REVIEW URRENT C OPINION
Impact of the feeding route on gut mucosal immunity Kazuhiko Fukatsu
Purpose of review Enteral nutrition is recommended as a standard nutritional therapy in clinical settings. The rationale behind enteral nutrition may be decreased infectious morbidities compared with parenteral nutrition. However, the mechanism may not be well understood. Recent findings Animal studies have revealed that enteral nutrition, compared with parenteral nutrition, preserves the gutassociated lymphoid tissue mass and function with well controlled gut cytokine milieu and intracellular signaling pathway, leading to the maintenance of intestinal and extraintestinal acquired mucosal immunity. Moreover, enteral nutrition can enhance the gut innate immunity by increasing the antimicrobial peptides, such as secretory phospholipase A2. More importantly, a recent clinical study demonstrated preoperative parenteral nutrition without enteral nutrition to decrease the number of T cells, IgA-producing cells, and mature dendritic cells in human terminal ileum, which are consistent with the data obtained from animal studies. Investigation of the mechanism has given us some surrogates of enteral nutrition during parenteral nutrition, such as glutamine, butyric acid, cytokines, and other mediators. However, to date, no surrogates can restore parenteral-nutrition-induced impairment of host defense completely. Summary Because enteral nutrition is a practical way to preserve gut immunity, clinicians should make any efforts to shorten the period of enteral nutrition absence and increase the dose according to the degree of tolerance. Keywords antimicrobial peptide, gut-associated lymphoid tissue, gut microbiota, immunoglobulin A, intestinal epithelial cell
INTRODUCTION Early enteral feeding is now recommended for critically ill, severely injured, and surgical patients [1 ]. The clinical trials have demonstrated decreased rates of infectious morbidities and even mortalities in early enterally fed patients, compared with the control group [2]. However, because the size of these trials is relatively small and the number of patients is limited, evidence level may be worried to be low. Nevertheless, we can peruse many reports examining the mechanisms why enteral route is superior to parenteral route in terms of host defense systems. Here, in this commentary, the accumulating basic research data on the impact of feeding route on host defense, particularly gut mucosal immunity, are described. &
GUT AS AN IMMUNE ORGAN Gut is essential for the digestion and absorption of nutrients, and is also the largest immune organ in www.co-clinicalnutrition.com
human body. Under normal condition, there is a mutually beneficial symbiosis between host and gut microbiota [3]. The resident bacterial populations improve digestive efficiency, help immune system development, and limit pathogen colonization. On the other hand, host provides nutrient-rich environment to the gut microbiota. Severe surgical stress and various therapeutic methods disturb both gut mucosal barrier and gut microflora.
GUT-ASSOCIATED LYMPHOID TISSUE Gut mucosal cells are organized in the gut-associated lymphoid tissue (GALT) [4]. Intraluminal Surgical Center, The University of Tokyo, Tokyo, Japan Correspondence to Kazuhiko Fukatsu, MD, PhD, Surgical Center, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Tel: +81 3 3815 5411; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:164–170 DOI:10.1097/MCO.0000000000000033 Volume 17 Number 2 March 2014
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Impact of the feeding route on gut mucosal immunity Fukatsu
KEY POINTS Gut is important not only as an organ for digestion and absorption of nutrients, but also as an immune organ. Lack of enteral nutrition impairs the GALT size and function, leading to extraintestinal mucosal barrier dysfunction. Lack of enteral nutrition also impairs the gut innate immunity and physical barrier. There are some surrogates for enteral nutrition in terms of the maintenance of gut immunity, but the effects are limited. Beneficial effect of enteral nutrition on gut immunity is the rationale for clinical recommendation of early enteral nutrition in critically ill, severely injured, and surgical patients.
antigens are sampled by the M cells and processed by the dendritic cells within the Peyer’s patches, the epithelial dome of specialized intestinal lymphoid
structures. Bacteria-laden dendritic cells interact with naı¨ve T and B cells migrating from the capillaries through interactions with endothelial cell adhesion molecule MAdCAM-1 in Peyer’s patches. The dendritic cells sensitize the lymphocytes and differentiate B cells to plasma cells, which produce IgA against the intestinal bacteria. Therefore, Peyer’s patches work as inductive sites of gut mucosal immunity. The sensitized T cells and IgA-producing plasma cells move to the mesenteric lymph nodes for maturation and proliferation, then return to systemic circulation via thoracic duct and home to intestinal intraepithelial spaces and lamina propria (Fig. 1). IgA produced by the plasma cells in the lamina propria are taken up by the intestinal epithelial cells (IECs) and transcytosed to the apical surface. Secretory IgA binds to the bacterial surface antigens and inhibits the attachment of the bacteria to the mucosa, without activating the complement system. Lamina propria CD4þ T cells mainly consist of two types, that is, IL-17-producing Th17 cells and regulatory T cells [3]. Th17 cells increase the Extra intestinal mucosa
Systemic circulation Thoracic duct
Mesenteric lymph node
Ig
e ecr As
n tio
Homing
Maturation and proliferation
GALT
Peyer patch Systemic circulation
Lamina propria lymphocytes T
MAdCAM–1
Mucous
B
Cytokines
Ag presentation
DC
Antimicrobial peptides
Sensitization
M cell
IgA secretion Ag
Gut microbiota Intestinal epithelial cells
Goblet cell
Paneth cell
Clear damaged cells
Intraepithelial lymphocytes
FIGURE 1. Gut-associated lymphoid tissue (GALT) and systemic mucosal immunity. Intestinal epithelial cells also contribute to the preservation of gut mucosal barrier. 1363-1950 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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proinflammatory immune response, whereas regulatory T cells suppress excessive inflammatory response. By achieving an adequate balance of these two types of cells, the gut maintains the immune responses in the lamina propria. Intraepithelial lymphocytes (IELs) are located in the epithelial layer and enriched with TCRgd cells and CD8þ cells. Although the details of the function of IELs remain unclear, IELs have cytotoxic activity to clear infected or damaged IECs, maintaining the gut barrier function. IELs also produce antimicrobial peptide, RegIIIg, as IECs do. Thus, intestinal lamina propria and intraepithelial cells are recognized to be the effector sites of gut mucosal immunity. More importantly, a portion of the sensitized lymphocytes in the GALT home to the extraintestinal mucosal sites such as respiratory tract and thereby contribute to the mucosal defense. Consequently, GALT works as a center of gut and systemic mucosal barrier.
