AGA Clinical Practice Update on Diet and Nutritional Therapies in Patients With Inflammatory Bowel Disease: Expert Review.

DESCRIPTION: Diet plays a critical role in human health, but especially for patients with inflammatory bowel disease (IBD). Guidance about diet for patients with IBD are often controversial and a source of uncertainty for many physicians and patients. The role of diet has been investigated as a risk factor for IBD etiopathogenesis and as a therapy for active disease. Dietary restrictions, along with the clinical complications of IBD, can result in malnutrition, an underrecognized condition among this patient population. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update (CPU) is to provide best practice advice statements, primarily to clinical gastroenterologists, covering the topics of diet and nutritional therapies in the management of IBD, while emphasizing identification and treatment of malnutrition in these patients. We provide guidance for tailored dietary approaches during IBD remission, active disease, and intestinal failure. A healthy Mediterranean diet will benefit patients with IBD, but may require accommodations for food texture in the setting of intestinal strictures or obstructions. New data in Crohn's disease supports the use of enteral liquid nutrition to help induce remission and correct malnutrition in patients heading for surgery. Parenteral nutrition plays a critical role in patients with IBD facing acute and/or chronic intestinal failure. Registered dietitians are an essential part of the interdisciplinary team approach for optimal nutrition assessment and management in the patient population with IBD. METHODS: This expert review was commissioned and approved by the AGA Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPU Committee and external peer review through standard procedures of Gastroenterology. The best practice advice statements were drawn from reviewing existing literature combined with expert opinion to provide practical advice on the role of diet and nutritional therapies in patients with IBD. Because this was not a systematic review, formal rating of the quality of evidence or strength of the presented considerations was not performed. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Unless there is a contraindication, all patients with IBD should be advised to follow a Mediterranean diet rich in a variety of fresh fruits and vegetables, monounsaturated fats, complex carbohydrates, and lean proteins and low in ultraprocessed foods, added sugar, and salt for their overall health and general well-being. No diet has consistently been found to decrease the rate of flares in adults with IBD. A diet low in red and processed meat may reduce ulcerative colitis flares, but has not been found to reduce relapse in Crohn's disease. BEST PRACTICE ADVICE 2: Patients with IBD who have symptomatic intestinal strictures may not tolerate fibrous, plant-based foods (ie, raw fruits and vegetables) due to their texture. An emphasis on careful chewing and cooking and processing of fruits and vegetables to a soft, less fibrinous consistency may help patients with IBD who have concomitant intestinal strictures incorporate a wider variety of plant-based foods and fiber in their diets. BEST PRACTICE ADVICE 3: Exclusive enteral nutrition using liquid nutrition formulations is an effective therapy for induction of clinical remission and endoscopic response in Crohn's disease, with stronger evidence in children than adults. Exclusive enteral nutrition may be considered as a steroid-sparing bridge therapy for patients with Crohn's disease. BEST PRACTICE ADVICE 4: Crohn's disease exclusion diet, a type of partial enteral nutrition therapy, may be an effective therapy for induction of clinical remission and endoscopic response in mild to moderate Crohn's disease of relatively short duration. BEST PRACTICE ADVICE 5: Exclusive enteral nutrition may be an effective therapy in malnourished patients before undergoing elective surgery for Crohn's disease to optimize nutritional status and reduce postoperative complications. BEST PRACTICE ADVICE 6: In patients with IBD who have an intra-abdominal abscess and/or phlegmonous inflammation that limits ability to achieve optimal nutrition via the digestive tract, short-term parenteral nutrition may be used to provide bowel rest in the preoperative phase to decrease infection and inflammation as a bridge to definitive surgical management and to optimize surgical outcomes. BEST PRACTICE ADVICE 7: We suggest the use of parenteral nutrition for high-output gastrointestinal fistula, prolonged ileus, short bowel syndrome, and for patients with IBD with severe malnutrition when oral and enteral nutrition has been trialed and failed or when enteral access is not feasible or contraindicated. BEST PRACTICE ADVICE 8: In patients with IBD and short bowel syndrome, long-term parenteral nutrition should be transitioned to customized hydration management (ie, intravenous electrolyte support and/or oral rehydration solutions) and oral intake whenever possible to decrease the risk of developing long-term complications. Treatment with glucagon-like peptide-2 agonists can facilitate this transition. BEST PRACTICE ADVICE 9: All patients with IBD warrant regular screening for malnutrition by their provider by means of assessing signs and symptoms, including unintended weight loss, edema and fluid retention, and fat and muscle mass loss. When observed, more complete evaluation for malnutrition by a registered dietitian is indicated. Serum proteins are no longer recommended for the identification and diagnosis of malnutrition due to their lack of specificity for nutritional status and high sensitivity to inflammation. BEST PRACTICE ADVICE 10: All patients with IBD should be monitored for vitamin D and iron deficiency. Patients with extensive ileal disease or prior ileal surgery (resection or ileal pouch) should be monitored for vitamin B12 deficiency. BEST PRACTICE ADVICE 11: All outpatients and inpatients with complicated IBD warrant co-management with a registered dietitian, especially those who have malnutrition, short bowel syndrome, enterocutaneous fistula, and/or are requiring more complex nutrition therapies (eg, parenteral nutrition, enteral nutrition, or exclusive enteral nutrition), or those on a Crohn's disease exclusion diet. We suggest that all newly diagnosed patients with IBD have access to a registered dietitian. BEST PRACTICE ADVICE 12: Breastfeeding is associated with a lower risk for diagnosis of IBD during childhood. A healthy, balanced, Mediterranean diet rich in a variety of fruits and vegetables and decreased intake of ultraprocessed foods have been associated with a lower risk of developing IBD.

