Glutamine Improves Innate Immunity and Prevents Bacterial Enteroinvasion During Parenteral Nutrition

Background: Patients receiving parenteral nutrition (PN) are at increased risk of infectious complications compared with enteral feeding, which is in part explained by impaired mucosal immune function during PN. Adding glutamine (GLN) to PN has improved outcome in some clinical patient groups. Although GLN improves acquired mucosal immunity, its effect on innate mucosal immunity (defensins, mucus, lysozymes) has not been investigated. Methods: Forty‐eight hours following venous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 10), PN (n = 12), or PN + GLN (n = 13) for 5 days. Small intestine tissue and luminal fluid were collected for mucin 2 (MUC2), lysozyme, cryptdin 4 analysis, and luminal interleukin (IL)–4, IL‐10, and IL‐13 level measurement. Tissue was also harvested for ex vivo intestinal segment culture to assess tissue susceptibility to enteroinvasive Escherichia coli. Results: In both luminal and tissue samples, PN reduced MUC2 and lysozyme (P < .0001, respectively) compared with chow, whereas GLN addition increased MUC2 and lysozyme (luminal, P < .05; tissue, P < .0001, respectively) compared with PN alone. PN significantly suppressed cryptdin 4 expression, while GLN supplementation significantly enhanced expression. IL‐4, IL‐10, and IL‐13 decreased significantly with PN compared with chow, whereas GLN significantly increased these cytokines compared with PN. Functionally, bacterial invasion increased with PN compared with chow (P < .05), while GLN significantly decreased enteroinvasion to chow levels (P < .05). Conclusions: GLN‐supplemented PN improves innate immunity and resistance to bacterial mucosal invasion lost with PN alone. This work confirms a clinical rationale for providing glutamine for the protection of the intestinal mucosa.     

Cranberry Proanthocyanidins Improve the Gut Mucous Layer Morphology and Function in Mice Receiving Elemental Enteral Nutrition

Background: Lamina propria Th2 cytokines, interleukin (IL)‐4 and IL‐13, stimulate goblet cell (GC) proliferation and MUC2 production, which protect the intestinal mucosa. Elemental enteral nutrition (EEN) reduces tissue IL‐4 and impairs barrier function. Proanthocyanidins (PACs) stimulate oral mucin levels. We hypothesized that adding PAC to EEN would maintain Th2–without stimulating Th1–cytokines and preserve luminal MUC2 vs EEN alone. Materials and Methods: Seventy mice were randomized to 5 diet groups–standard chow, intragastric EEN, or EEN with lowPAC, midPAC (50 mg), or highPAC (100 mg PAC/kg BW)–for 5 days, starting 2 days after gastric cannulation. Ileal tissue was analyzed for histomorphology and the cytokines IL‐4, IL‐13, IL‐1β, IL‐6, and TNF‐α by enzyme‐linked immunosorbent assay. MUC2 was measured in intestinal washes. Results: EEN lowered IL‐13 (P < .05) compared with standard chow, whereas IL‐4 was not significant (P < .07). LowPAC and midPAC increased IL‐13 (P < .05), whereas highPAC increased both IL‐4 and IL‐13 (P < .05) compared with EEN. All EEN diets reduced (P < .05) crypt depth compared with the chow group. Compared with standard chow, GC numbers and luminal MUC2 were reduced with EEN (P < .05). These effects were attenuated (P < .05) with midPAC and highPAC. No changes were observed in tissue Th1 cytokines. Conclusions: Adding PACs to EEN reverses impaired intestinal barrier function following EEN by improving the gut mucous layer and function through increased GC size and number as well as levels of MUC2 and ileal IL‐4 and IL‐13.     

