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.     

Differential Effects on Intestinal Adaptation Following Exogenous Glucagon‐Like Peptide 2 Therapy With and Without Enteral Nutrition in Neonatal Short Bowel Syndrome

Background: We aim to study the efficacy of exogenously administered glucagon‐like peptide 2 (GLP‐2) on intestinal adaptation in 2 preclinical models of neonatal short bowel syndrome (SBS) according to remnant intestinal anatomy, with and without ileum. Furthermore, we aim to determine if this adaptive effect was potentiated with enteral nutrition (EN). Methods: Neonatal piglets were block‐randomized to 75% mid‐intestinal (JI group, retains ileum) or distal‐intestinal (JC group, has no ileum) resection or no resection (sham control) and GLP‐2 treatment (11 nmol/kg/d) or saline control for 7 days. Piglets received nutrition support, either 100% parenteral nutrition (PN; 0% EN, n = 32 in total) or 80% PN + 40% EN (n = 28 in total). Adaptation was assessed by morphological and histological changes, as well as RT quantitative polymerase chain reaction of nutrient transporters and tight junctional proteins and fat absorption. Data are analyzed by 3‐way analysis of variance (ANOVA) and 2‐way ANOVA per EN level. Results: GLP‐2 treatment lengthened villi, deepened crypts, and improved intestinal weight in the remnant intestine of JC piglets. EN was a more potent adaptive stimulus for JI piglets. Small intestinal lengthening occurred only in the JI group, when given EN. There was no difference in total fat absorption and messenger RNA expression of nutrient transporters and tight junctional proteins. Conclusions: GLP‐2 administration augmented structural adaptation in JC piglets with distal intestinal resection. Given JI anatomy, further stimulation by GLP‐2 treatment over innate adaptation and stimulation by EN was modest and restricted to ileum. The differential effect of GLP‐2 in neonatal SBS, depending on remnant anatomy, has important implications for clinical translation and planning of clinical trials.     

Effects of Polymeric Formula vs Elemental Formula in Neonatal Piglets With Short Bowel Syndrome

Background: Intestinal adaptation is important for recovery in short bowel syndrome (SBS). This process is dependent on the presence of enteral nutrition (EN) and trophic factors, such as glucagon‐like peptide‐2 (GLP‐2). In clinical practice, elemental formula is often used to feed neonates with SBS, whereas animal studies suggest polymeric formula promotes better intestinal adaptation. In neonatal piglet models of SBS, with or without ileum, we compared the elemental with the polymeric formula, including the effect on endogenous GLP‐2. Materials and Methods: Forty‐eight piglets underwent 75% mid‐intestinal resection with jejunoileal anastomosis, 75% distal‐intestinal resection with jejunocolic anastomosis (JC), or sham without resection. Parenteral nutrition (PN) started postoperatively, tapering as EN was increased, according to clinical criteria, based on diarrhea and weight. Within groups, piglets were randomized to an isocaloric/isonitrogenous elemental (amino acid) or polymeric (intact protein) diet. Plasma GLP‐2 and histology for adaptation were measured at 14 days. Results: Within both SBS and control groups, no difference in adaptation was observed according to diet. A difference was observed only within the JC piglet group with regard to clinical outcomes. In these piglets, compared with elemental formula, the polymeric formula was associated with more diarrhea (P = .023) and longer duration of PN support (P = .047). Conclusion: An overall benefit of the polymeric formula over the elemental formula on gut adaptation was not observed. Furthermore, SBS piglets without ileum had less ability to tolerate polymeric formula, contributing to more days of PN support.     

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.     