Expert consensus report on lipid mediators: Role in resolution of inflammation and muscle preservation.

This meeting report presents a consensus on the biological aspects of lipid emulsions in parenteral nutrition, emphasizing the unanimous support for the integration of lipid emulsions, particularly those containing fish oil, owing to their many potential benefits beyond caloric provision. Lipid emulsions have evolved from simple energy sources to complex formulations designed to improve safety profiles and offer therapeutic benefits. The consensus highlights the critical role of omega-3 polyunsaturated fatty acids (PUFAs), notably eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found in fish oil and other marine oils, for their anti-inflammatory properties, muscle mass preservation, and as precursors to the specialized pro-resolving mediators (SPMs). SPMs play a significant role in immune modulation, tissue repair, and the active resolution of inflammation without impairing host defense mechanisms. The panel's agreement underscores the importance of incorporating fish oil within clinical practices to facilitate recovery in conditions like surgery, critical illness, or immobility, while cautioning against therapies that might disrupt natural inflammation resolution processes. This consensus not only reaffirms the role of specific lipid components in enhancing patient outcomes, but also suggests a shift towards nutrition-based therapeutic strategies in clinical settings, advocating for the proactive evidence-based use of lipid emulsions enriched with omega-3 PUFAs. Furthermore, we should seek to apply our knowledge concerning DHA, EPA, and their SPM derivatives, to produce more informative randomized controlled trial protocols, thus allowing more authoritative clinical recommendations.

Our Scientific Journey through the Ups and Downs of Blood Glucose Control in the ICU.

This article tells the story of our long search for the answer to one question: Is stress hyperglycemia in critically ill patients adaptive or maladaptive? Our earlier work had suggested the lack of hepatic insulin effect and hyperglycemia as jointly predicting poor outcome. Therefore, we hypothesized that insulin infusion to reach normoglycemia, tight glucose control, improves outcome. In three randomized controlled trials (RCTs), we found morbidity and mortality benefit with tight glucose control. Moving from the bed to the bench, we attributed benefits to the prevention of glucose toxicity in cells taking up glucose in an insulin-independent, glucose concentration gradient-dependent manner, counteracted rather than synergized by insulin. Several subsequent RCTs did not confirm benefit, and the large Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation, or "NICE-SUGAR," trial found increased mortality with tight glucose control associated with severe hypoglycemia. Our subsequent clinical and mechanistic research revealed that early use of parenteral nutrition, the context of our initial RCTs, had been a confounder. Early parenteral nutrition (early-PN) aggravated hyperglycemia, suppressed vital cell damage removal, and hampered recovery. Therefore, in our next and largest "TGC-fast" RCT, we retested our hypothesis, without the use of early-PN and with a computer algorithm for tight glucose control that avoided severe hypoglycemia. In this trial, tight glucose control prevented kidney and liver damage, though with much smaller effect sizes than in our initial RCTs without affecting mortality. Our quest ends with the strong recommendation to omit early-PN for patients in the ICU, as this reduces need of blood glucose control and allows cellular housekeeping systems to play evolutionary selected roles in the recovery process. Once again, less is more in critical care.

Impact of Intravenous Fat Emulsion Choice on Candida Biofilm, Hyphal Growth, and Catheter-Related Bloodstream Infections in Pediatric Patients.

BACKGROUND: Use of mixed-oil (MO) intravenous fat emulsion (IFE) was shown to inhibit Candida albicans biofilm formation and overall rate of catheter-related bloodstream infections (CR-BSIs) compared with soybean-oil (SO) IFE). We aimed to delineate this inhibitory mechanism and impact of IFE choice on distribution of fungal CR-BSIs. METHODS: Transcriptional profiling was conducted on C. albicans grown in SO-IFE, MO-IFE, or SO-IFE with capric acid. Overexpression strains of shared down-regulated genes were constructed using a tetracycline-off system to assess hypha and biofilm formation in IFEs. A 5-year retrospective multicenter cohort study was performed to assess differences in CR-BSIs caused by Candida species based on the IFE formulation received in pediatric patients. RESULTS: Genes significantly down-regulated in MO-IFE and SO-IFE with capric acid included CDC11, HGC1, and UME6. Overexpression of HGC1 or UME6 enabled filamentation in capric acid and MO-IFE. Interestingly, only overexpression of UME6 was sufficient to rescue biofilm growth in MO-IFE. MO-IFE administration was associated with a higher proportion of non-albicans Candida versus C. albicans CR-BSIs (42% vs 33%; odds ratio, 1.22 [95% confidence interval, .46-3.26]). CONCLUSIONS: MO-IFE affects C. albicans biofilm formation and hyphal growth via a UME6-dependent mechanism. A numerical but not statistically significant difference in distribution of Candida spp. among CR-BSIs was observed.