Route and type of nutrition and surgical stress influence secretory phospholipase A2 secretion of the murine small intestine

Background: The function of secretory phospholipase A2 (sPLA2) is site dependent. In tissue, sPLA2 regulates eicosanoid production; in circulation, sPLA2 primes neutrophils; and in the intestinal lumen, sPLA2 provides innate bactericidal immunity as a defensin‐related protein. Since parenteral nutrition (PN) primes leukocytes while suppressing intraluminal mucosal immunity, the authors hypothesized that (1) PN would diminish luminal sPLA2 activity but increase activity in intestinal tissue and serum and (2) stress would accentuate these changes. Methods: Mice received chow, a complex enteral diet (CED), intragastric PN (IG‐PN), or PN in experiment 1 and chow, chow+stress, PN, or PN+stress in experiment 2. Results: In experiment 1, luminal sPLA2 activity was greatest in chow and decreased in CED, IG‐PN, and PN, with PN lower than CED and IG‐PN. Compared to that after chow, serum sPLA2 activity dropped after CED, IG‐PN, and PN. Serum sPLA2 was higher in portal than systemic serum. In experiment 2, PN lowered luminal sPLA2 activity vs chow. Stress lowered luminal sPLA2 activity in chow, without change in PN. Following stress, luminal immunoglobulin A increased in chow but not PN. Serum sPLA2 activity increased in PN. Conclusions: PN attenuates sPLA2 activity in intestinal fluid, consistent with suppressed innate mucosal defense. Stress suppresses luminal fluid sPLA2 activity in chow but not the immunoglobulin A response; PN impairs both. Stress significantly elevates serum sPLA2 in PN‐fed mice, consistent with known increased neutrophil priming with PN. PN reduces innate bactericidal immunity of the gut but upregulates serum proinflammatory products poststress.     

Innate Mucosal Immune System Response of BALB/c vs C57BL/6 Mice to Injury in the Setting of Enteral and Parenteral Feeding

Background: Outbred mice exhibit increased airway and intestinal immunoglobulin A (IgA) following injury when fed normal chow, consistent with humans. Parenteral nutrition (PN) eliminates IgA increases at both sites. Inbred mice are needed for detailed immunological studies; however, specific strains have not been evaluated for this purpose. BALB/c and C57BL/6 are common inbred mouse strains but demonstrate divergent immune responses to analogous stress. This study addressed which inbred mouse strain best replicates the outbred mouse and human immune response to injury. Methods: Intravenously cannulated mice received chow or PN for 5 days and then underwent sacrifice at 0 or 8 hours following controlled surgical injury (BALB/c: n = 16–21/group; C57BL/6: n = 12–15/group). Bronchoalveolar lavage (BAL) was analyzed by enzyme‐linked immunosorbent assay for IgA, tumor necrosis factor–α (TNF‐α), interleukin (IL)–1β, and IL‐6, while small intestinal wash fluid (SIWF) was analyzed for IgA. Results: No significant increase in BAL IgA occurred following injury in chow‐ or PN‐fed BALB/c mice (chow: P = .1; PN: P = .7) despite significant increases in BAL TNF‐α and SIWF IgA (chow: 264 ± 28 vs 548 ± 37, P < .0001; PN: 150 ± 12 vs 301 ± 17, P < .0001). Injury significantly increased mucosal IgA in chow‐fed C57BL/6 mice (BAL: 149 ± 33 vs 342 ± 87, P = .01; SIWF: 236 ± 28 vs 335 ± 32, P = .006) and BAL cytokines. After injury, PN‐fed C57BL/6 mice exhibited no difference in BAL IgA (P = .9), BAL cytokines, or SIWF IgA (P = .1). Conclusions: C57BL/6 mice exhibit similar airway responses to injury as outbred mice and humans, providing an appropriate model for studying mucosal responses to injury. The BALB/c mucosal immune system responds differently to injury and does not replicate the human injury response.     

Bombesin Improves Adaptive Immunity of the Salivary Gland During Parenteral Nutrition