Enteral feeding induces early intestinal adaptation in a parenterally fed neonatal piglet model of short bowel syndrome

Background: Successful small intestinal (SI) adaptation following surgical resection is essential for optimizing newborn growth and development, but the potential for adaptation is unknown. The authors developed an SI resection model in neonatal piglets supported by intravenous and enteral nutrition. Methods: Piglets (n = 33, 12–13 days old) were randomized to 80% SI resection with parenteral nutrition feeding (R‐PN), 80% SI resection with PN + enteral feeding (R‐EN), or sham SI transection with PN + enteral feeding (sham‐EN). In resected pigs, the distal 100 cm of ileum (residual SI) and 30 cm of proximal SI were left intact. All pigs received parenteral nutrition postsurgery. Enteral nutrition piglets received continuous gastric infusion of elemental diet from day 3 (40:60 parenteral nutrition:enteral nutrition). Piglets were killed 4, 6, or 10 days postsurgery. Results: By 10 days, R‐EN piglets had longer residual SI than R‐PN and sham‐EN pigs (P < .05). At days 6 and 10, R‐EN piglets had greater weight per length of intact SI (P < .05) and isolated mucosa (P < .05) compared to other groups. Greater gut weight in R‐EN piglets was facilitated by a greater cellular proliferation index (P < .01) by 4 days compared to other groups and greater overall ornithine decarboxylase activity vs R‐PN piglets (P < .05). Conclusions: This new model demonstrated profound SI adaptation, initiated early postsurgery by polyamine synthesis and crypt cell proliferation and only in response to enteral feeding. These changes translated to greater gut mass and length within days, likely improving functional capacity long term.     

Parenteral Nutrition Electrolyte Abnormalities and Associated Factors Before and After Nutrition Support Team Initiation

Background: Studied since the 1940s, refeeding syndrome still has no universal definition, thus making comparison of studies difficult. Negative outcomes (eg, metabolic abnormalities) may occur with the use of specialized nutrition, such as parenteral nutrition (PN). Less than half of medical institutions have a nutrition support team (NST) managing PN. Interdisciplinary team management of PN may reduce negative outcomes of PN. The objective of this study was to show the value of the NST by measuring differences in PN variables, especially electrolyte abnormalities (EAs), before and after NST initiation at a large medical center and to identify factors associated with EAs among adult subjects receiving PN. Materials and Methods: During this retrospective study, computerized medical charts (N = 735) from 2007–2010 were reviewed for electrolyte changes (particularly potassium, magnesium, and phosphorus) the first 3 days following PN initiation in hospitalized adults. Changes in EAs with other variables were compared before and after NST implementation. Equivalent samples sizes were collected to better evaluate the impact of the team. Results: Following the implementation of the NST, fewer EAs were seen in PN patients (53%; χ² = 10.906, P = .004); significantly less potassium, phosphorus, and magnesium intravenous piggyback supplementation (88.8% vs 94%; χ² = 5.05, P = .026) was used; and mortality within 30 days of PN cessation was significantly less (12.7% vs 10.6%, P = .012). Conclusion: Our study complements existing research, finding that an NST was associated with a decreased occurrence of EAs and mortality in the hospitalized adult receiving PN.     

Intravenous Fish Oil and Pediatric Intestinal Failure–Associated Liver Disease: Changes in Plasma Phytosterols,Cytokines, and Bile Acids and Erythrocyte Fatty Acids

Background: Soybean oil (SO) emulsions are associated with intestinal failure–associated liver disease (IFALD); fish oil (FO) emulsions are used to treat IFALD. SO and FO differ with respect to their fatty acid and phytosterol content. In children with IFALD whose SO was replaced with FO, we aimed to (1) quantify changes in erythrocyte fatty acids and plasma phytosterols, cytokines, and bile acids and (2) correlate these changes with direct bilirubin (DB). Design: This study enrolled IFALD children who received 6 months of FO. Blood samples were collected prior to FO, and after 2 weeks and 3 and 6 months of FO. The primary outcome was 3‐month vs baseline biomarker concentrations. Results: At study initiation, the median patient age was 3 months (interquartile range, 3–17 months), and mean ± standard deviation DB was 5.6 ± 0.7 mg/dL (n = 14). Cholestasis reversed in 79% of subjects. Eicosapentaenoic and docosahexaenoic acid was greater than baseline (P < .001, all time points). Linoleic and arachidonic acid and sitosterol and stigmasterol were less than baseline (P < .05, all time points). Three‐ and 6‐month interleukin‐8 (IL‐8) and total and conjugated bile acids were less than baseline (P < .05). Baseline IL‐8 was correlated with baseline DB (r = 0.71, P < .01). Early changes in stigmasterol and IL‐8 were correlated with later DB changes (r = 0.68 and 0.75, P < .05). Conclusion: Specific fat emulsion components may play a role in IFALD. Stigmasterol and IL‐8 may predict FO treatment response.     