INTESTINAL EPITHELIAL CELLS Tight junction between the IECs forms a physical barrier between the gut lumen and the lamina propria, and is essential for the polarity of IECs. There are a variety of cell types in the IECs. Functions of the intestinal absorptive cells include uptake of various nutrients, resorption of unconjugated bile salt, and secretion of IgA produced by lamina propria plasma cells as mentioned above. Paneth cells release antimicrobial molecules such as defensins, lysozymes, cathelicidins, phospholipase A2, and C-type lectins [5 ]. These molecules contribute to the host innate immunity. Goblet cells produce heavily glycosylated mucins, covering the luminal surface of the IECs. The mucus layer traps the gut pathogens and plays an important role in microbiota sequestration [3]. Levels of secretory IgA and antimicrobial molecules are high in the mucus layer, thus providing appropriate environment for gut mucosal barrier. The IECs also produce various types of cytokines [3]. IL-7 enhances GALT lymphocyte proliferation. IL-15 is important for IEL maintenance. IgA production in the lamina propria is controlled by IEC-derived TNF-superfamily members. TGF-b inhibits the production of proinflammatory cytokines by dendritic cells, thereby controlling T-cell differentiation. &&
INFLUENCE OF SURGICAL INSULTS ON GUT IMMUNITY Various surgical insults make the gut barrier vulnerable and change the gut microbiota. Gut 166
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ischemia–reperfusion, an important mechanism for surgical insult-induced organ injury, prolonged GALT cell loss in Peyer’s patches, intraepithelial space, and lamina propria in mice [6]. Systemic administration of lipopolysaccharide has been demonstrated to cause Peyer’s patches atrophy. Truncal vagotomy, a standard surgical procedure for upper gastrointestinal tract malignancies, also caused transient reduction of lamina propria lymphocyte (LPL) numbers and changed the gut cytokine milieu [7]. Some anticancer drugs reduce GALT cell number [8]. Under normal condition, overgrowth of pathogens in the gut lumen is suppressed; however, gut hypoperfusion, secretion of proinflammatory mediators to the gut lumen, and prolonged antibiotic therapy, etc., may help the pathogens to proliferate dramatically and become more harmful (Fig. 2).
INFLUENCE OF NUTRITIONAL ROUTE ON GUT ACQUIRED IMMUNITY Nutritional route affects the GALT size and function. Through common mucosal immune system, extraintestinal mucosal defense is also influenced by the nutritional route.
Gut-associated lymphoid tissue size and mucosal IgA levels Using a murine feeding model with jugular vein catheterization and gastrostomy, impact of the feeding route on GALT size and its phenotypes, secretory IgA levels in the small intestinal and respiratory tract washings have been investigated. Consequently, significant reduction of GALT Peyer’s patches, intraepithelial cells, and lamina propria lymphocyte number with reduced CD4þ/CD8þ ratio was observed in the IV-TPN (parenteral nutrition without enteral nutrition) group, compared with the CHOW (normal diet with saline infusion) and CED (complex enteral diet via gastrostomy) groups (Fig. 2). The CHOW and CED groups did not show marked differences, but the IG-TPN (parenteral nutrition solution via gastrostomy: an elemental diet model) mice showed moderate recovery of these parameters when compared with the IV-TPN group. In association with the changes in the GALT cell number, both small intestinal and respiratory tract secretory IgA levels were higher in the CHOW and CED than in the IV-TPN group, whereas the IG-TPN data were midway between the CHOW and IV-TPN groups (Table 1). In addition, the recent study revealed that a CED enriched with whey protein and antioxidants enlarges the GALT Volume 17 Number 2 March 2014
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Impact of the feeding route on gut mucosal immunity Fukatsu
Lack of EN
Changes in gut microbiota Commensal bacteria vs. pathogens
GALT immune cells
Intestinal epithelial cells
Adhesion molecule (MAdCAM–1)
Tight junction Cytokines (IL–7
IFNγ
Intracellular signalings
)
Cytokines (Th1
Th2
)
Antimicrobial peptides GALT cell number plgR production IgA production Innate immunity Acquired immunity
FIGURE 2. Lack of enteral nutrition (EN) changes the gut microbiota and gut innate and acquired immunity. These factors affect each other.
size compared with a standard formula [9]. These data clearly demonstrate profound impact of nutritional route and type on the GALT cellularity and function. Surprisingly, reduction of GALT population occurs very quickly within 1 or 2 days after the initiation of parenteral nutrition without enteral nutrition, whereas restoration of the size with oral refeeding is observed within 1 or 2 days in mice. This quick response may give some rationale for the recommendation of avoidance of fasting and early
oral feeding after surgery in the enhanced recovery after surgery (ERAS) protocols [10].
Extraintestinal mucosal sites As demonstrated in Fig. 1, the GALT plays a central role in the maintenance of systemic mucosal defense. Respiratory tract IgA levels correlate with the GALT size and intestinal IgA levels. Lack of enteral nutrition delayed the increase of IgA-producing cell number in nasal passage after
Table 1. Summary of the nutritional route and type effects on gut immunity
Normal diet Complex enteral diet (CED) CED enriched with whey and antioxidants
GALT mass
Mucosal IgA
þþþþ
þþþþ
þþþ
þþþ
þþþþ
þþþþ
Intragastric TPN solution
þþ
þþ
Intravenous TPN solution
þ
þ
2% GLN TPN
þþþ
þþþ
1% ARG TPN
þ
þ
w-3 PUFA TPN
þ
þ
w-6 PUFA TPN
þ
þ
þþ
þþ
Neuropeptide
þþþ
þþþ
Interleukin-7
þþþ
þþþ
Butyric acid TPN
GALT, gut-associated lymphoid tissue; PUFA, polyunsaturated fatty acid; TPN, total parenteral nutrition.
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influenza virus immunization in mice [11]. IV-TPN impaired the already established respiratory tract immunity. After immunization with nasally given influenza virus or Pseudomonas antigen, establishment of immunity against the virus or bacteria was verified. Nevertheless, initiation of IV-TPN deprived the immunity, that is, IV-TPN mice could not eliminate influenza virus after re-innoculation of the virus, and IV-TPN mice could not survive pneumonia after tracheal instillation of live Pseudomonas [4].