Background: The parotid and submandibular salivary glands are gut‐associated lymphoid tissues (GALTs) that secrete immune compounds into the oral cavity. Parenteral nutrition (PN) without enteral stimulation decreases GALT function, including intestinal lymphocyte counts and secretory immunoglobulin A (sIgA) levels. Since the neuropeptide bombesin (BBS), a gastrin‐releasing peptide analogue, stimulates intestinal function and restores GALT parameters, we hypothesized that PN + BBS would stimulate parotid and salivary gland IgA levels, T lymphocytes, and IgA plasma cell counts compared with PN alone. Methods: Male (Institute of Cancer Research) ICR mice received intravenous catheters and were randomized to chow with saline, PN, or PN + BBS (15 µg/tid/mouse) for 5 days (8/group), 2 days after cannulation. Salivary glands were weighed and either frozen for IgA and amylase analysis or fixed for histological analysis of acinar cells, IgA+ plasma cells, and T lymphocytes. Small intestinal wash fluid was collected for IgA regression analysis with salivary glands. Results: PN reduced organ weight, acinar cell size, and amylase activity compared with chow; BBS had no significant effects on these parameters. Compared with chow, PN significantly reduced salivary gland IgA levels, IgA+ plasma cells, and T lymphocytes. PN + BBS significantly elevated IgA and restored cellularity compared with PN. Salivary gland tissue homogenate IgA levels significantly correlated with intestinal fluid IgA levels. Conclusions: Compared with chow, PN results in atrophy of the salivary glands characterized by reduced amylase, IgA, and immune cellularity. BBS has no effect on acinar cells or amylase activity compared with PN but maintains tissue IgA and plasma cells and T‐lymphocyte numbers compared with chow.     

Parenteral Nutrition Decreases Paneth Cell Function and Intestinal Bactericidal Activity While Increasing Susceptibility to Bacterial Enteroinvasion

Introduction: Parenteral nutrition (PN) increases the risk of infection in patients with contraindication to enteral feeding. Paneth cells produce and secrete antimicrobial products that protect the mucosa from pathogens. Their loss is associated with increased host‐pathogen interactions, mucosal inflammation, and altered microbiome composition. Hypothesis: We hypothesized that PN reduces Paneth cell product expression, and these changes would reduce bactericidal properties of tissue secretions following cholinergic stimulation, increase mucosal enteroinvasion, and shift the intestinal microbiome. Method: Experiment 1: Male ICR mice were randomized to Chow (n = 8) or PN (n = 8). Ileum tissue was collected for Paneth cell antimicrobial expression using RT‐PCR, stimulated with a cholinergic agonist degranulate Paneth cells bactericidal activity, or used to assess bacterial enteroinvasion in EVISC. Experiment 2: Mice were randomized to Chow (n = 11) or PN (n = 8) and ileum washing was collected for 16s pyrosequencing analysis. Results: Compared to Chow, PN decreased tissue expression of REGIII‐g (p < 0.002), lysozyme (p < 0.002), and cryptdin‐4 (p < 0.03). At the phylum level, PN decreased total Firmicutes but increased total Bacteroidetes, and Proteobacteria. Functionally, secretions from PN tissue was less bactericidal (p < 0.03) and demonstrated increased susceptibility to enteroinvasion by E coli (p < 0.02). Conclusion: PN without enteral nutrition impairs innate mucosal immune function. Tissue expression of Paneth cell antimicrobial proteins decreases associated with compositional shifts to the microbiome, decreased bactericidal activity of mucosal secretions and greater susceptibility of to enteroinvasion by E coli. These changes may explain in‐part the increased risk of infection in parenterally fed patients.     

Surgical Anatomy Does Not Affect the Progression of Intestinal Failure–Associated Liver Disease in Neonatal Piglets

Background: Intestinal failure–associated liver disease (IFALD) causes significant morbidity in neonates with short bowel syndrome (SBS) dependent on parenteral nutrition (PN). Resected ileum, with loss of the ileocecal valve (ICV), is the most common anatomy in SBS, yet its impact on IFALD has not been adequately studied. Methods: Neonatal piglets were randomized to 75% intestinal resection with jejunocolic anastomosis (JC, n = 12), 75% resection with jejunoileal anastomosis and intact ICV (JI, n = 13), PN‐fed sham (sham, n = 14), or sow‐fed control (SF, n = 8). Surgical and sham piglets received 100% PN for 14 days before bile flow was measured and blood chemistry, liver pathology, jejunal permeability, and bacterial translocation were assessed. Results: Bile flow was lower for PN‐fed compared with SF (P = .002) but not different between the PN‐fed groups. Total bilirubin (P = .03) and liver pathology (P < .001) were greater in PN‐fed than SF groups but not different between PN‐fed groups. Serum bile acids were increased in sham (P = .01) but not different between SBS groups. PN‐fed piglets with sepsis had lower bile flow (P = .001) and increased bilirubin (P = .04). Neither jejunal permeability nor bacterial translocation were different between JC, JI, or sham groups. Conclusion: Contrary to our hypothesis, the remnant anatomy does not appear to worsen the progression of IFALD. However, the role of sepsis in IFALD should be further explored, in addition to other mechanisms, including PN factors, host immune responses, and intestinal bacterial dysbiosis.     