Glucagon‐Like Peptide 2 Improves Cholestasis in Parenteral Nutrition–Associated Liver Disease

Background: Parenteral nutrition‐associated liver disease (PNALD) remains a significant cause of morbidity and mortality in neonates with intestinal failure. Although glucagon‐like peptide‐2 (GLP‐2) is being advanced as therapy, the effect of GLP‐2 treatment on PNALD is unknown. We aim to investigate the effect of exogenous GLP‐2 administration on hepatic function in a neonatal piglet model of PNALD. Methods: Neonatal piglets (aged 2–6 days) underwent jugular venous catheterization to receive isonitrogenous, isocaloric parenteral nutrition (PN). Piglets were allocated to 2 groups: group 1 (n = 8) received saline while group 2 (n = 7) received GLP‐2 (at 11 nmol/kg/d). After 17 days, piglets underwent terminal laparotomy, and bile flow was measured. Liver specimens were analyzed histologically and with immunoperoxidase staining. Age‐matched sow‐reared control piglets (group 3, n = 8) were used for comparison. Results: Both groups 1 and 2 receiving PN developed cholestasis relative to sow‐reared controls, as evidenced by a decrease in bile flow and increase in serum total bilirubin. However, group 2 had improved bile flow (1.35 vs 0.73 µL/g; P = .02) and diminished bilirubin (38.0 vs 78.5 µmol/L; P = .008) compared with group 1. Group 2 also had lower serum alanine aminotransferase levels, a marker of liver injury. Histologically, the liver specimens in group 1 had marked hepatocyte pigmentation, which was decreased in group 2 specimens. Conclusions: The exogenous administration of GLP‐2 is associated with the improvement of cholestasis and liver injury. This study introduces a novel role for GLP‐2 in improving PNALD in the setting of prolonged PN duration.     

Lipid Emulsion Formulation of Parenteral Nutrition Affects Intestinal Microbiota and Host Responses in Neonatal Piglets

Background: Total parenteral nutrition (TPN) is a cause of intestinal microbial dysbiosis and impaired gut barrier function. This may contribute to life‐threatening parenteral nutrition–associated liver disease and sepsis in infants. We compared the effects of a lipid emulsion containing long‐chain ω‐3 polyunsaturated fatty acids (PUFAs; SMOFlipid) and a predominantly ω‐6 PUFA emulsion (Intralipid) on microbial composition and host response at the mucosal surface. Materials and Methods: Neonatal piglets were provided isocaloric, isonitrogenous TPN for 14 days versus sow‐fed (SF) controls. Equivalent lipid doses (10 g/kg/d) were given of either SMOFlipid (ML; n = 10) or Intralipid (SO; n = 9). Ileal segments and mucosal scrapings were used to characterize microbial composition by 16S rRNA gene sequencing and quantitative gene expression of tight junction proteins, mucins, antimicrobial peptides, and inflammatory cytokines. Results: The microbial composition of TPN piglets differed from SF, while ML and SO differed from each other (analysis of molecular variance; P < .05); ML piglets were more similar to SF, as indicated by UniFrac distance (P < .05). SO piglets showed a specific and dramatic increase in Parabacteroides (P < .05), while ML showed an increase in Enterobacteriaceae (P < .05). Gene expression of mucin, claudin 1, β‐defensin 2, and interleukin 8 were higher in TPN; overall increases were significantly less in ML versus SO (P < .05). Conclusion: The formulation of parenteral lipid is associated with differences in the gut microbiota and host response of TPN‐fed neonatal piglets. Inclusion of ω‐3 long‐chain PUFAs appears to improve host‐microbial interactions at the mucosal surface, although mechanisms are yet to be defined.     

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.     