Mechanisms underlying the parenteralnutrition-related changes in gut immunity Multiple factors are associated with parenteralnutrition-related changes in gut immunity. MAdCAM-1 Using I-125 and I-131 radiolabeled antibody technique, MAdCAM-1 expression was examined in mice. MAdCAM-1 expression was lower in the IV-TPN than in the enterally fed animals, correlating with the GALT size [12]. Accordingly, failure of interaction between lymphocytes and endothelial cells in the Peyer’s patches possibly results in the reduction of Peyer’s patches cell number, and subsequently decrease of GALT effector cell numbers (Fig. 2). Gut cytokine milieu Th1 cytokines inhibit but Th2 cytokines stimulate IgA production. ELISA and RT-PCR confirmed that Th2 cytokine (IL-4 and IL-10) levels in the gut were decreased with IV-TPN compared with enteral nutrition groups. On the other hand, gut IFNg, a representative Th1 cytokine, levels were unchanged with IV-TPN. Thus, the unbalanced Th1/Th2 cytokine milieu in the gut is disadvantageous for IgA production in the gut (Fig. 2) [4]. Gut IL-4 upregulates polymeric immunoglobulin receptor (pIgR), an epithelial transport protein which is needed for the transport of IgA across the mucosa to the gut lumen [13]. Parenteral nutrition also reduces IL-4 levels in the gut impairing the IgA-related immunity [4]. The IECs produce IL-7, a potent stimulator of GALT cell proliferation. IV-TPN reportedly decreases IL-7 production by the IECs, another possible mechanism for parenteral-nutrition-related GALT atrophy [14]. Indeed, exogenous IL-7 during parenteral nutrition restored GALT cell number almost to the level of CHOW animals. The preservation of gut barrier function in IL-7-treated parenteral nutrition mice was tested by observing the survival in a gut-derived sepsis model [15].
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Absence of glutamine and butyric acid in parenteral nutrition solutions L-Glutamine is a conditionally essential amino acid and is an important fuel for gut mucosal cells and immune cells. Absence of L-glutamine in the standard parenteral nutrition solutions is a mechanism for GALT atrophy during parenteral nutrition feeding. Glutamine-supplemented parenteral nutrition resulted in the recovery of GALT cell number and mucosal IgA levels, in association with the preservation of IL-4 and IL-10 mRNA levels within the lamina propria lymphocytes [16] (Table 1). Adding butyric acid, a short-chain fatty acid, by replacing half of acetic acid in the parenteral nutrition solution moderately but significantly restored Peyer’s patches cell number compared with the standard parenteral nutrition group, with moderate increase of IgA levels in the small intestinal and respiratory tract washings [17]. Thus, the absence of specific nutrients may be an important mechanism underlying the standard parenteralnutrition-induced impairment of gut immunity. Alteration of intracellular signaling Influences of parenteral nutrition on intracellular signaling have also been documented using mice models (Fig. 2). The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway provides the intracellular signaling required for a wide array of cytokines including IL-4 and IL-13, both of which are Th2 cytokines and stimulate differentiation and maturation of B cells [13]. Parenteral nutrition was demonstrated to decrease the JAK–STAT pathway by reducing the levels of phosphorylated STAT-6 and JAK-1 [13]. Parenteral nutrition also reduces lymphotoxin b receptor (LTbR) expression in the Peyer’s patches and intestine. Intracellular signal via LTbR upregulates alternative NF-kB pathway, leading to increased expression of MAdCAM-1 in the Peyer’s patches and production of IL-4 and IL-10 [18]. Therefore, changes in MAdCAM-1 expression and gut cytokine milieu during parenteral nutrition may at least partly derive from the reduced LTbR expression. Phosphorylation of extracellular signalregulated kinase (ERK), a MAP kinase, in the LPLs and IELs after in-vitro stimulation with phorbol myristate acetate is also blunted during parenteral nutrition [19]. Once phosphorylated, ERK promotes cell differentiation and proliferation, cytokine production, and immune activation. Therefore, blunted ERK phosphorylation may also be a mechanism for impaired gut immunity during parenteral nutrition.
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Impact of the feeding route on gut mucosal immunity Fukatsu
Miyasaka et al. [20] demonstrated parenteral nutrition to cause significant expansion of Proteobacteria within the intestinal microbiota and increased proinflammatory lamina propria cytokines through MyD88-dependent mechanism, suggesting close relationship between the intestinal microbiota and lamina propria inflammation.
INFLUENCE OF NUTRITIONAL ROUTE ON GUT INNATE IMMUNITY Route of nutrition has great impact not only on the acquired immunity, but also on the innate immunity (Fig. 2). As previously described, IECs secrete various antimicrobial peptides. Secretion of antimicrobial protein secretory phospholipase A2 (sPLA2) from the Paneth cells was evaluated with an ex-vivo intestinal segment culture model [21,22]. Parenteral nutrition resulted in suppressed secretion of the sPLA2 and bactericidal capacity in the ileum compared with CHOW group. Moreover, tissue mRNA expression of other antimicrobial peptides, RegIII-g, lysozyme, and cryptdin, was reduced in the ileum tissue [5 ]. &&
INFLUENCE OF NUTRITIONAL ROUTE ON INTESTINAL EPITHELIAL CELL BARRIER FUNCTION Parenteral nutrition did not increase IFNg levels in the whole intestine, but increased its expression by intraepithelial lymphocytes in mice [4,22]. Parenteral nutrition also increased TNFa and TNFR1 [23 ]. Through the enhanced production of these proinflammatory cytokines, physical barrier of IECs is reportedly compromised. Small intestine transepithelial resistance was decreased and tracer permeability was increased in the IV-TPN group compared with controls. Tight junction protein was downregulated in the TPN mice (Fig. 2). However, IFNg-knockout mice showed recovery of the gut permeability. All of these changes were partly ameliorated with TNFa blocking. &
CLINICAL EVIDENCES OF NUTRITIONAL ROUTE ON GUT IMMUNITY Duran [24] performed a systematic review on the effects of long-term TPN on gut immunity in children with short bowel syndrome. As there was no direct evidence suggesting that TPN promotes bacterial overgrowth, impairs neutrophil functions, inhibits blood bactericidal effect, causes villous atrophy, nor causes death, the conclusion was that the negative effects of TPN on gut immunity are
unproven. However, no observation of gut IgA levels or GALT size was included in this review. Immunohistochemical staining of the terminal ileum tissue resected for colon cancer surgery revealed that patients who had received oral intake before surgery had more T-cell number in the intraepithelial space and lamina propria, more IgAproducing cell number in the lamina propria, and more mature dendritic cells in the lamina propria than those who had not received oral or enteral feeding but had been fed parenterally before surgery [25 ]. Very interestingly, morbidities of infectious complications including surgical site infections, pneumonia, enteritis, and blood stream infections were significantly higher in the parenteral nutrition than in the oral feeding group. These findings are consistent with the data obtained from animal studies and strongly support the beneficial effects of enteral nutrition on gut immunity. &&
HOW TO RESTORE GUT IMMUNITY DURING PARENTERAL NUTRITION? Investigating the mechanisms for parenteralnutrition-induced impairment of gut immunity has given us various insights on how to restore gut immunity during parenteral nutrition. Addition of specific nutrients such as L-glutamine and butyric acid, exogenous administration of cytokines such as IL-7, IL-25 and IL-10, blocking of proinflammatory cytokines IFNg and TNFa, stimulating some intracellular signal pathways, and intravenous injection of some neuropeptides including bombesin, cholecystokinin, and gastrin may be surrogates of enteral nutrition for the restoration of gut immunity during parenteral nutrition [4,13,15,26,27]. However, all of these methods have limitations and cannot fully normalize the gut immunity. Gut microbiota has tremendous contribution to the maintenance of gut immunity through interactions with IECs and GALT. Unfortunately, lack of enteral nutrition changes the gut microflora, but none of the abovementioned therapies could completely retrieve normal commensals in the gut (Table 1).