Parenteral Nutrition Rapidly Reduces Hepatic Mononuclear Cell Numbers and Lipopolysaccharide Receptor Expression on Kupffer Cells in Mice

Background: Parenteral nutrition (PN) reduces the number of hepatic mononuclear cell (MNCs) and impairs their function, resulting in poor survival after intraportal bacterial challenge in mice. Our recent animal study demonstrated resumption of enteral nutrition after PN to rapidly restore hepatic MNC numbers (in 12 hours) and lipopolysaccharide (LPS) receptor expression on Kupffer cells (in 48 hours). The present study examined the time courses of hepatic MNC number reductions and LPS receptor expression changes in mice receiving PN. Methods: Male mice (n = 49) from the Institute of Cancer Research were divided into chow (n = 8), PN0.5 (n = 8), PN1 (n = 8), PN2 (n = 9), PN3 (n = 9), and PN5 (n = 7) groups. The chow group was given chow with an intravenous saline infusion. The PN groups were fed parenterally for 0.5, 1, 2, 3, or 5 days following the chow‐feeding courses. After 7 days of nutrition support, hepatic MNCs were isolated and counted. The expression of LPS receptors on Kupffer cells was analyzed by flow cytometry. Results: Hepatic MNC numbers rapidly reached their lowest level in the PN0.5 and PN1 groups but were somewhat restored thereafter and remained stable after the third day, without significant differences between any 2 of the PN groups. CD14 and Toll‐like receptor 4/MD‐2 expressions both showed significant reductions in the PN1 group compared with the chow group and gradually decreased to their lowest levels in the PN5 group. Conclusions: PN administration rapidly reduces hepatic MNC numbers and LPS receptor expression on Kupffer cells.     

Effect of Recombinant Human Growth Hormone on Intestinal Absorption and Body Composition in Children With Short Bowel Syndrome

This prospective study aimed to establish the effect of recombinant human growth hormone (rhGH) on intestinal function in children with short bowel syndrome (SBS). Eight children with neonatal SBS were included. All were dependent on parenteral nutrition (PN) for >3 years (range, 3.8–11.6 years), with PN providing >50% of recommended dietary allowance for age (range, 50%–65%). The subjects received rhGH (Humatrope) 0.13 mg/kg/d subcutaneously over a 12‐week period. The follow‐up was continued over a 12‐month period after rhGH discontinuation. Clinical and biological assessments were performed at baseline, at the end of the treatment period, and 12 months after the end of treatment. No side effects related to rhGH were observed. PN requirements were decreased in all children during the course of rhGH treatment. Between baseline and the end of treatment, significant increases were observed in concentrations (mean ± standard deviation) of serum insulin‐like growth factor 1 (103.1 ± 49.9 µg/L vs 153.5 ± 82.2 µg/L; P < .01), serum insulin‐like growth factor–binding protein 3 (1.7 ± 0.6 mg/L vs 2.5 ± 0.9 mg/L; P < .001), and plasma citrulline (16.5 ± 14.8 µmol/L vs 25.2 ± 18.3 µmol/L; P < .05). A median 54% increase in enteral intake (range, 10%–244%) was observed (P < .001) and net energy balance improved significantly (P < .002). It was necessary for 6 children to be maintained on PN or restarted after discontinuation of rhGH treatment, and they remained on PN until the end of the follow‐up period. A 12‐week high‐dose rhGH treatment allowed patients to decrease PN, but only 2 patients could be definitively weaned from PN. Indications and cost‐effectiveness of rhGH treatment for SBS pediatric patients need further evaluation.     

