Parenteral Nutrition Is Associated With Intestinal Morphologic and Functional Changes in Humans

Buchman, Alan L.; Moukarzel, Adib; Bhuta, Sunita; Belle, Malleswari; Ament, Marvin E.; Eckhert, Curtis D.; Hollander, Daniel; Gornbein, Jeff; Kopple, J D; Vijayaroghavan, S. R.

doi:10.1177/0148607195019006453

Cited by 377 publications

(188 citation statements)

References 33 publications

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“…It is therefore frequently necessary to support the patient with parenteral nutrition which is associated with a decreased enzyme activity and an increased intestinal permeability, potentially leading to an increased risk of bacteraemia and endotoxaemia (Guedon et al, 1986;Buchman et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Oral glutamine in paediatric oncology patients: a dose finding study

et al. 2003

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Objective: The purpose of this study was to determine the most appropriate dose of oral glutamine to use in a further clinical study in paediatric oncology patients. Design: This was a phase I, pharmokinetic study. Setting: The study was carried out at The Yorkshire Regional Centre for Paediatric Oncology and Haematology, St James's University Hospital, Leeds, UK. Subjects: Thirteen patients undergoing treatment for paediatric malignancy participated in this study. All 13 completed the study. Interventions: The most appropriate dose was determined by patient acceptability and by plasma glutamine and ammonia levels measured at timed intervals after ingestion of a single glutamine dose. Results: Doses of 0.35, 0.5 and 0.65 g=kg were well tolerated with no untoward plasma glutamine and ammonia levels. One patient was recruited to a higher dose of 0.75 g=kg, but the plasma glutamine and ammonia levels peaked at 2601 and 155 mmol=l, respectively. The ammonia level was greater than the acceptable upper limit. It was difficult to disperse the glutamine adequately at this dose, resulting in the suspension being found to be unpalatable and therefore no further patients were recruited at this dose. Conclusion: It was concluded that 0.65 g=kg is a safe dose of glutamine to use in a clinical study in paediatric oncology patients. Sponsorship: Scientific Hospital Supplies UK Ltd provided the L-glutamine and financial help for the biochemical analysis.

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Section: Introductionmentioning

confidence: 99%

Oral glutamine in paediatric oncology patients: a dose finding study

et al. 2003

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“…The molecular mechanisms that govern barrier function are incompletely understood, but it is clear that under conditions of starvation and disease, the gut barrier becomes impaired, leading to significant morbidity and mortality (1)(2)(3)(4)(5)(6)(7)(8). Trophic enteral feeding to prevent gut mucosal atrophy and resultant barrier dysfunction has become part of the standard treatment of intensive care unit patients (9)(10)(11)(12)(13)(14).…”

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Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition

Goldberg

Austen

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

314

323

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Under conditions of starvation and disease, the gut barrier becomes impaired, and trophic feeding to prevent gut mucosal atrophy has become a standard treatment of critically ill patients. However, the mechanisms responsible for the beneficial effects of enteral nutrition have remained a mystery. Using in vitro and in vivo models, we demonstrate that the brush-border enzyme, intestinal alkaline phosphatase (IAP), has the ability to detoxify lipopolysaccharide and prevent bacterial invasion across the gut mucosal barrier. IAP expression and function are lost with starvation and maintained by enteral feeding. It is likely that the IAP silencing that occurs during starvation is a key component of the gut mucosal barrier dysfunction seen in critically ill patients.A mong the most critical functions of the mammalian gut mucosa is to provide a barrier to luminal microbes and toxins while simultaneously allowing for the necessary digestion and absorption of dietary nutrients. The molecular mechanisms that govern barrier function are incompletely understood, but it is clear that under conditions of starvation and disease, the gut barrier becomes impaired, leading to significant morbidity and mortality (1-8). Trophic enteral feeding to prevent gut mucosal atrophy and resultant barrier dysfunction has become part of the standard treatment of intensive care unit patients (9-14). The mechanism(s) responsible for the beneficial effects of trophic feeding are not understood.Intestinal alkaline phosphatase (IAP), a brush-border protein that hydrolyzes monophosphate esters, is expressed exclusively in villus-associated enterocytes and is considered an excellent marker for crypt-villus differentiation (15-18). Narisawa et al. (19) reported that compared with their wild-type (WT) littermates, mice lacking IAP gained more weight under conditions of a high-fat diet. In addition, several studies have shown that the IAP enzyme is capable of detoxifying LPS, likely through dephosphorylation of the lipid A moiety, the primary source of its endotoxic effects (20). Despite these few reports, the physiological role of IAP within the gut has not been elucidated. Results and DiscussionTo examine the functional role of IAP, we developed in vitro model systems using intestinal cell lines (T84, HT-29, and IEC-6) that express little or no IAP under basal conditions. Stable cell lines were created that overexpress IAP (Fig. 1A), and enzyme assays were used to determine the cellular localization of the ectopically expressed IAP protein. The results in Fig. 1B show that parent cells make little, if any, endogenous IAP. In contrast, large amounts of IAP enzyme are seen in the stably transfected cells. Importantly, the vast majority of the IAP activity is in the membrane fraction as opposed to the cytosol. Fig. 1C shows the results of the control experiment used to validate our separation of membranous and cytosolic fractions, confirming that the majority of the MAPK enzyme activity exists within the cytosol rather than the membrane. This membrane ...