CONCLUSION In addition to the possible combinations of these therapies, modulation of the gut bacterial flora by probiotics, prebiotics, and synbiotics needs to be tested. Clarifying more precise mechanism for parenteral-nutrition-induced impairment of gut immunity will surely give us good ideas of enteral nutrition surrogates. As gut immunity may quickly change with enteral nutrition refeeding and the amount of enteral nutrition given correlates to
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the size of the GALT and gut IgA levels, clinicians should make any efforts to restart enteral nutrition feeding as soon as possible and increase the dose according to the degree of tolerance. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: & international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637. The former version did not include nutrition therapy; however, this new guidelines refer to the beneficial effects of enteral nutrition. 2. Doig GS, Heighes PT, Simpson F, et al. 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; 35:2018–2027. 3. Goto Y, Ivanov II. Intestinal epithelial cells as mediators of the commensal–host immune crosstalk. Immunol Cell Biol 2013; 91:204– 214. 4. Fukatsu K, Kudsk KA. Nutrition and gut immunity. Surg Clin North Am 2011; 91:755–770. 5. Heneghan AF, Pierre JF, Tandee K, et al. Parenteral nutrition decreases && paneth cell function and intestinal bactericidal activity while increasing susceptibility to bacterial enteroinvasion. JPEN J Parenter Enteral Nutr 2013. [Epub ahead of print]. Beneficial effects of enteral nutrition are demonstrated in terms of gut innate immunity and gut microbiota. 6. Fukatsu K, Sakamoto S, Hara E, et al. Gut ischemia–reperfusion affects gut mucosal immunity: a possible mechanism for infectious complications after severe surgical insults. Crit Care Med 2006; 34:182–187. 7. Mitsui T, Fukatsu K, Yanagawa M, et al. Truncal vagotomy temporarily decreases the pro- and anti-inflammatory cytokine levels in the small intestine. Surg Today 2013. [Epub ahead of print] 8. Moriya T, Fukatsu K, Noguchi M, et al. Intravenous administration of high-dose paclitaxel reduces gut-associated lymphoid tissue cell number and respiratory immunoglobulin A concentrations in mice. Surg Infect (Larchmt) 2013. [Epub ahead of print] 9. Yanagawa M, Fukatsu K, Mitsui T, et al. Effects of a new immunemodulating diet enriched with whey-hydrolyzed peptide, fermented milk, and isomaltulose on gut associated lymphoid tissue in mice. e-SPEN 2013; 8:e241–e245.
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10. Coolsen MM, van Dam RM, van der Wilt AA, et al. Systematic review and meta-analysis of enhanced recovery after pancreatic surgery with particular emphasis on pancreaticoduodenectomies. World J Surg 2013; 37:1909– 1918. 11. Johnson CD, Kudsk KA, Fukatsu K, et al. Route of nutrition influences generation of antibody-forming cells and initial defense to an active viral infection in the upper respiratory tract. Ann Surg 2003; 237:565–573. 12. Ikeda S, Kudsk KA, Fukatsu K, et al. Enteral feeding preserves mucosal immunity despite in vivo MAdCAM-1 blockade of lymphocyte homing. Ann Surg 2003; 237:677–685. 13. Heneghan AF, Pierre JF, Kudsk KA. IL-25 improves IgA levels during parenteral nutrition through the JAK–STAT pathway. Ann Surg 2013; 258:1065–1071. 14. Yang H, Sun X, Haxhija EQ, et al. Intestinal epithelial cell-derived interleukin-7: a mechanism for the alteration of intraepithelial lymphocytes in a mouse model of total parenteral nutrition. Am J Physiol Gastrointest Liver Physiol 2007; 292:G84–G91. 15. Fukatsu K, Moriya T, Murakoshi S, et al. Interleukin-7 treatment reverses parenteral nutrition-induced impairment of resistance to bacterial pneumonia with increased secretory immunoglobulin A levels. J Surg Res 2012; 174:334–338. 16. Fukatsu K, Kudsk KA, Zarzaur BL, et al. TPN decreases IL-4 and IL-10 mRNA expression in lipopolysaccharide stimulated intestinal lamina propria cells but glutamine supplementation preserves the expression. Shock 2001; 15:318– 322. 17. Murakoshi S, Fukatsu K, Omata J, et al. Effects of adding butyric acid to PN on gut-associated lymphoid tissue and mucosal immunoglobulin A levels. JPEN J Parenter Enteral Nutr 2011; 35:465–472. 18. Lan J, Heneghan AF, Sano Y, et al. Parenteral nutrition impairs lymphotoxin b receptor signaling via NF-kB. Ann Surg 2011; 253:996–1003. 19. Maeshima Y, Fukatsu K, Kang W, et al. Lack of enteral nutrition blunts extracellular-regulated kinase phosphorylation in gut-associated lymphoid tissue. Shock 2007; 27:320–325. 20. Miyasaka EA, Feng Y, Poroyko V, et al. Total parenteral nutrition-associated lamina propria inflammation in mice is mediated by a MyD88-dependent mechanism. J Immunol 2013; 190:6607–6615. 21. Omata J, Pierre JF, Heneghan AF, et al. Parenteral nutrition suppresses the bactericidal response of the small intestine. Surgery 2013; 153:17–24. 22. Yang H, Feng Y, Sun X, et al. Enteral versus parenteral nutrition: effect on intestinal barrier function. Ann N Y Acad Sci 2009; 1165:338–346. 23. Feng Y, Teitelbaum DH. 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. Relationship between inflammation and gut barrier function during parenteral nutrition is revealed. 24. Duran B. The effects of long-term total parenteral nutrition on gut mucosal immunity in children with short bowel syndrome: a systematic review. BMC Nurs 2005; 4:2. 25. Okamoto K, Fukatsu K, Hashiguchi Y, et al. Lack of preoperative enteral && nutrition reduces gut-associated lymphoid cell numbers in colon cancer patients: a possible mechanism underlying increased postoperative infectious complications during parenteral nutrition. Ann Surg 2013; 258:1059–1064. There are few clinical studies showing changes in GALT during parenteral nutrition in humans. This study is very important because clinical evidence of GALT atrophy is shown. 26. Genton L, Kudsk KA. Interactions between the enteric nervous system and the immune system: role of neuropeptides and nutrition. Am J Surg 2003; 186:253–258. 27. Sun X, Yang H, Nose K, et al. 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:G139–G147.
