Impact of a specialized oral nutritional supplement on quality of life in older adults following hospitalization: Post-hoc analysis of the NOURISH trial.

BACKGROUND & AIMS: Both during and after hospitalization, nutritional care with daily intake of oral nutritional supplements (ONS) improves health outcomes and decreases risk of mortality in malnourished older adults. In a post-hoc analysis of data from hospitalized older adults with malnutrition risk, we sought to determine whether consuming a specialized ONS (S-ONS) containing high protein and beta-hydroxy-beta-methylbutyrate (HMB) can also improve Quality of Life (QoL). METHODS: We analyzed data from the NOURISH trial-a randomized, placebo-controlled, multi-center, double-blind study conducted in patients with congestive heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease. Patients received standard care + S-ONS or placebo beverage (target 2 servings/day) during hospitalization and for 90 days post-discharge. SF-36 and EQ-5D QoL outcomes were assessed at 0-, 30-, 60-, and 90-days post-discharge. To account for the missing QoL observations (27.7%) due to patient dropout, we used multiple imputation. Data represent differences between least squares mean (LSM) values with 95% Confidence Intervals for groups receiving S-ONS or placebo treatments. RESULTS: The study population consisted of 622 patients of mean age ±standard deviation: 77.9 ± 8.4 years and of whom 52.1% were females. Patients consuming placebo had lower (worse) QoL domain scores than did those consuming S-ONS. Specifically for the SF-36 health domain scores, group differences (placebo vs S-ONS) in LSM were significant for the mental component summary at day 90 (-4.23 [-7.75, -0.71]; p = 0.019), the domains of mental health at days 60 (-3.76 [-7.40, -0.12]; p = 0.043) and 90 (-4.88 [-8.41, -1.34]; p = 0.007), vitality at day 90 (-3.33 [-6.65, -0.01]; p = 0.049) and social functioning at day 90 (-4.02 [-7.48,-0.55]; p = 0.023). Compared to placebo, differences in LSM values for the SF-36 general health domain were significant with improvement in the S-ONS group at hospital discharge and beyond: day 0 (-2.72 [-5.33, -0.11]; p = 0.041), day 30 (-3.08 [-6.09, -0.08]; p = 0.044), day 60 (-3.95 [-7.13, -0.76]; p = 0.015), and day 90 (-4.56 [-7.74, -1.38]; p = 0.005). CONCLUSIONS: In hospitalized older adults with cardiopulmonary diseases and evidence of poor nutritional status, daily intake of S-ONS compared to placebo improved post-discharge QoL scores for mental health/cognition, vitality, social functioning, and general health. These QoL benefits complement survival benefits found in the original NOURISH trial analysis. CLINICAL TRIAL REGISTRATION: NCT01626742.

Reduced mortality risk in malnourished hospitalized older adult patients with COPD treated with a specialized oral nutritional supplement: Sub-group analysis of the NOURISH study.