Delivery of carbohydrates, amino acids, and lipids via intravenous catheters is necessary for some patients to supply daily caloric needs. These nutrient-dense parenteral solutions can promote microbial biofilm growth on the catheter surface, which may seed subsequent catheter-related bloodstream infection (CR-BSI). In fact, receipt of parenteral nutrition is an established risk factor for CR-BSI caused by the polymorphic fungal pathogen Candida albicans. New intravenous fat emulsions (IFEs) have gained market share and IFEs containing capric acid (mixed-oil [MO] IFE) compared with those without (soybean-oil [SO] IFE) impair the C. albicans yeast-to-hypha switch­a trait strongly associated with pathogenicity and biofilm formation. In this study, we found that MO-IFE and capric acid reduced expression of a transcriptional regulator involved in hyphal extension (UME6) and down-regulated genes involved in cell partitioning (HGC1). Overexpression of these genes enabled hyphal growth in MO-IFE. Secondly, we sought to determine whether the type of IFE administered was associated with the clinical incidence of CR-BSIs caused by C. albicans or other common non-albicans Candida species. There was a nonsignificant numerical reduction in C. albicans infections in patients administered MO-IFE compared with SO-IFE. Collectively, this work shows that IFEs differentially affect Candida biology with potential infectious consequences for the patient.

Intraduodenal fecal microbiota transplantation ameliorates gut atrophy and cholestasis in a novel parenteral nutrition piglet model.

Total parenteral nutrition (TPN) provides lifesaving nutritional support intravenously; however, it is associated with significant side effects. Given gut microbial alterations noted with TPN, we hypothesized that transferring fecal microbiota from healthy controls would restore gut-systemic signaling in TPN and mitigate injury. Using our novel ambulatory model (US Patent: US 63/136,165), 31 piglets were randomly allocated to enteral nutrition (EN), TPN only, TPN + antibiotics (TPN-A), or TPN + intraduodenal fecal microbiota transplant (TPN + FMT) for 14 days. Gut, liver, and serum were assessed through histology, biochemistry, and qPCR. Stool samples underwent 16 s rRNA sequencing. Permutational multivariate analysis of variance, Jaccard, and Bray-Curtis metrics were performed. Significant bilirubin elevation in TPN and TPN-A versus EN (P < 0.0001) was prevented with FMT. IFN-G, TNF-α, IL-ß, IL-8, and lipopolysaccharide (LPS) were significantly higher in TPN (P = 0.009, P = 0.001, P = 0.043, P = 0.011, P < 0.0001), with preservation upon FMT. Significant gut atrophy by villous-to-crypt ratio in TPN (P < 0.0001) and TPN-A (P = 0.0001) versus EN was prevented by FMT (P = 0.426 vs. EN). Microbiota profiles using principal coordinate analysis demonstrated significant FMT and EN overlap, with the largest separation in TPN-A followed by TPN, driven primarily by Firmicutes and Fusobacteria. TPN-altered gut barrier was preserved upon FMT; upregulated cholesterol 7 α-hydroxylase and bile salt export pump in TPN and TPN-A and downregulated fibroblast growth factor receptor 4, EGF, farnesoid X receptor, and Takeda G Protein-coupled Receptor 5 (TGR5) versus EN was prevented by FMT. This study provides novel evidence of prevention of gut atrophy, liver injury, and microbial dysbiosis with intraduodenal FMT, challenging current paradigms into TPN injury mechanisms and underscores the importance of gut microbes as prime targets for therapeutics and drug discovery.NEW & NOTEWORTHY Intraduodenal fecal microbiota transplantation presents a novel strategy to mitigate complications associated with total parenteral nutrition (TPN), highlighting gut microbiota as a prime target for therapeutic and diagnostic approaches. These results from a highly translatable model provide hope for TPN side effect mitigation for thousands of chronically TPN-dependent patients.

Parenteral nutrition results in peripheral ileal to hepatic circadian discordance in mice.