Teduglutide‐Stimulated Intestinal Adaptation Is Complemented and Synergistically Enhanced by Partial Enteral Nutrition in a Neonatal Piglet Model of Short Bowel Syndrome

Background: Teduglutide, a glucagon‐like peptide‐2 (GLP‐2) analogue, is available for long‐term use by parenteral nutrition (PN)–dependent adults to promote intestinal adaptation but is not approved for use in pediatric patients. The objective of this study was to assess teduglutide‐stimulated induced intestinal adaptation, potential synergies with partial enteral nutrition (PEN), and distinct temporal markers of adaptation in a neonatal piglet model of short bowel syndrome (SBS). Materials and Methods: Neonatal piglets (48 hours old; n = 72) underwent an 80% jejunoileal resection and were randomized to 1 of 4 treatment groups, in a 2 × 2 factorial design, with PN or PEN (80% standard PN/20% standard enteral nutrition) and teduglutide (0.1 mg/kg/d) or control. Piglets received nutrient infusions for 4 hours, 48 hours, or 7 days. Results: Teduglutide improved (P < .05) mucosal surface area (villus height: duodenum, jejunum, ileum; crypt depth: ileum, colon; proliferation: duodenum, jejunum, ileum; colon; apoptosis: jejunum, ileum, colon) and acute nutrient processing capacity (glucose: duodenum, jejunum, ileum; glutamine: duodenum, jejunum). These effects were complemented and synergistically enhanced by PEN in both site and timing of action. Structural adaptations preceded functional adaptations, but crypt depth remained a strong indicator of adaptation, regardless of time. Conclusions: The combination of teduglutide and PEN enhances intestinal adaptation beyond that of either therapy alone.     

Partial Enteral Nutrition Preserves Elements of Gut Barrier Function,Including Innate Immunity,Intestinal Alkaline Phosphatase (IAP) Level,and Intestinal Microbiota in Mice

Lack of enteral nutrition (EN) during parenteral nutrition (PN) leads to higher incidence of infection because of gut barrier dysfunction. However, the effects of partial EN on intestina linnate immunity, intestinal alkaline phosphatase (IAP) and microbiota remain unclear. The mice were randomized into six groups to receive either standard chow or isocaloric and isonitrogenous nutritional support with variable partial EN to PN ratios. Five days later, the mice were sacrificed and tissue samples were collected. Bacterial translocation, the levels of lysozyme, mucin 2 (MUC2), and IAP were analyzed. The composition of intestinal microbiota was analyzed by 16S rRNA pyrosequencing. Compared with chow, total parenteral nutrition (TPN) resulted in a dysfunctional mucosal barrier, as evidenced by increased bacterial translocation (p < 0.05), loss of lysozyme, MUC2, and IAP, and changes in the gut microbiota (p < 0.001). Administration of 20% EN supplemented with PN significantly increased the concentrations of lysozyme, MUC2, IAP, and the mRNA levels of lysozyme and MUC2 (p < 0.001). The percentages of Bacteroidetes and Tenericutes were significantly lower in the 20% EN group than in the TPN group (p < 0.001). These changes were accompanied by maintained barrier function in bacterial culture (p < 0.05). Supplementation of PN with 20% EN preserves gut barrier function, by way of maintaining innate immunity, IAP and intestinal microbiota.     

Effect of Hyperalimentation and Insulin‐Treated Hyperglycemia on Tyrosine Levels in Very Preterm Infants Receiving Parenteral Nutrition

