms/kg). In another experiment, rats fed a chow diet and treated with saline or BBS were given MTX (20 micrograms/kg) or a single intraperitoneal injection. In all experiments, small and large bowel mucosa and pancreas were removed and analyzed for BBS-mediated proliferation. RESULTS: Bombesin produced significant mucosal proliferation of the small bowel at day 14, but not at day 7, in rats fed regular chow. In contrast, BBS treatment for 7 days produced significant proliferation in both the atrophic and injured gut mucosa of rats given elemental diet or MTX. CONCLUSIONS: Bombesin may be an important enterotrophic factor for normal mucosal proliferation and may be clinically beneficial as an agent to restore or maintain gut mucosa during periods of atrophy or injury.     

Current aspects of mucosal immunology and its influence by nutrition

BACKGROUND: A significant body of clinical literature demonstrates that enteral feeding significantly reduces the incidence of pneumonia compared to patients fed parenterally. An immunologic link between the gastrointestinal tract and respiratory tract is postulated via the common mucosal immune hypothesis. This hypothesis states that cells are sensitized within the Peyer's patches of the small intestine and are subsequently distributed to submucosal locations in both intestinal and extra intestinal sites. This system is exquisitely sensitive to route and type of nutrition. DATA SOURCE: This review examines the laboratory data regarding cell numbers, cell phenotypes, cytokine profile, and immunologic function in both intestinal and extra intestinal sites in animals that have been administered either parenteral feeding or various types of enteral feeding. It also establishes links between a specific nutrient, glutamine, the enteric nervous system, by way of neuropeptides, and mucosal immunity. CONCLUSION: Progress in understanding relationships between nutrient availability, enteric nervous system stimulation, and nutrient delivery on mucosal immunity offers opportunities to explore immune systems previously not appreciated by clinicians and basic scientists. These opportunities offer new challenges to the physician scientist, basic scientist, and clinician to understand, manipulate, and apply these concepts to the critically ill patient population by favorably influencing immunologic barriers and the inflammatory response.     

Maintenance of gut mass in bypassed bowel of orally vs parenterally nourished rats.

Twenty-six male rats (experimental) underwent bypass of more than 70% of their small bowel, and nine rats underwent small bowel transection and reanastomosis. Rats were fed standard laboratory chow for the initial 18 postoperative days and then were switched to an elemental nutrient solution consisting of amino acids, glucose, vitamins, and minerals, either orally or parenterally (TPN) for the next 10 to 13 days. At the end of the experiment, in continuity and bypassed segments from both parenterally and orally fed animals were compared to each other and to similar segments of bowel from control rats.Our data indicate that oral intake and/or digestion and absorption of nutrients by the in continuity alimentary tract provides a stimulus to hyperplasia in the in continuity small bowel and a systemic stimulus that permits maintenance of gut mass in large bypassed segments of small bowel. Such a systemic stimulus is absent when the rat is provided TPN. Bypassed rats, remaining on oral nutrition throughout the 28- to 31-day postoperative period, had bypassed segments that maintained bowel weight, mucosal protein and RNA and DNA content similar to comparable segments of control bowel, while bypassed bowel from the TPN group underwent atrophy. The systemic stimulus does not appear to be gastrin since serum and antral gastrin levels were similar in bypassed and control rats and serum levels were consistent with previously determined fasting gastrin levels.     

Use of L-glutamine in total parenteral nutrition

Gut atrophy develops during prolonged total parenteral nutrition (TPN). TPN solutions do not contain glutamine, an energy substrate of the intestinal tract. This study evaluated the effect of addition of L-glutamine to TPN on gut nitrogen content, histology, and disaccharidase enzyme activity. Five groups of six Fisher 344 rats received rat chow, D5W, TPN (23% calories as lipid), or TPN with 1 or 2% L-glutamine. Animals given TPN received 30 kcal and 0.22 g nitrogen/100 g/day. Metabolic cages allowed nitrogen balance for each group. After 6 days infusion, stomach, small bowel, and colon were assayed for total nitrogen and sucrase, lactase, and maltase activity. Mucosal height and fatty infiltration of the liver were determined from histologic sections. Adding either 1 or 2% L-glutamine resulted in no toxic clinical effects. Glutamine preserved intestinal nitrogen content of the stomach and colon compared to standard TPN and increased nitrogen content of small bowel to greater than that in chow-fed animals. Glutamine maintained mucosal height of the stomach and colon, but was no better than TPN alone in maintenance of small bowel mucosal height. One percent glutamine increased and standard TPN depressed maltase activity compared to chow. Standard TPN and 1% glutamine both stimulated sucrase and lactase activity compared to chow. Addition of 1 or 2% glutamine protected the liver from fatty infiltration seen with standard TPN. These studies would suggest the addition of glutamine might be beneficial during provision of standard total parenteral nutrition.     