Volume 17 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Impact of the feeding route on gut mucosal immunity Kazuhiko Fukatsu
Purpose of review Enteral nutrition is recommended as a standard nutritional therapy in clinical settings. The rationale behind enteral nutrition may be decreased infectious morbidities compared with parenteral nutrition. However, the mechanism may not be well understood. Recent findings Animal studies have revealed that enteral nutrition, compared with parenteral nutrition, preserves the gutassociated lymphoid tissue mass and function with well controlled gut cytokine milieu and intracellular signaling pathway, leading to the maintenance of intestinal and extraintestinal acquired mucosal immunity. Moreover, enteral nutrition can enhance the gut innate immunity by increasing the antimicrobial peptides, such as secretory phospholipase A2. More importantly, a recent clinical study demonstrated preoperative parenteral nutrition without enteral nutrition to decrease the number of T cells, IgA-producing cells, and mature dendritic cells in human terminal ileum, which are consistent with the data obtained from animal studies. Investigation of the mechanism has given us some surrogates of enteral nutrition during parenteral nutrition, such as glutamine, butyric acid, cytokines, and other mediators. However, to date, no surrogates can restore parenteral-nutrition-induced impairment of host defense completely. Summary Because enteral nutrition is a practical way to preserve gut immunity, clinicians should make any efforts to shorten the period of enteral nutrition absence and increase the dose according to the degree of tolerance. Keywords antimicrobial peptide, gut-associated lymphoid tissue, gut microbiota, immunoglobulin A, intestinal epithelial cell
INTRODUCTION Early enteral feeding is now recommended for critically ill, severely injured, and surgical patients [1 ]. The clinical trials have demonstrated decreased rates of infectious morbidities and even mortalities in early enterally fed patients, compared with the control group [2]. However, because the size of these trials is relatively small and the number of patients is limited, evidence level may be worried to be low. Nevertheless, we can peruse many reports examining the mechanisms why enteral route is superior to parenteral route in terms of host defense systems. Here, in this commentary, the accumulating basic research data on the impact of feeding route on host defense, particularly gut mucosal immunity, are described. &
GUT AS AN IMMUNE ORGAN Gut is essential for the digestion and absorption of nutrients, and is also the largest immune organ in www.co-clinicalnutrition.com
human body. Under normal condition, there is a mutually beneficial symbiosis between host and gut microbiota [3]. The resident bacterial populations improve digestive efficiency, help immune system development, and limit pathogen colonization. On the other hand, host provides nutrient-rich environment to the gut microbiota. Severe surgical stress and various therapeutic methods disturb both gut mucosal barrier and gut microflora.
GUT-ASSOCIATED LYMPHOID TISSUE Gut mucosal cells are organized in the gut-associated lymphoid tissue (GALT) [4]. Intraluminal Surgical Center, The University of Tokyo, Tokyo, Japan Correspondence to Kazuhiko Fukatsu, MD, PhD, Surgical Center, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Tel: +81 3 3815 5411; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:164–170 DOI:10.1097/MCO.0000000000000033 Volume 17 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Impact of the feeding route on gut mucosal immunity Fukatsu
KEY POINTS Gut is important not only as an organ for digestion and absorption of nutrients, but also as an immune organ. Lack of enteral nutrition impairs the GALT size and function, leading to extraintestinal mucosal barrier dysfunction. Lack of enteral nutrition also impairs the gut innate immunity and physical barrier. There are some surrogates for enteral nutrition in terms of the maintenance of gut immunity, but the effects are limited. Beneficial effect of enteral nutrition on gut immunity is the rationale for clinical recommendation of early enteral nutrition in critically ill, severely injured, and surgical patients.
antigens are sampled by the M cells and processed by the dendritic cells within the Peyer’s patches, the epithelial dome of specialized intestinal lymphoid
structures. Bacteria-laden dendritic cells interact with naı¨ve T and B cells migrating from the capillaries through interactions with endothelial cell adhesion molecule MAdCAM-1 in Peyer’s patches. The dendritic cells sensitize the lymphocytes and differentiate B cells to plasma cells, which produce IgA against the intestinal bacteria. Therefore, Peyer’s patches work as inductive sites of gut mucosal immunity. The sensitized T cells and IgA-producing plasma cells move to the mesenteric lymph nodes for maturation and proliferation, then return to systemic circulation via thoracic duct and home to intestinal intraepithelial spaces and lamina propria (Fig. 1). IgA produced by the plasma cells in the lamina propria are taken up by the intestinal epithelial cells (IECs) and transcytosed to the apical surface. Secretory IgA binds to the bacterial surface antigens and inhibits the attachment of the bacteria to the mucosa, without activating the complement system. Lamina propria CD4þ T cells mainly consist of two types, that is, IL-17-producing Th17 cells and regulatory T cells [3]. Th17 cells increase the Extra intestinal mucosa
Systemic circulation Thoracic duct
Mesenteric lymph node
Ig
e ecr As
n tio
Homing
Maturation and proliferation
GALT
Peyer patch Systemic circulation
Lamina propria lymphocytes T
MAdCAM–1
Mucous
B
Cytokines
Ag presentation
DC
Antimicrobial peptides
Sensitization
M cell
IgA secretion Ag
Gut microbiota Intestinal epithelial cells
Goblet cell
Paneth cell
Clear damaged cells
Intraepithelial lymphocytes
FIGURE 1. Gut-associated lymphoid tissue (GALT) and systemic mucosal immunity. Intestinal epithelial cells also contribute to the preservation of gut mucosal barrier. 1363-1950 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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proinflammatory immune response, whereas regulatory T cells suppress excessive inflammatory response. By achieving an adequate balance of these two types of cells, the gut maintains the immune responses in the lamina propria. Intraepithelial lymphocytes (IELs) are located in the epithelial layer and enriched with TCRgd cells and CD8þ cells. Although the details of the function of IELs remain unclear, IELs have cytotoxic activity to clear infected or damaged IECs, maintaining the gut barrier function. IELs also produce antimicrobial peptide, RegIIIg, as IECs do. Thus, intestinal lamina propria and intraepithelial cells are recognized to be the effector sites of gut mucosal immunity. More importantly, a portion of the sensitized lymphocytes in the GALT home to the extraintestinal mucosal sites such as respiratory tract and thereby contribute to the mucosal defense. Consequently, GALT works as a center of gut and systemic mucosal barrier.