BACKGROUND: We have developed a mouse model of Parenteral Nutrition Associated Liver Disease in which PN infusion results in cholestatic liver injury. In the liver, the master circadian genes Arntl/Bmal drive rhythmic gene expression and regulate circadian expression of hepatic functions including bile acid synthesis. The aim of this study was to examine the effect of continuous PN on ileal and hepatic expression of circadian regulatory (CR) genes, FXR signaling and bile acid synthesis in mice. METHODS: WT mice were exposed to continuous soy oil lipid emulsion-based PN infusion through a central venous catheter for 4 days (PN). Water was provided ad libitum, but no nutrients were provided enterally. On d4, mice were sacrificed every 6 hours (7AM, 1PM, 7PM and 1AM), and ileal, hepatic tissue and serum harvested. From tissue samples, the relative expression of circadian transcription factors and FXR signaling was assessed. RESULTS: Administration of 4d PN increased hepatic injury, inflammatory cytokine expression and gut permeability. In the ileum, PN activated FXR and induced expression of Fgf15 and Nr0b2. In the liver, expression of FXR-downstream targets was dysregulated. PN administrations impacted hepatic and ileal circadian transcription factor mRNA expression which was discordant between the two organs. CONCLUSIONS: Dysregulation of circadian regulatory machinery is in part due to discordance of the gut-liver axis during PN. Pharmacologic targeting of CR as a therapeutic strategy for PNALD thus deserves further investigation.

A Medium-Chain Fatty Acid Analogue Prevents Intestinal Failure-Associated Liver Disease in Preterm Yorkshire Piglets.

BACKGROUND & AIMS: At least 20%-30% of patients with intestinal failure receiving long-term parenteral nutrition will develop intestinal failure-associated liver disease (IFALD), for which there are few therapeutic options. SEFA-6179 is a first-in-class structurally engineered medium-chain fatty acid analogue that acts through GPR84, PPARα, and PPARγ agonism. We hypothesized that SEFA-6179 would prevent biochemical and histologic liver injury in a preterm piglet model of IFALD. METHODS: Preterm Yorkshire piglets were delivered by cesarean section, and parenteral nutrition was provided for 14 days via implanted central venous catheters. Animals were treated with either medium-chain triglyceride vehicle control or SEFA-6179. RESULTS: Compared to medium-chain triglyceride vehicle at day of life 15, SEFA-6179 prevented biochemical cholestasis (direct bilirubin: 1.9 vs <0.2 mg/dL, P = .01; total bilirubin: 2.7 vs 0.4 mg/dL, P = .02; gamma glutamyl transferase: 172 vs 30 U/L, P = .01). SEFA-6179 also prevented steatosis (45.6 vs 13.9 mg triglycerides/g liver tissue, P = .009), reduced bile duct proliferation (1.6% vs 0.5% area cytokeratin 7 positive, P = .009), and reduced fibrosis assessed by a masked pathologist (median Ishak score: 3 vs 1, P = 0.007). RNA sequencing of liver tissue demonstrated that SEFA-6179 broadly impacted inflammatory, metabolic, and fibrotic pathways, consistent with its in vitro receptor activity (GPR84/PPARα/PPARγ agonist). CONCLUSIONS: In a preterm piglet model of IFALD, SEFA-6179 treatment prevented biochemical cholestasis and steatosis and reduced bile duct proliferation and fibrosis. SEFA-6179 is a promising first-in-class therapy for the prevention and treatment of IFALD that will be investigated in an upcoming phase II clinical trial.

Size of lipid emulsion droplets influences metabolism in human CD4+ T cells.

SCOPE: Triglyceride-based lipid emulsions are critical for total parenteral nutrition (TPN), but their long-term use has adverse effects, such as severe liver dysfunction necessitating improved formulations. This study compares the uptake mechanism and intracellular fate of novel glycerol-stabilized nano-sized lipid emulsions with conventional emulsions in CD4+ T cells, focusing on their impact on cellular metabolism. METHODS AND RESULTS: Nanoemulsions were formulated with increased glycerol content. Uptake of emulsions in primary human CD4+ T cells was investigated using different endocytic blockers, then quantified by flow cytometry, and visualized by confocal microscopy. To investigate emulsion intracellular fate, fatty acids in membrane phospholipids were quantified by GC-MS/MS and cellular metabolism was assessed by Seahorse technology. Results show T cells internalize both conventional and nano-sized emulsions using macropinocytosis. Fatty acids from emulsions are stored as neutral lipids in intracellular vesicles and are incorporated into phospholipids of cellular membranes. However, only nanoemulsions additionally use clathrin-mediated endocytosis and deliver fatty acids to mitochondria for increased ß-oxidation. CONCLUSIONS: Size of lipid emulsion droplets significantly influences their uptake and subsequent metabolism in CD4+ T cells. Our results highlight the potential for improved nutrient utilization with nanoemulsions in TPN formulations possibly leading to less adverse effects.

Impact of nutritional support routes on mortality in acute pancreatitis: A network meta-analysis of randomized controlled trials.