Total parenteral nutrition inhibits intestinal adaptive hyperplasia in young rats: reversal by feeding

To determine whether the inhibition of intestinal adaptation by total parenteral nutrition (TPN) in young growing animals is reversible, 130 7-week-old rats with 70% resection of the midportion of the small bowel were given an amino acid and glucose TPN solution parenterally or orally or a chow diet for 10 days. After TPN administration, villous height, crypt depth, DNA and RNA content, RNA:DNA ratio, and sucrase activity were decreased. After returning to 4 weeks of chow feeding, rats given TPN achieved similar body weight and 15% greater intestinal length as compared with rats fed chow from the start, although their jejunal villous height, ileal crypt depth, and RNA:DNA were decreased. Therefore, the inhibition by TPN of intestinal adaptation after intestinal resection in young growing rats is largely reversible. Furthermore, oral feeding of a high-calorie, high-protein liquid diet before feeding of a normal diet appears to promote adaptation after intestinal resection in immature, growing rats.     

The effects of total parenteral nutrition on gastrointestinal growth and development

Total parenteral nutrition (TPN) is vital for the nutritional support of infants with disorders of the gastrointestinal tract that prevent adequate enteral intake. Studies in adult rodents maintained on TPN have demonstrated intestinal atrophy and decreased activity of the brush border enzymes of the small bowel mucosa. We studied the effects of TPN during the phase of rapid intestinal growth and development in piglets. Matched groups of three 6-week-old weaned piglet littermates received a glucose (45 g/kg/d), amino acid (8 g/kg/d), and fat (2.5 g/kg/d) solution intravenously (IV) or by gastrostomy (GF), or were given hog chow (Chow) at an equivalent caloric value for three weeks. No differences were noted in the mean weight gain (13-15 g/kg/d), total serum protein (4.5-4.8 g/dL), BUN (9-12 mg/dL), or Hct (25% to 30%). The IV and GF animals, compared to the Chow animals, had decreased growth of the stomach, small bowel, and pancreas with decreased small bowel mucosal disaccharidase activity. The IV group, compared to Day 0 animal measurements, had decreased small bowel length and weight and pancreatic weight. Histology of the proximal small bowel mucosa in the IV animals showed decreased mucosal depth, villus height, crypt depth, and epithelial cell number from the crypt base to the midvillus. These findings suggest that stomach, small bowel, and pancreatic growth are dependent on the route of administration and/or the composition of the diet, the small bowel mucosa and the pancreas atrophies in young piglets maintained on TPN, the activity of some intestinal brush border disaccharidases are decreased in the small bowel in piglets maintained on either an intravenous or an intragastric infusion of a TPN solution.     

Cholecystokinin prophylaxis of parenteral nutrition-induced gallbladder disease.

Recent studies indicate that long-term total parenteral nutrition (TPN) induces gallstone formation and acalculous cholecystitis in humans. Cholecystectomy is hazardous for these patients because they frequently have multiple medical problems and have undergone numerous abdominal operations. The present study was designed to develop a method to prevent TPN-induced gallbladder disease. The authors tested the hypothesis that a single daily intravenous infusion of cholecystokinin-octapeptide (CCK-OP) will prevent TPN-induced gallbladder stasis. Eleven prairie dogs received TPN for 10 days. Six of these animals were given a daily infusion of CCK-OP. Control animals were fed ad lib. Each animal's bile salt pool was labeled with intravenous 3H-cholic acid 16 hours prior to acute terminal experiments. The ratio of gallbladder to hepatic bile 3H-cholic acid specific activity (Rsa) provides an index of gallbladder stasis. A Rsa of less than 1.0 indicates gallbladder stasis. TPN animals had a Rsa of 0.54 +/- 0.13 (p less than 0.01 vs. controls), indicating stasis of bile in the gallbladder. Daily CCK-OP infusions resulted in a Rsa of 0.92 +/- 0.10 (p less than 0.05 vs. TPN without CCK-OP), indicating that TPN-induced gallbladder stasis is prevented by daily CCK-OP. Control animals had a Rsa of 1.03 +/- 0.06. The cholesterol saturation indices of gallbladder and hepatic bile were not increased by TPN or CCK-OP. These data indicate that 1) TPN induces gallbladder stasis but does not increase bile lithogenic index; and 2) daily injections of CCK-OP prevent TPN-induced gallbladder stasis.     