INTESTINAL EPITHELIAL CELLS Tight junction between the IECs forms a physical barrier between the gut lumen and the lamina propria, and is essential for the polarity of IECs. There are a variety of cell types in the IECs. Functions of the intestinal absorptive cells include uptake of various nutrients, resorption of unconjugated bile salt, and secretion of IgA produced by lamina propria plasma cells as mentioned above. Paneth cells release antimicrobial molecules such as defensins, lysozymes, cathelicidins, phospholipase A2, and C-type lectins [5 ]. These molecules contribute to the host innate immunity. Goblet cells produce heavily glycosylated mucins, covering the luminal surface of the IECs. The mucus layer traps the gut pathogens and plays an important role in microbiota sequestration [3]. Levels of secretory IgA and antimicrobial molecules are high in the mucus layer, thus providing appropriate environment for gut mucosal barrier. The IECs also produce various types of cytokines [3]. IL-7 enhances GALT lymphocyte proliferation. IL-15 is important for IEL maintenance. IgA production in the lamina propria is controlled by IEC-derived TNF-superfamily members. TGF-b inhibits the production of proinflammatory cytokines by dendritic cells, thereby controlling T-cell differentiation. &&
INFLUENCE OF SURGICAL INSULTS ON GUT IMMUNITY Various surgical insults make the gut barrier vulnerable and change the gut microbiota. Gut 166
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ischemia–reperfusion, an important mechanism for surgical insult-induced organ injury, prolonged GALT cell loss in Peyer’s patches, intraepithelial space, and lamina propria in mice [6]. Systemic administration of lipopolysaccharide has been demonstrated to cause Peyer’s patches atrophy. Truncal vagotomy, a standard surgical procedure for upper gastrointestinal tract malignancies, also caused transient reduction of lamina propria lymphocyte (LPL) numbers and changed the gut cytokine milieu [7]. Some anticancer drugs reduce GALT cell number [8]. Under normal condition, overgrowth of pathogens in the gut lumen is suppressed; however, gut hypoperfusion, secretion of proinflammatory mediators to the gut lumen, and prolonged antibiotic therapy, etc., may help the pathogens to proliferate dramatically and become more harmful (Fig. 2).
INFLUENCE OF NUTRITIONAL ROUTE ON GUT ACQUIRED IMMUNITY Nutritional route affects the GALT size and function. Through common mucosal immune system, extraintestinal mucosal defense is also influenced by the nutritional route.
Gut-associated lymphoid tissue size and mucosal IgA levels Using a murine feeding model with jugular vein catheterization and gastrostomy, impact of the feeding route on GALT size and its phenotypes, secretory IgA levels in the small intestinal and respiratory tract washings have been investigated. Consequently, significant reduction of GALT Peyer’s patches, intraepithelial cells, and lamina propria lymphocyte number with reduced CD4þ/CD8þ ratio was observed in the IV-TPN (parenteral nutrition without enteral nutrition) group, compared with the CHOW (normal diet with saline infusion) and CED (complex enteral diet via gastrostomy) groups (Fig. 2). The CHOW and CED groups did not show marked differences, but the IG-TPN (parenteral nutrition solution via gastrostomy: an elemental diet model) mice showed moderate recovery of these parameters when compared with the IV-TPN group. In association with the changes in the GALT cell number, both small intestinal and respiratory tract secretory IgA levels were higher in the CHOW and CED than in the IV-TPN group, whereas the IG-TPN data were midway between the CHOW and IV-TPN groups (Table 1). In addition, the recent study revealed that a CED enriched with whey protein and antioxidants enlarges the GALT Volume 17 Number 2 March 2014
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Impact of the feeding route on gut mucosal immunity Fukatsu
Lack of EN
Changes in gut microbiota Commensal bacteria vs. pathogens
GALT immune cells
Intestinal epithelial cells
Adhesion molecule (MAdCAM–1)
Tight junction Cytokines (IL–7
IFNγ
Intracellular signalings
)
Cytokines (Th1
Th2
)
Antimicrobial peptides GALT cell number plgR production IgA production Innate immunity Acquired immunity
FIGURE 2. Lack of enteral nutrition (EN) changes the gut microbiota and gut innate and acquired immunity. These factors affect each other.
size compared with a standard formula [9]. These data clearly demonstrate profound impact of nutritional route and type on the GALT cellularity and function. Surprisingly, reduction of GALT population occurs very quickly within 1 or 2 days after the initiation of parenteral nutrition without enteral nutrition, whereas restoration of the size with oral refeeding is observed within 1 or 2 days in mice. This quick response may give some rationale for the recommendation of avoidance of fasting and early
oral feeding after surgery in the enhanced recovery after surgery (ERAS) protocols [10].
Extraintestinal mucosal sites As demonstrated in Fig. 1, the GALT plays a central role in the maintenance of systemic mucosal defense. Respiratory tract IgA levels correlate with the GALT size and intestinal IgA levels. Lack of enteral nutrition delayed the increase of IgA-producing cell number in nasal passage after
Table 1. Summary of the nutritional route and type effects on gut immunity
Normal diet Complex enteral diet (CED) CED enriched with whey and antioxidants
GALT mass
Mucosal IgA
þþþþ
þþþþ
þþþ
þþþ
þþþþ
þþþþ
Intragastric TPN solution
þþ
þþ
Intravenous TPN solution
þ
þ
2% GLN TPN
þþþ
þþþ
1% ARG TPN
þ
þ
w-3 PUFA TPN
þ
þ
w-6 PUFA TPN
þ
þ
þþ
þþ
Neuropeptide
þþþ
þþþ
Interleukin-7
þþþ
þþþ
Butyric acid TPN
GALT, gut-associated lymphoid tissue; PUFA, polyunsaturated fatty acid; TPN, total parenteral nutrition.
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influenza virus immunization in mice [11]. IV-TPN impaired the already established respiratory tract immunity. After immunization with nasally given influenza virus or Pseudomonas antigen, establishment of immunity against the virus or bacteria was verified. Nevertheless, initiation of IV-TPN deprived the immunity, that is, IV-TPN mice could not eliminate influenza virus after re-innoculation of the virus, and IV-TPN mice could not survive pneumonia after tracheal instillation of live Pseudomonas [4].