BACKGROUND: Nutritional administration in acute pancreatitis (AP) management has sparked widespread discussion, yet contradictory mortality results across meta-analyses necessitate clarification. The optimal nutritional route in AP remains uncertain. Therefore, this study aimed to compare mortality among nutritional administration routes in patients with AP using consistency model. METHODS: This study searched four major databases for relevant randomized controlled trials (RCTs). Two authors independently extracted and checked data and quality. Network meta-analysis was conducted for estimating risk ratios (RRs) with 95% confidence interval (CI) based on random-effects model. Subgroup analyses accounted for AP severity and nutrition support initiation. RESULTS: A meticulous search yielded 1185 references, with 30 records meeting inclusion criteria from 27 RCTs (n = 1594). Pooled analyses showed the mortality risk reduction associated with nasogastric (NG) (RR = 0.34; 95%CI: 0.16-0.73) and nasojejunal (NJ) feeding (RR = 0.46; 95%CI: 0.25-0.84) in comparison to nil per os. Similarly, NG (RR = 0.45; 95%CI: 0.24-0.83) and NJ (RR = 0.60; 95%CI: 0.40-0.90) feeding also showed lower mortality risk than total parenteral nutrition. Subgroup analyses, stratified by severity, supported these findings. Notably, the timing of nutritional support initiation emerged as a significant factor, with NJ feeding demonstrating notable mortality reduction within 24 and 48 h, particularly in severe cases. CONCLUSION: For severe AP, both NG and NJ feeding appear optimal, with variations in initiation timings. NG feeding does not appear to merit recommendation within the initial 24 h, whereas NJ feeding is advisable within the corresponding timeframe following admission. These findings offer valuable insights for optimizing nutritional interventions in AP.

A randomized translational study on protein- and glucose metabolism in skeletal muscles evaluated by gene-ontology, following preoperative oral carbohydrate loading compared to overnight peripheral parenteral nutrition (PPN) before major cancer surgery.

BACKGROUND: Effects of preoperative drinks on muscle metabolism are unclear despite general recommendations. The aim of the present study was therefore to compare metabolic effects of a preoperative oral nutrition drink, recommended by protocols for enhanced recovery after surgery (ERAS), compared to overnight preoperative peripheral total parenteral nutrition (PPN) on skeletal muscle metabolism in patients aimed at major gastrointestinal cancer surgery. METHODS: Patients were randomized, based on diagnosis and clinical characteristics, to receive either a commercial carbohydrate-rich nutrition drink (Drink); or overnight (12 h) peripheral parenteral nutrition (PPN) as study regimens; compared to isotone Ringer-acetate as Control regimen. Arterial blood- and abdominal muscle tissue specimens were collected at start of surgery. Blood chemistry included substrate- and hormone concentrations. Muscle mRNA transcript analyses were performed by microarray and evaluated for changes in gene activities by Gene Ontology algorithms. RESULTS: Patient groups were comparable in all measured preoperative assessments. The Nutrition Drink had significant metabolic alterations on muscle glucose metabolism (p < 0.05), without any significant effects on amino acid- and protein metabolism. PPN showed similar significant effects on glucose metabolism as Drinks (p < 0.05), but indicated also major positive effects on amino acid- (p < 0.001) and protein anabolism (p < 0.05), particularly by inhibition of muscle protein degradation, related to both ubiquitination of proteins and autophagy/lysosome pathways (p < 0.05). CONCLUSION: Conventional overnight preoperative PPN seems effective to induce and support improved muscle protein metabolism in patients aimed at major cancer surgery while preoperative oral carbohydrate loading, according to ERAS-protocols, was ineffective to improve skeletal muscle catabolism and should therefore not be recommended before major cancer surgery. Trial registration Clinical trials.gov: NCT05080816, Registered June 10th 2021- Retrospectively registered. https://clinicaltrials.gov/study/NCT05080816.

The Impact of Teduglutide on Real-Life Health Care Costs in Children with Short Bowel Syndrome.

OBJECTIVES: To analyze the real-life health care costs of home parenteral nutrition (HPN) in children with short bowel syndrome with intestinal failure (SBS-IF) before and after treatment with teduglutide, and to compare those with costs of children with SBS-IF not treated with teduglutide. STUDY DESIGN: All consecutive children with SBS-IF on HPN treated with subcutaneous teduglutide starting from 2018 through 2020 in a tertiary French referral center were retrospectively included. These patients were matched to children with SBS-IF on HPN followed during the same 3-year period who were eligible for the teduglutide but were not treated. HPN direct medical costs included home-care charges, HPN bags, hospital admissions, and teduglutide. A comparison of costs before/after treatment and between patients treated/not treated was performed. RESULTS: Sixty children were included: 30 (50%) were treated with teduglutide and 30 (50%) were untreated. In the treated group, the median total costs of HPN significantly decreased after 1 (P < .001) and 2 years of treatment (P < .001) from 59 454 euros/year/patient to 43 885 euros/year/patient and 34 973 euros/year/patient, respectively. When we compared patients treated and not treated, the total HPN costs/year/patient were similar at baseline (P = .6) but were significantly lower in the teduglutide-treated group after 1 (P = .006) and 2 years of treatment (P < .001). When we added the cost of teduglutide into the analysis, the total cost increased significantly in the treated group and remained much greater even after modeling a reduction in the cost of the drug to one-third the present cost and PN weaning (P < .001). CONCLUSIONS: Treatment with teduglutide is associated with a significant reduction in the annual costs of HPN but still remains expensive because of the drug itself. Finding cost-saving strategies is essential.