Background: Hyperalimentation describes the increase in glucose, amino acids (AAs), and lipid intake designed to overcome postnatal growth failure in preterm infants. Preterm infants are dependent on phenylalanine metabolism to maintain tyrosine levels because of tyrosine concentration limits in parenteral nutrition (PN). We hypothesized that hyperalimentation would increase individual AA levels when compared with the control group but avoid high phenylalanine/tyrosine levels. Aim: To compare the plasma AA profiles on days 8–10 of life in preterm infants receiving a hyperalimentation vs a control regimen. Methods: Infants <29 weeks’ gestation were randomized to receive hyperalimentation (30% more PN macronutrients) or a control regimen. Data were collected to measure macronutrient (including protein) intake and PN intolerance, including hyperglycemia, insulin use, urea, and AA profile. Plasma profiles of 23 individual AA levels were measured on days 8–10 using ion exchange chromatography. Results: One hundred forty‐two infants were randomized with 118 AA profiles obtained on days 8–10. There were no differences in birth weight or gestation between groups. There was an increase (P < .05) in 8 of 23 median individual plasma AA levels when comparing hyperalimentation (n = 57) with controls (n = 61). Only tyrosine levels (median; interquartile range) were lower with hyperalimentation: 27 (15–52) µmol/L vs 43 (24–69) µmol/L (P < .01). Hyperalimentation resulted in more insulin‐treated hyperglycemia. No difference between the groups was apparent in tyrosine levels when substratified for insulin‐treated hyperglycemia. All insulin vs no insulin comparisons showed lower tyrosine levels with insulin treatment (P < .01). Conclusion: Hyperalimentation can result in paradoxically low plasma tyrosine levels associated with an increase in insulin‐treated hyperglycemia.     

ω‐3 Fatty Acids Prevent Hepatic Steatosis,Independent of PPAR‐α Activity,in a Murine Model of Parenteral Nutrition–Associated Liver Disease

Objectives: ω‐3 Fatty acids (FAs), natural ligands for the peroxisome proliferator‐activated receptor–α (PPAR‐α), attenuate parenteral nutrition–associated liver disease (PNALD). However, the mechanisms underlying the protective role of ω‐3 FAs are still unknown. The aim of this study was to determine the effects of ω‐3 FAs on hepatic triglyceride (TG) accumulation in a murine model of PNALD and to investigate the role of PPAR‐α and microsomal triglyceride transfer protein (MTP) in this experimental setting. Methods: 129S1/SvImJ wild‐type or 129S4/SvJaePparatm/Gonz/J PPAR‐α knockout mice were fed chow and water (controls); oral, fat‐free PN solution only (PN‐O); PN‐O plus intraperitoneal (IP) ω‐6 FA‐predominant supplements (PN–ω‐6); or PN‐O plus IP ω‐3 FA (PN–ω‐3). Control and PN‐O groups received sham IP injections of 0.9% NaCl. Hepatic histology, TG and cholesterol, MTP activity, and PPAR‐α messenger RNA were assessed after 19 days. Results: In all experimental groups, PN feeding increased hepatic TG and MTP activity compared with controls. Both PN‐O and PN–ω‐6 groups accumulated significantly greater amounts of TG when compared with PN–ω‐3 mice. Studies in PPAR‐α null animals showed that PN feeding increases hepatic TG as in wild‐type mice. PPAR‐α null mice in the PN‐O and PN–ω‐6 groups demonstrated variable degrees of hepatic steatosis, whereas no evidence of hepatic fat accumulation was found after 19 days of oral PN plus IP ω‐3 FAs. Conclusions: PN induces TG accumulation (steatosis) in wild‐type and PPAR‐α null mice. In PN‐fed wild‐type and PPAR‐α null mice given IP ω‐3 FAs, reduced hepatic TG accumulation and absent steatosis are found. Prevention of steatosis by ω‐3 FAs results from PPAR‐α–independent pathways.     

In a Neonatal Piglet Model of Intestinal Failure,Administration of Antibiotics and Lack of Enteral Nutrition Have a Greater Impact on Intestinal Microflora Than Surgical Resection Alone