Mechanisms underlying the parenteralnutrition-related changes in gut immunity Multiple factors are associated with parenteralnutrition-related changes in gut immunity. MAdCAM-1 Using I-125 and I-131 radiolabeled antibody technique, MAdCAM-1 expression was examined in mice. MAdCAM-1 expression was lower in the IV-TPN than in the enterally fed animals, correlating with the GALT size [12]. Accordingly, failure of interaction between lymphocytes and endothelial cells in the Peyer’s patches possibly results in the reduction of Peyer’s patches cell number, and subsequently decrease of GALT effector cell numbers (Fig. 2). Gut cytokine milieu Th1 cytokines inhibit but Th2 cytokines stimulate IgA production. ELISA and RT-PCR confirmed that Th2 cytokine (IL-4 and IL-10) levels in the gut were decreased with IV-TPN compared with enteral nutrition groups. On the other hand, gut IFNg, a representative Th1 cytokine, levels were unchanged with IV-TPN. Thus, the unbalanced Th1/Th2 cytokine milieu in the gut is disadvantageous for IgA production in the gut (Fig. 2) [4]. Gut IL-4 upregulates polymeric immunoglobulin receptor (pIgR), an epithelial transport protein which is needed for the transport of IgA across the mucosa to the gut lumen [13]. Parenteral nutrition also reduces IL-4 levels in the gut impairing the IgA-related immunity [4]. The IECs produce IL-7, a potent stimulator of GALT cell proliferation. IV-TPN reportedly decreases IL-7 production by the IECs, another possible mechanism for parenteral-nutrition-related GALT atrophy [14]. Indeed, exogenous IL-7 during parenteral nutrition restored GALT cell number almost to the level of CHOW animals. The preservation of gut barrier function in IL-7-treated parenteral nutrition mice was tested by observing the survival in a gut-derived sepsis model [15].
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Absence of glutamine and butyric acid in parenteral nutrition solutions L-Glutamine is a conditionally essential amino acid and is an important fuel for gut mucosal cells and immune cells. Absence of L-glutamine in the standard parenteral nutrition solutions is a mechanism for GALT atrophy during parenteral nutrition feeding. Glutamine-supplemented parenteral nutrition resulted in the recovery of GALT cell number and mucosal IgA levels, in association with the preservation of IL-4 and IL-10 mRNA levels within the lamina propria lymphocytes [16] (Table 1). Adding butyric acid, a short-chain fatty acid, by replacing half of acetic acid in the parenteral nutrition solution moderately but significantly restored Peyer’s patches cell number compared with the standard parenteral nutrition group, with moderate increase of IgA levels in the small intestinal and respiratory tract washings [17]. Thus, the absence of specific nutrients may be an important mechanism underlying the standard parenteralnutrition-induced impairment of gut immunity. Alteration of intracellular signaling Influences of parenteral nutrition on intracellular signaling have also been documented using mice models (Fig. 2). The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway provides the intracellular signaling required for a wide array of cytokines including IL-4 and IL-13, both of which are Th2 cytokines and stimulate differentiation and maturation of B cells [13]. Parenteral nutrition was demonstrated to decrease the JAK–STAT pathway by reducing the levels of phosphorylated STAT-6 and JAK-1 [13]. Parenteral nutrition also reduces lymphotoxin b receptor (LTbR) expression in the Peyer’s patches and intestine. Intracellular signal via LTbR upregulates alternative NF-kB pathway, leading to increased expression of MAdCAM-1 in the Peyer’s patches and production of IL-4 and IL-10 [18]. Therefore, changes in MAdCAM-1 expression and gut cytokine milieu during parenteral nutrition may at least partly derive from the reduced LTbR expression. Phosphorylation of extracellular signalregulated kinase (ERK), a MAP kinase, in the LPLs and IELs after in-vitro stimulation with phorbol myristate acetate is also blunted during parenteral nutrition [19]. Once phosphorylated, ERK promotes cell differentiation and proliferation, cytokine production, and immune activation. Therefore, blunted ERK phosphorylation may also be a mechanism for impaired gut immunity during parenteral nutrition.
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Impact of the feeding route on gut mucosal immunity Fukatsu
Miyasaka et al. [20] demonstrated parenteral nutrition to cause significant expansion of Proteobacteria within the intestinal microbiota and increased proinflammatory lamina propria cytokines through MyD88-dependent mechanism, suggesting close relationship between the intestinal microbiota and lamina propria inflammation.
INFLUENCE OF NUTRITIONAL ROUTE ON GUT INNATE IMMUNITY Route of nutrition has great impact not only on the acquired immunity, but also on the innate immunity (Fig. 2). As previously described, IECs secrete various antimicrobial peptides. Secretion of antimicrobial protein secretory phospholipase A2 (sPLA2) from the Paneth cells was evaluated with an ex-vivo intestinal segment culture model [21,22]. Parenteral nutrition resulted in suppressed secretion of the sPLA2 and bactericidal capacity in the ileum compared with CHOW group. Moreover, tissue mRNA expression of other antimicrobial peptides, RegIII-g, lysozyme, and cryptdin, was reduced in the ileum tissue [5 ]. &&
INFLUENCE OF NUTRITIONAL ROUTE ON INTESTINAL EPITHELIAL CELL BARRIER FUNCTION Parenteral nutrition did not increase IFNg levels in the whole intestine, but increased its expression by intraepithelial lymphocytes in mice [4,22]. Parenteral nutrition also increased TNFa and TNFR1 [23 ]. Through the enhanced production of these proinflammatory cytokines, physical barrier of IECs is reportedly compromised. Small intestine transepithelial resistance was decreased and tracer permeability was increased in the IV-TPN group compared with controls. Tight junction protein was downregulated in the TPN mice (Fig. 2). However, IFNg-knockout mice showed recovery of the gut permeability. All of these changes were partly ameliorated with TNFa blocking. &
CLINICAL EVIDENCES OF NUTRITIONAL ROUTE ON GUT IMMUNITY Duran [24] performed a systematic review on the effects of long-term TPN on gut immunity in children with short bowel syndrome. As there was no direct evidence suggesting that TPN promotes bacterial overgrowth, impairs neutrophil functions, inhibits blood bactericidal effect, causes villous atrophy, nor causes death, the conclusion was that the negative effects of TPN on gut immunity are
unproven. However, no observation of gut IgA levels or GALT size was included in this review. Immunohistochemical staining of the terminal ileum tissue resected for colon cancer surgery revealed that patients who had received oral intake before surgery had more T-cell number in the intraepithelial space and lamina propria, more IgAproducing cell number in the lamina propria, and more mature dendritic cells in the lamina propria than those who had not received oral or enteral feeding but had been fed parenterally before surgery [25 ]. Very interestingly, morbidities of infectious complications including surgical site infections, pneumonia, enteritis, and blood stream infections were significantly higher in the parenteral nutrition than in the oral feeding group. These findings are consistent with the data obtained from animal studies and strongly support the beneficial effects of enteral nutrition on gut immunity. &&
HOW TO RESTORE GUT IMMUNITY DURING PARENTERAL NUTRITION? Investigating the mechanisms for parenteralnutrition-induced impairment of gut immunity has given us various insights on how to restore gut immunity during parenteral nutrition. Addition of specific nutrients such as L-glutamine and butyric acid, exogenous administration of cytokines such as IL-7, IL-25 and IL-10, blocking of proinflammatory cytokines IFNg and TNFa, stimulating some intracellular signal pathways, and intravenous injection of some neuropeptides including bombesin, cholecystokinin, and gastrin may be surrogates of enteral nutrition for the restoration of gut immunity during parenteral nutrition [4,13,15,26,27]. However, all of these methods have limitations and cannot fully normalize the gut immunity. Gut microbiota has tremendous contribution to the maintenance of gut immunity through interactions with IECs and GALT. Unfortunately, lack of enteral nutrition changes the gut microflora, but none of the abovementioned therapies could completely retrieve normal commensals in the gut (Table 1).