Liver Disease,Systemic Inflammation,and Growth Using a Mixed Parenteral Lipid Emulsion,Containing Soybean Oil,Fish Oil,and Medium Chain Triglycerides,Compared With Soybean Oil in Parenteral Nutrition–Fed Neonatal Piglets

Background: The optimal parenteral lipid emulsion for neonates should reduce the risk of intestinal failure–associated liver disease and inflammation, while supporting growth and development. This could be best achieved by balanced content of ω‐6 and ω‐3 polyunsaturated fatty acids (PUFAs). Using a neonatal piglet model of parenteral nutrition (PN), we compared a 100% soy oil–based emulsion (ω‐6:ω‐3 PUFA: 7:1) with a mixed lipid emulsion comprising 30% soy oil, 30% medium‐chain triglycerides, 25% olive oil, and 15% fish oil (ω‐6:ω‐3 PUFA: approximately 2.5:1) with regard to liver disease, inflammation, and fatty acid content in plasma and brain. Method: Neonatal piglets, 3–6 days old, underwent jugular catheter insertion for isonitrogenous, isocaloric PN delivery over 14 days. The IL group (n = 8) was treated with Intralipid; the ML group (n = 10) was treated with the mixed lipid (SMOFlipid). Bile flow, liver chemistry, C‐reactive protein (CRP), and PUFA content in plasma phospholipids and brain were compared. Results: Compared with the IL group, ML‐treated piglets had increased bile flow (P = .008) and lower total bilirubin (P = .001) and CRP (P = .023) concentrations. The ω‐6 long‐chain PUFA content was lower in plasma and brain for the ML group. The key ω‐3 long‐chain PUFA for neonatal development, docosahexaenoic acid (DHA), was not different between groups. Conclusion: The mixed lipid, having less ω‐6 PUFA and more ω‐3 PUFA, was able to prevent liver disease and reduce systemic inflammation in PN‐fed neonatal piglets. However, this lipid did not increase plasma or brain DHA status, which would be desirable for neonatal developmental outcomes.     

Supplemental Parenteral Vitamin E Into Conventional Soybean Lipid Emulsion Does Not Prevent Parenteral Nutrition–Associated Liver Disease in Full‐Term Neonatal Piglets

Background: Parenteral nutrition–associated liver disease (PNALD) continues to cause morbidity and mortality for neonates with intestinal failure. Lipid peroxidation is one potential etiological factor. This study was designed to test if supplementing vitamin E into conventional soy‐based lipid would reduce the risk of PNALD. Methods: Sixteen piglets, aged 2–5 days and weighing 1.8–2.5 kg, were randomized to parenteral nutrition (PN) with soy lipid (SO, n = 8) or the same lipid plus α‐tocopherol, the most bioactive form of vitamin E (SO+E, n = 8). After 17 days, bile flow, liver chemistry, gene expression associated with bile acid metabolism, and bile acid composition were assessed. C‐reactive protein (CRP) and oxidative stress markers, including plasma 8‐isoprostane, were measured. All results were compared with a sow‐reared control group (CON). Results: Comparing PN‐treated groups, SO vs SO+E mean bile flow (5.91 vs 5.54 µL/g liver; P = .83), serum bile acid concentration (39.2 vs 26.6 µmol/L; P = .12), and total bilirubin (35.2 vs 26.9 µmol/L; P = .56) were not different. Gene expression related to bile acid metabolism and bile composition was not different between PN groups. There was no difference in CRP (41.8 vs 36.8 µg/mL; P = .22) or in plasma 8‐isoprostane (27.9 vs 26.1 pg/mL; P = .77). Conclusions: In term neonatal piglets, supplemental vitamin E did not prevent cholestasis. Additional vitamin E was not associated with reduced inflammation or oxidative stress. The benefit of supplementing vitamin E into conventional lipid, vs adding fish oil, to prevent early onset of PNALD requires further clarification.     