BACKGROUND: Hospitalized, malnourished older adults with chronic obstructive pulmonary disease (COPD) have an elevated risk of readmission and mortality. OBJECTIVE: Post-hoc, sub-group analysis from the NOURISH study cohort examined the effect of a high-protein oral nutritional supplement (ONS) containing HMB (HP-HMB) in malnourished, hospitalized older adults with COPD and to identify predictors of outcomes. METHODS: The NOURISH study (n = 652) was a multicenter, randomized, placebo-controlled, double-blind trial. The COPD subgroup (n = 214) included hospitalized, malnourished (based on Subjective Global Assessment), older adults (≥65 y), with admission diagnosis of COPD who received either standard-of-care plus HP-HMB (n = 109) or standard-of-care and a placebo supplement (n = 105) prescribed 2 servings/day from within 3 days of hospital admission (baseline) and up to 90 days after discharge. The primary study outcome was a composite endpoint of incidence of death or non-elective readmission up to 90-day post-discharge, while secondary endpoints included changes in hand-grip strength, body weight, and nutritional biomarkers over time. Categorical outcomes were analyzed using Cochran-Mantel-Haenszel tests, longitudinal data by repeated measures analysis of covariance; and changes from baseline by analysis of covariance. p-values ≤ 0.05 were considered statistically significant. Multivariate logistic regression was used to model predictors of the primary outcome and components. RESULTS: In patients with COPD, 30, 60, and 90-day hospital readmission rate did not differ, but in contrast, 30, 60, and 90-day mortality risk was approximately 71% lower with HP-HMB supplementation relative to placebo (1.83%, 2.75%, 2.75% vs. 6.67%, 9.52% and 10.48%, p = 0.0395, 0.0193, 0.0113, resp.). In patients with COPD, compared to placebo, intake of HP-HMB resulted in a significant increase in handgrip strength (+1.56 kg vs. -0.34 kg, p = 0.0413) from discharge to day 30; increased body weight from baseline to hospital discharge (0.66 kg vs. -0.01 kg, p < 0.05) and, improvements in blood nutritional biomarker concentrations. The multivariate logistic regression predictors of the death, readmission or composite endpoints in these COPD patients showed that participants who were severely malnourished (p = 0.0191) and had a Glasgow prognostic score (GPS) Score of 1 or 2 had statistically significant odds of readmission or death (p = 0.0227). CONCLUSIONS: Among malnourished, hospitalized patients with COPD, supplementation with HP-HMB was associated with a markedly decreased mortality risk, and improved handgrip strength, body weight, and nutritional biomarkers within a 90-day period after hospital discharge. This post-hoc, subgroup analysis highlights the importance of early identification of nutritional risk and administration of high-protein ONS in older, malnourished patients with COPD after hospital admission and continuing after hospital discharge.

Readmission and mortality in malnourished, older, hospitalized adults treated with a specialized oral nutritional supplement: A randomized clinical trial.

BACKGROUND: Hospitalized, malnourished older adults have a high risk of readmission and mortality. OBJECTIVE: Evaluation of a high-protein oral nutritional supplement (HP-HMB) containing beta-hydroxy-beta-methylbutyrate on postdischarge outcomes of nonelective readmission and mortality in malnourished, hospitalized older adults. DESIGN: Multicenter, randomized, placebo-controlled, double-blind trial. SETTING: Inpatient and posthospital discharge. PATIENTS: Older (≥65 years), malnourished (Subjective Global Assessment [SGA] class B or C) adults hospitalized for congestive heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease. INTERVENTIONS: Standard-of-care plus HP-HMB (n = 328) or a placebo supplement (n = 324), 2 servings/day. MEASUREMENTS: Primary composite endpoint was 90-day postdischarge incidence of death or nonelective readmission. Other endpoints included 30- and 60-day postdischarge incidence of death or readmission, length of stay (LOS), SGA class, body weight, and activities of daily living (ADL). RESULTS: The primary composite endpoint was similar between HP-HMB (26.8%) and placebo (31.1%). No between-group differences were observed for 90-day readmission rate, but 90-day mortality was significantly lower with HP-HMB relative to placebo (4.8% vs. 9.7%; relative risk 0.49, 95% confidence interval [CI], 0.27 to 0.90; p = 0.018). The number-needed-to-treat to prevent 1 death was 20.3 (95% CI: 10.9, 121.4). Compared with placebo, HP-HMB resulted in improved odds of better nutritional status (SGA class, OR, 2.04, 95% CI: 1.28, 3.25, p = 0.009) at day 90, and an increase in body weight at day 30 (p = 0.035). LOS and ADL were similar between treatments. LIMITATIONS: Limited generalizability; patients represent a selected hospitalized population. CONCLUSIONS: Although no effects were observed for the primary composite endpoint, compared with placebo HP-HMB decreased mortality and improved indices of nutritional status during the 90-day observation period. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.govNCT01626742.

Evidence-based recommendations for addressing malnutrition in health care: an updated strategy from the feedM.E. Global Study Group.