CONCLUSION In addition to the possible combinations of these therapies, modulation of the gut bacterial flora by probiotics, prebiotics, and synbiotics needs to be tested. Clarifying more precise mechanism for parenteral-nutrition-induced impairment of gut immunity will surely give us good ideas of enteral nutrition surrogates. As gut immunity may quickly change with enteral nutrition refeeding and the amount of enteral nutrition given correlates to
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the size of the GALT and gut IgA levels, clinicians should make any efforts to restart enteral nutrition feeding as soon as possible and increase the dose according to the degree of tolerance. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: & international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637. The former version did not include nutrition therapy; however, this new guidelines refer to the beneficial effects of enteral nutrition. 2. Doig GS, Heighes PT, Simpson F, et al. 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; 35:2018–2027. 3. Goto Y, Ivanov II. Intestinal epithelial cells as mediators of the commensal–host immune crosstalk. Immunol Cell Biol 2013; 91:204– 214. 4. Fukatsu K, Kudsk KA. Nutrition and gut immunity. Surg Clin North Am 2011; 91:755–770. 5. Heneghan AF, Pierre JF, Tandee K, et al. Parenteral nutrition decreases && paneth cell function and intestinal bactericidal activity while increasing susceptibility to bacterial enteroinvasion. JPEN J Parenter Enteral Nutr 2013. [Epub ahead of print]. Beneficial effects of enteral nutrition are demonstrated in terms of gut innate immunity and gut microbiota. 6. Fukatsu K, Sakamoto S, Hara E, et al. Gut ischemia–reperfusion affects gut mucosal immunity: a possible mechanism for infectious complications after severe surgical insults. Crit Care Med 2006; 34:182–187. 7. Mitsui T, Fukatsu K, Yanagawa M, et al. Truncal vagotomy temporarily decreases the pro- and anti-inflammatory cytokine levels in the small intestine. Surg Today 2013. [Epub ahead of print] 8. Moriya T, Fukatsu K, Noguchi M, et al. Intravenous administration of high-dose paclitaxel reduces gut-associated lymphoid tissue cell number and respiratory immunoglobulin A concentrations in mice. Surg Infect (Larchmt) 2013. [Epub ahead of print] 9. Yanagawa M, Fukatsu K, Mitsui T, et al. Effects of a new immunemodulating diet enriched with whey-hydrolyzed peptide, fermented milk, and isomaltulose on gut associated lymphoid tissue in mice. e-SPEN 2013; 8:e241–e245.
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10. Coolsen MM, van Dam RM, van der Wilt AA, et al. Systematic review and meta-analysis of enhanced recovery after pancreatic surgery with particular emphasis on pancreaticoduodenectomies. World J Surg 2013; 37:1909– 1918. 11. Johnson CD, Kudsk KA, Fukatsu K, et al. Route of nutrition influences generation of antibody-forming cells and initial defense to an active viral infection in the upper respiratory tract. Ann Surg 2003; 237:565–573. 12. Ikeda S, Kudsk KA, Fukatsu K, et al. Enteral feeding preserves mucosal immunity despite in vivo MAdCAM-1 blockade of lymphocyte homing. Ann Surg 2003; 237:677–685. 13. Heneghan AF, Pierre JF, Kudsk KA. IL-25 improves IgA levels during parenteral nutrition through the JAK–STAT pathway. Ann Surg 2013; 258:1065–1071. 14. Yang H, Sun X, Haxhija EQ, et al. Intestinal epithelial cell-derived interleukin-7: a mechanism for the alteration of intraepithelial lymphocytes in a mouse model of total parenteral nutrition. Am J Physiol Gastrointest Liver Physiol 2007; 292:G84–G91. 15. Fukatsu K, Moriya T, Murakoshi S, et al. Interleukin-7 treatment reverses parenteral nutrition-induced impairment of resistance to bacterial pneumonia with increased secretory immunoglobulin A levels. J Surg Res 2012; 174:334–338. 16. Fukatsu K, Kudsk KA, Zarzaur BL, et al. TPN decreases IL-4 and IL-10 mRNA expression in lipopolysaccharide stimulated intestinal lamina propria cells but glutamine supplementation preserves the expression. Shock 2001; 15:318– 322. 17. Murakoshi S, Fukatsu K, Omata J, et al. Effects of adding butyric acid to PN on gut-associated lymphoid tissue and mucosal immunoglobulin A levels. JPEN J Parenter Enteral Nutr 2011; 35:465–472. 18. Lan J, Heneghan AF, Sano Y, et al. Parenteral nutrition impairs lymphotoxin b receptor signaling via NF-kB. Ann Surg 2011; 253:996–1003. 19. Maeshima Y, Fukatsu K, Kang W, et al. Lack of enteral nutrition blunts extracellular-regulated kinase phosphorylation in gut-associated lymphoid tissue. Shock 2007; 27:320–325. 20. Miyasaka EA, Feng Y, Poroyko V, et al. Total parenteral nutrition-associated lamina propria inflammation in mice is mediated by a MyD88-dependent mechanism. J Immunol 2013; 190:6607–6615. 21. Omata J, Pierre JF, Heneghan AF, et al. Parenteral nutrition suppresses the bactericidal response of the small intestine. Surgery 2013; 153:17–24. 22. Yang H, Feng Y, Sun X, et al. Enteral versus parenteral nutrition: effect on intestinal barrier function. Ann N Y Acad Sci 2009; 1165:338–346. 23. Feng Y, Teitelbaum DH. 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. Relationship between inflammation and gut barrier function during parenteral nutrition is revealed. 24. Duran B. The effects of long-term total parenteral nutrition on gut mucosal immunity in children with short bowel syndrome: a systematic review. BMC Nurs 2005; 4:2. 25. Okamoto K, Fukatsu K, Hashiguchi Y, et al. Lack of preoperative enteral && nutrition reduces gut-associated lymphoid cell numbers in colon cancer patients: a possible mechanism underlying increased postoperative infectious complications during parenteral nutrition. Ann Surg 2013; 258:1059–1064. There are few clinical studies showing changes in GALT during parenteral nutrition in humans. This study is very important because clinical evidence of GALT atrophy is shown. 26. Genton L, Kudsk KA. Interactions between the enteric nervous system and the immune system: role of neuropeptides and nutrition. Am J Surg 2003; 186:253–258. 27. Sun X, Yang H, Nose K, et al. 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:G139–G147.
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