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“…The necessity for parenteral nutrition (PN) support represents a pathological situation for the gut that is characterized by greater intestinal permeability with potential for intestinal atrophy (16). Furthermore, PN modulates the immune response of the intestine leading to higher risk of infection (17,18).…”

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Cysteinyl-glycine reduces mucosal proinflammatory cytokine response to fMLP in a parenterally-fed piglet model

Nosworthy

Brunton

2016

Pediatr Res

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Background: PepT1 transports dietary and bacterial peptides in the gut. We hypothesized that cysteinyl-glycine would ameliorate the inflammatory effect of a bacterial peptide, formylmethionyl-leucyl-phenylalanine (fMLP), in both sow-fed and parenterally-fed piglets. Methods: An intestinal perfusion experiment was performed in piglets (N = 12) that were sow-reared or provided with parenteral nutrition (PN) for 4 d. In each piglet, five segments of isolated intestine were perfused with five treatments including cysteine and glycine, cysteinyl-glycine, fMLP, free cysteine and glycine with fMLP, or cysteinyl-glycine with fMLP. Mucosal cytokine responses and intestinal morphology was assessed in each gut segment. results: PN piglets had lower mucosal IL-10 by approximately 20% (P < 0.01). Cysteinyl-glycine lowered TNF-α response to fMLP in PN-fed animals and IFN-γ response to fMLP in both groups (P < 0.05). The free cysteine and glycine treatment reduced TNF-α in sow-fed animals (P < 0.05). fMLP affected villus height in parenterally (P < 0.05), but not sow-fed animals. conclusion: Parenteral feeding conferred a susceptibility to mucosal damage by fMLP. The dipeptide was more effective at attenuating the inflammatory response to a bacterial peptide than free amino acids. This may be due to competitive inhibition of fMLP transport or a greater efficiency of transport of dipeptides. t he products of protein digestion that are absorbed by the small intestinal epithelium include free amino acids and small peptides of two to three residues in length. These di/tripeptides are removed from the nutrient rich intestinal lumen by a H + /peptide symporter, peptide transporter 1 or PepT1 (1). This transporter is localized to the apical surface of the intestinal villi and has broad substrate specificity. Potential substrates for PepT1 include almost all possible dietary di/ tripeptides (1), some antibiotics (2-4) and proinflammatory bacterial peptides (5-8).The primary neutrophil chemotactic substance produced by Escherichia coli is formyl-methionyl-leucyl-phenylalanine (fMLP) (9). This tripeptide is the most predominant N-formylated peptide present in the colonic lumen of humans (9).PepT1-mediated transport of fMLP has been demonstrated in cell culture where uptake of fMLP was inhibited by the presence of known substrates of PepT1 (10,11). Further, the presence of fMLP induced neutrophil migration across an epithelial monolayer, an activity that was abolished if fMLP uptake was inhibited. PepT1-mediated transport of fMLP has also been demonstrated using in vivo rat models (12,13). In particular, uptake of fMLP has been investigated in rats using an intestinal perfusion approach (12). Marked inflammatory response occurred in jejunal segments perfused with fMLP, an intestinal position known to have high expression of PepT1. This inflammation was accompanied by an increase in DNA binding by NFκβ, a transcription factor involved in the regulation of proinflammatory cytokines. This transcription factor is capable of inducing transcri...

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Parenteral Nutrition Is Associated With Intestinal Morphologic and Functional Changes in Humans

Cited by 377 publications

References 33 publications

Oral glutamine in paediatric oncology patients: a dose finding study

Oral glutamine in paediatric oncology patients: a dose finding study

Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition

Cysteinyl-glycine reduces mucosal proinflammatory cytokine response to fMLP in a parenterally-fed piglet model

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