Background: Data are limited on how short bowel syndrome (SBS) affects the healthy developing intestinal microbiome, with even less assessing different SBS anatomical surgical models. This study was conducted to describe the “ileal” and “colonic” microflora in 2 surgical models of SBS. Materials and Methods: Neonatal piglets (2–5 days old) underwent intestinal resection, leaving the ileum (JI anatomy, n = 6) or removing the ileum and ileocecal valve (JC anatomy, n = 5), or sham surgery (sham; n = 4). JI, JC, and sham piglets commenced parenteral nutrition on day 0 and received ampicillin and trimethoprim‐sulfadoxine on days 0–4 for prevention of line sepsis. At day 7, ileal and colonic digesta were collected, and they were also collected from age‐matched sow‐fed piglets (n = 6). DNA extraction, sequencing, and annotation followed standard procedures. Results: Colonic and ileal bacterial genus diversity and relative bacterial abundance were greater (P < .05) in sow‐fed compared with JI, JC, and sham piglets; however, minor differences were observed in either location between sham, JI, and JC piglets and within the surgical model. In the colon, sow‐fed piglets had higher (P < .05) abundance of Lactobacillus (26%) and tended to have lower (P = .06) abundance of Enterococcus (<.1%) than JI, JC, or sham piglets, in which Lactobacillus and Enterococcus abundance averaged <.1% and 9%, respectively. Conclusions: Intestinal resection reduces bacterial diversity in the large bowel, and the difference is associated with the presence/absence of the ileum and ileocecal valve. The lack of enteral nutrition and antibiotic administration (ie, sow‐fed vs surgery) had a greater influence on the observed shift in diversity and relative abundance than intestinal resection.     

Incidence,Prevention, and Treatment of Parenteral Nutrition–Associated Cholestasis and Intestinal Failure–Associated Liver Disease in Infants and Children

Background: Cholestasis is a significant life‐threatening complication in children on parenteral nutrition (PN). Strategies to prevent/treat PN‐associated cholestasis (PNAC) and intestinal failure–associated liver disease (IFALD) have reached moderate success with little supporting evidence. Aims of this systematic review were (1) to determine the incidence of PNAC/IFALD in children receiving PN for ≥14 days and (2) to review the efficacy of measures to prevent/treat PNAC/IFALD. Methods: Of 4696 abstracts screened, 406 relevant articles were reviewed, and studies on children with PN ≥14 days and cholestasis (conjugated bilirubin ≥ 2 mg/dL) were included. Analyzed parameters were (1) PNAC/IFALD incidence by decade and by PN length and (2) PNAC/IFALD prevention and treatment (prospective studies). Results: Twenty‐three articles (3280 patients) showed an incidence of 28.2% and 49.8% of PNAC and IFALD, respectively, with no evident alteration over the last decades. The incidence of PNAC was directly proportional to the length of PN (from 15.7% for PN ≤1 month up to 60.9% for PN ≥2 months; P < .0001). Ten studies on PNAC met inclusion criteria. High or intermediate‐dose of oral erythromycin and aminoacid‐free PN with enteral whey protein gained significant benefits in preterm neonates (P < .05, P = .003, and P < .001, respectively). None of the studies reviewed met inclusion criteria for treatment. Conclusions: The incidence of PNAC/IFALD in children has no obvious decrease over time. PNAC is directly correlated to the length of PN. Erythromycin and aminoacid‐free PN with enteral whey protein have shown to prevent PNAC in preterm neonates. There is a lack of high‐quality prospective studies, especially on IFALD.     

Characterization of Fatty Acid Profiles in Infants With Intestinal Failure–Associated Liver Disease

Background

The purpose of this study was to characterize fatty acid profiles (FAPs) in parenteral nutrition (PN)‐dependent infants with intestinal failure–associated liver disease (IFALD) receiving soybean oil–based lipid emulsion (SO) doses of ～3 and ～1 g/kg/d.

Methods

Prospectively collected data were retrospectively reviewed. Serum FAPs of patients <1 year old who experienced development of IFALD while receiving standard PN with SO were examined before transitioning to a fish oil–based lipid emulsion for IFALD treatment. Time on SO, dose, gestational age, and weight‐ and length‐for‐age z scores were also reviewed.