Achieving Enteral Autonomy in Children with Intestinal Failure Following Inpatient Admission: A Case Series.

We describe cases of intestinal failure wherein inpatient admission was critical toward enteral autonomy. We performed a retrospective chart review of 6 children with long-term parenteral nutrition dependence who were weaned from parenteral nutrition after admission. Admissions included feeding and medication titration, interdisciplinary care, and a home parenteral nutrition team consultation.

Adverse Metabolic Phenotypes in Parenterally Fed Neonatal Pigs Do Not Persist into Adolescence.

BACKGROUND: Nutrition during fetal and neonatal life is an important determinant for the risk of adult-onset diseases, especially type 2 diabetes and obesity. OBJECTIVES: We aimed to determine whether total parenteral nutrition (TPN) compared with enteral formula feeding [enteral nutrition (EN)] in term piglets during the first 2 wk after birth would increase the long-term (5-mo) development of metabolic syndrome phenotypes with adverse glucose homeostasis, fatty liver disease, and obesity. METHODS: Neonatal female pigs were administered TPN (n = 12) or fed enterally with a liquid enteral milk-replacer formula (EN, n = 12) for 14 d. After transitioning TPN pigs to enteral feeding of liquid formula (days 15-26), both groups were adapted to a solid high-fat diet (30% of the total diet) and sucrose (20% of the total diet) diet (days 27-33), which was fed until the end of the study (140 d). Body composition was measured by dual-energy X-ray absorptiometry at 14, 45, and 140 d. Serum biochemistry and glucose-insulin values (after a fasting intravenous glucose tolerance test) were obtained at 140 d. Liver and muscle were analyzed for insulin receptor signaling and triglycerides. RESULTS: Body weight was similar, but percent fat was higher, whereas percent lean and bone mineral density were lower in TPN than in EN pigs (P < 0.01) at 45 d of age but not at 140 d. At 140 d, there were no differences in serum markers of liver injury or lipidemia. Intravenous glucose tolerance test at 140 d showed a lower (P < 0.05) AUC for both glucose and insulin in TPN than in EN pigs, but the ratio of AUCs of insulin and glucose was not different between groups. CONCLUSIONS: Administration of TPN during the neonatal period increased adipose deposition that transiently persisted in early adolescence when challenged with a high-fat diet but was not sustained or manifested as glucose intolerance.

Safety and Efficacy of a Composite Lipid Emulsion with Fish Oil in Hospitalized Neonates and Infants Requiring Prolonged Parenteral Nutrition - A Randomized, Double-Blind, Multicenter, Controlled Trial.

BACKGROUND: Intravenous lipids are critical to the care of extremely premature and other high-risk infants. OBJECTIVE: The study evaluated safety and efficacy of parenteral nutrition (PN) with composite intravenous lipid emulsion (CO-ILE) with fish oil compared to pure soybean oil lipid emulsion (SOLE). METHODS: Randomized, controlled, double-blind, multicenter study (NCT02579265) in neonates/ infants anticipated to require ≥28 days of PN due to gastrointestinal malformations or injury. Duration of the initial and extended treatment phase was 28 days and 84 days (for patients with PN indication after day 28). RESULTS: 83/ 78 patients (mean postnatal age: 11.4/ 8.3 days, 54/ 59 preterm) received CO-ILE and SOLE, respectively. 33 patients per group completed 28 days on treatment. Risk of having conjugated bilirubin values > 2 mg/dL confirmed by a second sample 7 days after the first during the initial treatment phase (primary outcome) was 2.4% (2 of 83) with CO-ILE and 3.8% (3 of 78) with SOLE (risk ratio 0.59 [95% CI: 0.09, 3.76]). Between days 29 and 84, the number of patients with confirmed conjugated bilirubin values > 2 mg/dL did not increase in the CO-ILE group (n=2) and increased in the SOLE group (n=9). At the end of the initial treatment phase, conjugated bilirubin concentrations were 45.6% lower under CO-ILE than under SOLE (p=0.006). There was no clinical or laboratory evidence of essential fatty acid deficiency in patients in the CO-ILE group. Median time to discharge alive was 56.7 and 66.4 days with CO-ILE and SOLE, respectively (hazard ratio: 1.16; 95% CI: 0.81, 1.68). CONCLUSIONS: CO-ILE was associated with a possible lower risk of cholestasis and significantly lower conjugated bilirubin at the end of the initial treatment phase in high-risk neonates and infants as compared to patients treated with SOLE. In summary, these data indicate that CO-ILE can be considered safe and may be preferable over SOLE in high-risk neonates. CLINICAL TRIAL REGISTRY NUMBER: Clinicaltrials.gov, study ID NCT02579265.