The effect of parenteral nutrition on gastrointestinal immunity. The importance of enteral stimulation.

Secretory IgA (S-IgA), an immunoglobulin present in secretions, prevents the adherence of bacteria to mucosal cells and is the principle component of the gut mucosal defense system. The purpose of this study was to determine whether the route of nutrient administration affects S-IgA. Twenty-five female Fisher rats were randomized into three groups. Groups I and II were fed an isonitrogenous, isocaloric standard hyperalimentation solution, Group I intravenously and Group II via a gastrostomy. Group III (control) was fed rat chow and water ad lib. Since bile is one of the principle sources of S-IgA, animals had biliary T-tubes placed for sampling of bile every 4 days. At day 16, Group I animals were fed rat chow and water for an additional 8 days. S-IgA was measured by the ELISA immunoassay. Results indicated at day 16 that the S-IgA level in mg/ml of Group I was 1.1 +/- 0.2, while the S-IgA in Groups II and III was 2.2 +/- 0.6 and 2.2 +/- 0.26, respectively. Furthermore, the S-IgA level in Group I after 8 days of enteral feeding rose to 1.8 +/- 0.4. The difference in S-IgA levels between enterally and parenterally fed rats suggests that an important defense barrier is compromised during parenteral hyperalimentation. Rats fed the same nutrients by gastrostomy maintained S-IgA levels better than rats fed the same nutrients intravenously. The rapid return to normal levels after resumption of enteral feeding suggests that the intraluminal presence of foodstuffs is essential for maintenance of S-IgA.     

Enteral nutrition prevents remote organ injury and death after a gut ischemic insult

OBJECTIVE: To determine whether parenteral feeding (IV-TPN) influences the local and systemic response to an intestinal insult. SUMMARY BACKGROUND DATA: Parenteral feeding increases ICAM-1 expression and attracts neutrophils (PMNs) to the intestine compared with enterally fed animals. Because the gut is a priming bed for PMNs, the authors hypothesized that IV-TPN may affect organ injury after gut ischemia-reperfusion (I/R). METHODS: Mice were randomized to chow, IV-TPN, intragastric TPN, or complex enteral diet for 5 days' feeding. In experiment 1, 162 mice underwent 15 or 30 minutes of gut I/R, and death was recorded at 72 hours. In experiment 2, 43 mice underwent 15 minutes of gut ischemia and permeability was measured by 125I-labeled albumin at 3 hours after reperfusion. Lung PMN accumulation was measured by myeloperoxidase assay. In experiment 3, albumin leak was tested in the complex enteral diet group (n = 5) and the intragastric TPN group (n = 5) after 30 minutes of gut ischemia and 1 hour of reperfusion. RESULTS: In experiment 1, enteral feeding significantly reduced the death rate compared with IV-TPN after 15 minutes of I/R. After 30 minutes of gut ischemia, the IV-TPN and intragastric TPN groups showed a higher death rate than the chow and enteral diet groups. In experiment 2, IV-TPN significantly increased pulmonary and hepatic 125I albumin leak compared with enteral feeding without increasing pulmonary myeloperoxidase levels. In experiment 3, there were no differences in 125I albumin leak between the complex enteral diet and intragastric TPN groups. CONCLUSION: Enteral feeding reduced the death rate and organ permeability after 15 minutes of ischemia. However, prolonged ischemia (30 minutes) eliminated any benefits of intragastric TPN on survival.