Minimal Enteral Nutrition to Improve Adaptation After Intestinal Resection in Piglets and Infants

Background: Minimal enteral nutrition (MEN) may induce a diet‐dependent stimulation of gut adaptation following intestinal resection. Bovine colostrum is rich in growth factors, and we hypothesized that MEN with colostrum would stimulate intestinal adaptation, compared with formula, and would be well tolerated in patients with short bowel syndrome. Methods: In experiment 1, 3‐day‐old piglets with 50% distal small intestinal resection were fed parenteral nutrition (PN, n = 10) or PN plus MEN given as either colostrum (PN‐COL, n = 5) or formula (PN‐FORM, n = 9) for 7 days. Intestinal nutrient absorption and histomorphometry were performed. In experiment 2, tolerance and feasibility of colostrum supplementation were tested in a pilot study on 5 infants who had undergone intestinal resection, and they were compared with 5 resected infants who served as controls. Results: In experiment 1, relative wet‐weight absorption and intestinal villus height were higher in PN‐COL vs PN (53% vs 23% and 362 ± 13 vs 329 ± 7 µm, P < .05). Crypt depth and tissue protein synthesis were higher in PN‐COL (233 ± 7 µm, 22%/d) and PN‐FORM (262 ± 13 µm, 22%/d) vs PN (190 ± 4 µm, 9%/d, both P < .05). In experiment 2, enteral colostrum supplementation was well tolerated, and no infants developed clinical signs of cow’s milk allergy. Conclusion: Minimal enteral nutrition feeding with bovine colostrum and formula induced similar intestinal adaptation after resection in piglets. Colostrum was well tolerated by newly resected infants, but the clinical indication for colostrum supplementation to infants subjected to intestinal resection remains to be determined.     

Long‐Term Fish Oil Lipid Emulsion Use in Children With Intestinal Failure–Associated Liver Disease

Background: Fish oil lipid emulsion (FOLE) and multidisciplinary care for infants with intestinal failure (IF) have been associated with reduced morbidity and mortality due to IF‐associated liver disease (IFALD). With increased survival, a greater proportion of infants with IF are now able to remain on parenteral nutrition (PN) in the long term. The purpose of this study was to examine outcomes in children with IFALD who have required long‐term PN and FOLE therapy due to chronic IF. Materials and Methods: A review of prospectively collected data was performed for children with IFALD who required at least 3 years of PN and FOLE therapy due to chronic IF. Outcomes examined include the incidence of death, transplantation, and essential fatty acid deficiency (EFAD), as well as growth parameters and the biochemical markers of liver disease. Results: Of 215 patients with IFALD treated from 2004–2015, 30 required PN and FOLE therapy for at least 3 years (median, 4.6 years). To date, no patients have died, required transplantation, or developed EFAD. Biochemical markers of liver disease normalized within the first year of therapy with no recurrent elevations in the long term. Weight‐for age and length‐for‐age z scores improved and PN dependence decreased in the first year of therapy, with a stable rate of growth in the long term. Conclusions: Children with IFALD who required long‐term PN and FOLE for chronic IF had no mortality, need for transplantation, EFAD, or recurrence of liver disease in the long term, allowing for continued intestinal rehabilitation.     

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.     

Serum vitamins in adult patients with short bowel syndrome receiving intermittent parenteral nutrition

Background: Short bowel syndrome (SBS) occurs after massive intestinal resection, and parenteral nutrition (PN) therapy may be necessary even after a period of adaptation. The purpose of this study was to determine the vitamin status in adults with SBS receiving intermittent PN. Methods: The study was conducted on hospitalized adults with SBS who were receiving intermittent PN therapy (n = 8). Nine healthy volunteers, paired by age and sex, served as controls. Food ingestion, anthropometry, plasma folic acid, and vitamins B₁₂, C, A, D, E, and K were evaluated. Results: The levels of vitamins A, D, and B₁₂ in both groups were similar. SBS patients presented higher values of folic acid (21.3 ± 4.4 vs 14.4 ± 5.2, P = .01) and lower values of vitamin C (0.9 ± 0.4 vs 1.2 ± 0.3 mg/dL, P = .03), α‐tocopherol (16.3 ± 3.4 vs 24.1 ± 2.7 µmol/L, P < .001), and phylloquinone (0.6 ± 0.2 vs 1.0 ± 0.5 nmol/L, P < .03). Eight‐seven percent of patients had vitamin D deficiency, and all patients presented with serum vitamin E levels below reference values. Conclusions: Despite all efforts to offer all the nutrients mentioned above, SBS patients had lower serum levels of vitamins C, E, and K, similar to those observed in patients on home PN. These findings suggest that the administered vitamins were not sufficient for the intermittent PN scheme and that individual adjustments are needed depending on the patient's vitamin status.     