The Effect of Nutrient Deprivation on Early Life Small Intestinal Mucosal Microbiome and Host Proteome.

BACKGROUND: Nutrition plays a vital role in shaping the intestinal microbiome. However, many hospitalized children undergo periods of fasting during medical treatment. Changes to the small intestinal microbiota in early life in the setting of enteral deprivation have not been well described. OBJECTIVE: The aim of this study was to investigate the impact of enteral deprivation on the small intestinal mucosal microbiome and to identify factors that shape this interaction in infancy. METHODS: Intestinal biopsies were collected from proximal (fed) and distal (unfed) small bowel at the time of ostomy closure in children with a small intestinal enterostomy. Mucosal and luminal microbiome comparisons were performed including ß-diversity and differential abundance and correlations with clinical factors were analyzed. Host proteomics were compared between fed and unfed samples and correlated with microbiome parameters. Finally, microbial results were validated in another cohort of pediatric patients. RESULTS: Samples from 13 children (median age 84 d) were collected. Mucosal microbiome communities in the fed and unfed segments were strikingly similar [paired UniFrac distance (ß-diversity)], whereas luminal effluent differed significantly from fed samples (PERMANOVA, P = 0.003). Multivariate analysis revealed patient as the strongest predictor of the UniFrac distance. Environmental variables did not influence the intrapatient microbial dissimilarity. Host proteomics were similar intrapatient (paired fed-unfed Euclidian distance) and showed a correlation with the UniFrac distance (Spearman rho = 0.71, P < 0.001). Specific proteins and functional clusters were significantly different between paired samples, including lipid metabolism and intracellular trafficking, whereas no difference was seen in innate immune proteins. The microbiome results were validated in a different cohort with similar characteristics. CONCLUSION: We found the host to be the most dominant factor in the structure of the early life small intestinal mucosal microbiome. Nutrient deprivation was associated with specific changes in the host proteome. Further research is needed to better understand this host-microbe-nutrition interaction.

Physiological response to fetal intravenous lipid emulsion.

In preterm neonates unable to obtain sufficient oral nutrition, intravenous lipid emulsion is life-saving. The contribution of post-conceptional level of maturation to pathology that some neonates experience is difficult to untangle from the global pathophysiology of premature birth. In the present study, we determined fetal physiological responses to intravenous lipid emulsion. Fetal sheep were given intravenous Intralipid 20® (n = 4 females, 7 males) or Lactated Ringer's Solution (n = 7 females, 4 males) between 125 ± 1 and 133 ± 1 d of gestation (term = 147 d). Manufacturer's recommendation for premature human infants was followed: 0.5-1 g/kg/d initial rate, increased by 0.5-1 to 3 g/kg/d. Hemodynamic parameters and arterial blood chemistry were measured, and organs were studied postmortem. Red blood cell lipidomics were analyzed by LC-MS. Intravenous Intralipid did not alter hemodynamic or most blood parameters. Compared with controls, Intralipid infusion increased final day plasma protein (P=0.004; 3.5 ± 0.3 vs. 3.9 ± 0.2 g/dL), albumin (P = 0.031; 2.2 ± 0.1 vs. 2.4 ± 0.2 g/dL), and bilirubin (P<0.001; conjugated: 0.2 ± 0.1 vs. 0.6 ± 0.2 mg/dL; unconjugated: 0.2 ± 0.1 vs. 1.1 ± 0.4 mg/dL). Circulating IGF-1 decreased following Intralipid infusion (P<0.001; 66 ± 24 vs. 46 ± 24 ng/mL). Compared with control Oil Red O liver stains (median score 0), Intralipid-infused fetuses scored 108 (P=0.0009). Lipidomic analysis revealed uptake and processing of infused lipids into red blood cells, increasing abundance of saturated fatty acids. The near-term fetal sheep tolerates intravenous lipid emulsion well, although lipid accumulates in the liver. Increased levels of unconjugated bilirubin may reflect increased red blood cell turnover or impaired placental clearance. Whether Intralipid is less well tolerated earlier in gestation remains to be determined.

Targeted metabolomics unravels altered phenylalanine levels in piglets receiving total parenteral nutrition.