Results

Among the 49 patients analyzed, there were no differences in demographics or anthropometrics between patients who received standard SO (SO‐S) (n = 14, range of dosage 2.06–3.31 g/kg/d) and reduced SO (SO‐R) (n = 35, range of dosage 0.90–1.34 g/kg/d). Patients received SO for a median of 53 days (interquartile range 39, 73) before FAP measurement. Patients who received SO‐R had significantly higher Mead acid and lower α‐linolenic, eicosapentaenoic, linoleic, stearic, total ω‐3, and total ω‐6 fatty acid levels than patients who received SO‐S (P < .01). Triene:tetraene ratios were higher in patients who received SO‐R (P = .0009), and no patients experienced biochemical essential fatty acid deficiency (EFAD).

Conclusion

PN‐dependent infants with IFALD receiving SO‐R have different FAPs than patients receiving SO‐S. No patients in either group had biochemical EFAD.     

Parenteral Plant Sterols Accumulate in the Liver Reflecting Their Increased Serum Levels and Portal Inflammation in Children With Intestinal Failure

Background: Parenteral plant sterols (PSs) are considered hepatotoxic; however, liver PSs and their associations with liver injury in patients with intestinal failure (IF) have not been reported. Materials and Methods: We analyzed liver and serum PS (avenasterol, campesterol, sitosterol, and stigmasterol) concentrations and ratios to cholesterol and their associations with biochemical and histologic liver damage in children with IF during (n = 7) parenteral nutrition (PN) and after weaning off it (n = 9), including vegetable oil–based lipid emulsions. Results: Liver avenasterol, sitosterol, and total PS concentrations and cholesterol ratios were 2.4‐fold to 5.6‐fold higher in PN‐dependent patients (P < .05). Parenteral PS delivery reflected liver avenasterol and sitosterol ratios to cholesterol (r = 0.83–0.89, P = .02–.04), while serum and liver total PS levels were positively interrelated (r = 0.98, P < .01). Any liver histopathology was equally common while portal inflammation more frequent (57 vs 0%, P = .02) in PN‐dependent patients. All liver PS fractions correlated positively with histologic portal inflammation (r = 0.53–0.66, P < .05), and their total concentration was significantly (P = .01) higher among patients with versus without portal inflammation. In PN‐dependent patients, liver fibrosis and any histopathology correlated with liver campesterol and stigmasterol levels (r = 0.79–0.87, P ≤ .03). Conclusion: Among children with IF, parenteral PSs accumulate in the liver, reflect their increased serum levels, and relate with biochemical liver injury, portal inflammation, and liver fibrosis, thus supporting their role in promoting liver damage.     

Soluble Dietary Fiber Ameliorates Radiation‐Induced Intestinal Epithelial‐to‐Mesenchymal Transition and Fibrosis

Background: Intestinal fibrosis is a late complication of pelvic radiotherapy. Epithelial‐to‐mesenchymal transition (EMT) plays an important role in tissue fibrosis. The aim of this study was to examine the effect of soluble dietary fiber on radiation‐induced intestinal EMT and fibrosis in a mouse model. Materials and Methods: Apple pectin (4% wt/wt in drinking water) was administered to wild‐type and pVillin‐Cre‐EGFP transgenic mice with intestinal fibrosis induced by a single dose of abdominal irradiation of 10 Gy. The effects of pectin on intestinal EMT and fibrosis, gut microbiota, and short‐chain fatty acid (SCFA) concentration were evaluated. Results: Intestinal fibrosis in late radiation enteropathy showed increased submucosal thickness and subepithelial collagen deposition. Enhanced green fluorescent protein (EGFP)⁺/vimentin⁺ and EGFP⁺/α–smooth muscle actin (SMA)⁺ coexpressing cells were most clearly observed at 2 weeks after irradiation and gradually decreased at 4 and 12 weeks. Pectin significantly attenuated the thickness of submucosa and collagen deposition at 12 weeks (24.3 vs 27.6 µm in the pectin + radiation‐treated group compared with radiation‐alone group, respectively, P < .05; 69.0% vs 57.1%, P < .001) and ameliorated EMT at 2 and 4 weeks. Pectin also modulated the intestinal microbiota composition and increased the luminal SCFA concentration. Conclusion: The soluble dietary fiber pectin protected the terminal ileum against radiation‐induced fibrosis. This effect might be mediated by altered SCFA concentration in the intestinal lumen and reduced EMT in the ileal epithelium.