Effect of Intestinal Atrophy and Hepatic Impairment Induced by Parenteral Nutrition on Drug Absorption and Disposition in Rats

Background: Long‐term parenteral nutrition (PN) has a high risk of hepatic dysfunction and intestinal atrophy. The present study investigated the effect of PN‐induced intestinal atrophy and hepatic impairment on drug pharmacokinetics by using 2 contrasting compounds: phenolsulfonphthalein (PSP) and cyclosporin A (CyA). Materials and Methods: PSP or CyA was administered to 7‐day PN‐fed Rats (PN rats) and sham operated rats (control rats) via intravenous (IV) or intraloop administration of the intestine. Pharmacokinetic parameters with 2‐compartment analysis including area under the concentration vs time curve (AUC) and the permeability after in situ intraloop administration (P_loop) were obtained from both concentration profiles after different administration routes. Results: After IV administration of PSP to control and PN rats, there was no notable difference in any of the pharmacokinetic parameters. In contrast, after intraloop administration, AUC and P_loop in PN rats were approximately 2.6‐ and 2.0‐fold higher than that in control rats, respectively. On the other hand, after IV administration of CyA, the terminal half‐life and total body clearance were prolonged and decreased in PN rats, respectively, resulting in 2.0‐fold increase in AUC. After intraloop administration, the AUC of PN rats was increased to approximately 1.3‐fold that of control rats, whereas no notable difference was observed in P_loop. Conclusion: The intestinal permeability of PSP was enhanced by intestinal atrophy induced by PN, while the metabolism of CyA was diminished by hepatic impairment by PN. These results revealed the physicochemical property‐based pharmacokinetic alterations during PN; for a more detailed understanding, however, further studies are needed.     

Oleanolic Acid Improves Gut Atrophy Induced by Parenteral Nutrition

Background: Nutrition support with parenteral nutrition (PN) is associated with gut atrophy. Prior studies have shown improvement with enteral chenodeoxycholic acid, a dual agonist for the farnesoid X receptor (FXR) and bile acid receptor TGR5. We hypothesized that gut growth is induced by TGR5 activation, and gut atrophy during PN administration could be prevented with the TGR5‐specific agonist oleanolic acid (OA). Methods: Neonatal pigs were implanted with duodenal and jugular vein catheters. Animals were provided equi‐nutritious PN or enteral swine milk. A PN subgroup received enteral OA at 50 mg/kg/d. Results: PN caused marked gut atrophy compared with enterally fed (EN) control animals. OA treatment led to preservation of gut mass demonstrated grossly and histologically. The mean ± SD gut weight as a percentage of body weight was 4.30 ± 0.26 for EN, 1.92 ± 0.06 for PN (P < .05, EN vs PN), and 3.39 ± 0.79 for PN+OA (P < .05, PN+OA vs PN). Mean ± SD gut density (g/cm) was 0.31 ± 0.03 for EN, 0.18 ± 0.03 for PN (P < .05 EN vs PN), and 0.27 ± 0.01 for PN+OA (P < .05 PN+OA vs PN). Histologically, a markedly decreased villous to crypt ratio was noted with PN, and OA significantly prevented this decrease. The mean ± SD v/c ratio was 3.51 ± 0.59 for EN, 1.69 ± 0.10 for PN (P < .05, EN vs PN), and 2.90 ± 0.23 for PN+OA (P < .05, PN+OA vs PN). Gut TGR5 messenger RNA expression was significantly elevated with OA treatment compared with both PN and EN. Conclusion: The bile acid–activated G protein–coupled receptor TGR5 agonist OA prevented gut atrophy associated with PN.     

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.