Parenteral nutrition, received by many patients with intestinal failure, can induce hepatobiliary complications, which is termed as parenteral nutrition-associated liver disease (PNALD). The spectrum of PNALD ranges from cholestasis and steatosis to fibrosis and cirrhosis. Although many factors contribute to the pathogenesis of PNALD, the underlying mechanisms remain unclear. In this study, we performed targeted metabolomics to characterize the metabolomic profile in neonatal piglets receiving total parenteral nutrition (TPN) or enteral nutrition (EN) for 1 or 2 weeks. Overall, the metabolomic signature of TPN groups differed from EN groups at both time points. Among the 20 acylcarnitines identified, a majority of them were significantly reduced in TPN groups. KEGG pathway analysis showed that phenylalanine metabolism-associated pathways were dysregulated accompanied by more progressive liver steatosis associated with TPN. Next, we evaluated phenylalanine catabolism and its association with fatty acid oxidation in piglets and rats with PNALD. We showed that the hepatic expression of phenylalanine-degrading enzyme phenylalanine hydroxylase (PAH) was reduced and systemic phenylalanine levels were increased in both animal models of PNALD. Moreover, carnitine palmitoyltransferase 1A, a central regulator of fatty acid oxidation, was downregulated and its expression was negatively correlated with phenylalanine levels in TPN-fed animals. To explore the effects of phenylalanine accumulation on lipid metabolism, we treated HepG2 cells with phenylalanine co-cultured with sodium palmitate or soybean oil emulsion to induce lipid accumulation. We found that phenylalanine treatment exacerbated lipid accumulation by inhibiting fatty acid oxidation without affecting fatty acid synthesis. In summary, our findings establish a pathogenic role of increased phenylalanine levels in driving liver steatosis, linking dysregulation of phenylalanine catabolism with lipid accumulation in the context of PNALD.

Impaired FXR-CPT1a signaling contributes to parenteral nutrition-induced villus atrophy in short-bowel syndrome.

Parenteral nutrition (PN)-induced villus atrophy is a major cause of intestinal failure (IF) for children suffering from short bowel syndrome (SBS), but the precise mechanism remains unclear. Herein, we report a pivotal role of farnesoid X receptor (FXR) signaling and fatty acid oxidation (FAO) in PN-induced villus atrophy. A total of 14 pediatric SBS patients receiving PN were enrolled in this study. Those patients with IF showed longer PN duration and significant intestinal villus atrophy, characterized by remarkably increased enterocyte apoptosis concomitant with impaired FXR signaling and decreased FAO genes including carnitine palmitoyltransferase 1a (CPT1a). Likewise, similar changes were found in an in vivo model of neonatal Bama piglets receiving 14-day PN, including villus atrophy and particularly disturbed FAO process responding to impaired FXR signaling. Finally, in order to consolidate the role of the FXR-CPT1a axis in modulating enterocyte apoptosis, patient-derived organoids (PDOs) were used as a mini-gut model in vitro. Consequently, pharmacological inhibition of FXR by tauro-ß-muricholic acid (T-ßMCA) evidently suppressed CPT1a expression leading to reduced mitochondrial FAO function and inducible apoptosis. In conclusion, impaired FXR/CPT1a axis and disturbed FAO may play a pivotal role in PN-induced villus atrophy, contributing to intestinal failure in SBS patients.

Biallelic variants of the first Kunitz domain of SPINT2 cause a non-syndromic form of congenital diarrhea and tufting enteropathy.

Biallelic SPINT2 pathogenic variants cause a syndromic form of congenital diarrhea and enteropathy (OMIM 270420). To date, 35 patients have been reported and all presented with additional extra-intestinal features, apart from one case. We report on a 5-year-old girl who presented early in life with diarrhea and was found to have a novel homozygous variant in SPINT2. Pathological studies confirmed tufting enteropathy, and during her 5 years of life, she has not developed any extra-intestinal features. Molecular analysis detected a homozygous variant (NM_021102.4: c.203A>G (p. [Tyr68Cys]) in SPINT2. This is the first missense variant reported in the first Kunitz domain (KD1) of SPINT2 in humans. In vitro functional studies of this variant confirmed the deleterious effect leading to the loss of inhibitory activity of the intestinal serine proteases. This is the first description of SPINT2-related diarrhea in a patient who lived without long-term total parenteral nutrition. This study expands the clinical and molecular characteristics of SPINT2-related conditions.

Molecular Mechanisms Underlying Hepatoprotective Activity of Lutein in the Context of Intestinal Failure-Associated Liver Disease.

Intestinal failure-associated liver disease (IFALD) is a spectrum of liver diseases occurring in patients not exposed to liver-damaging factors other than those linked to intestinal dysfunction. The pathogenesis of this disease is multifactorial. It is estimated that up to 90% of people taking long-term parenteral nutrition may develop IFALD, with particular risk for premature neonates and infants due to their immature antioxidant protection and bile acid metabolism. The lack of effective prevention and treatment methods for IFALD encourages scientists to search for new therapeutic solutions. The use of lutein as a substance with antioxidant and anti-inflammatory effects seems to be of great potential in such indication, especially since patients on parenteral nutrition are at risk of deficits in various plant-based nutrients, including lutein. In this review, we explain the pathogenesis of IFALD and summarize knowledge of the hepatoprotective properties of lutein, underscoring its potential as a treatment option. The hepatoprotective effects of lutein and their proposed mechanisms of action are supported by studies on cells and animals exposed to various liver-damaging factors, such as lipopolysaccharide, high-fat diet, alcohol, and more. Finally, we provide perspectives on the future application of lutein in therapy.