The prevalence of malnutrition ranges up to 50% among patients in hospitals worldwide, and disease-related malnutrition is all too common in long-term and other health care settings as well. Regrettably, the numbers have not improved over the past decade. The consequences of malnutrition are serious, including increased complications (pressure ulcers, infections, falls), longer hospital stays, more frequent readmissions, increased costs of care, and higher risk of mortality. Yet disease-related malnutrition still goes unrecognized and undertreated. To help improve nutrition care around the world, the feedM.E. (Medical Education) Global Study Group, including members from Asia, Europe, the Middle East, and North and South America, defines a Nutrition Care Pathway that is simple and can be tailored for use in varied health care settings. The Pathway recommends screen, intervene, and supervene: screen patients' nutrition status on admission or initiation of care, intervene promptly when needed, and supervene or follow-up routinely with adjustment and reinforcement of nutrition care plans. This article is a call-to-action for health caregivers worldwide to increase attention to nutrition care.

Short bowel syndrome: highlights of patient management, quality of life, and survival.

Short bowel syndrome (SBS) occurs as a result of intestinal resection, and in many patients is associated with complications, such as diarrhea, dehydration, weight loss, and nutrition deficiencies. Many individuals with SBS develop intestinal failure and require parenteral nutrition (PN) and/or intravenous (IV) fluids (PN/IV). Although PN is essential for survival, some patients with SBS who require long-term PN experience significant complications that contribute to morbidity and mortality. Consequently, therapies that decrease reliance on PN are of considerable importance. Intestinal adaptation, which results in morphologic and functional changes that increase performance of the remnant bowel, occurs spontaneously after intestinal resection. These effects can be enhanced with nutrition and pharmaceutical approaches. For example, oral or tube-fed nutrients stimulate growth and adaptation of intestinal tissues. In addition, prebiotics support growth of beneficial intestinal microbiota that produce short-chain fatty acids, which have been shown in preclinical studies to enhance intestinal structure and function. Finally, glucagon-like peptide 2 (GLP-2) is an endogenous peptide that promotes intestinal rehabilitation and improves intestinal absorption. Teduglutide, a recombinant human GLP-2 analog, has recently been approved in the United States for the treatment of adults with SBS who are dependent on PN. In pharmacodynamic and clinical studies, teduglutide has been shown to promote changes in intestinal structure, such as increases in villus height and crypt depth, and to improve intestinal absorption, as indicated by reduced PN/IV dependence. This article presents a brief overview of SBS, including effects on survival and quality of life and current treatment options.

Critical role of nutrition in improving quality of care: an interdisciplinary call to action to address adult hospital malnutrition.

The current era of healthcare delivery, with its focus on providing high-quality, affordable care, presents many challenges to hospital-based health professionals. The prevention and treatment of hospital malnutrition offer a tremendous opportunity to optimize the overall quality of patient care, improve clinical outcomes, and reduce costs. Unfortunately, malnutrition continues to go unrecognized and untreated in many hospitalized patients. This article represents a call to action from the interdisciplinary Alliance to Advance Patient Nutrition to highlight the critical role of nutrition intervention in clinical care and to suggest practical ways to promptly diagnose and treat malnourished patients and those at risk for malnutrition. We underscore the importance of an interdisciplinary approach to addressing malnutrition both in the hospital and in the acute posthospital phase. It is well recognized that malnutrition is associated with adverse clinical outcomes. Although data vary across studies, available evidence shows that early nutrition intervention can reduce complication rates, length of hospital stay, readmission rates, mortality, and cost of care. The key is to systematically identify patients who are malnourished or at risk and to promptly intervene. We present a novel care model to drive improvement, emphasizing the following 6 principles: (1) create an institutional culture where all stakeholders value nutrition, (2) redefine clinicians' roles to include nutrition care, (3) recognize and diagnose all malnourished patients and those at risk, (4) rapidly implement comprehensive nutrition interventions and continued monitoring, (5) communicate nutrition care plans, and (6) develop a comprehensive discharge nutrition care and education plan.

Soluble fiber dextrin and soluble corn fiber supplementation modify indices of health in cecum and colon of Sprague-Dawley rats.

The objective of this study was to evaluate health outcomes resulting from dietary supplementation of novel, low-digestible carbohydrates in the cecum and colon of Sprague-Dawley rats randomly assigned to one of four treatment groups for 21 days: 5% cellulose (Control), Pectin, soluble fiber dextrin (SFD), or soluble corn fiber (SCF). Rats fed Pectin had a higher average daily food intake, but no differences in final body weights or rates of weight gain among treatments were observed. No differences were observed in total short-chain fatty acid (SCFA) or branched-chain fatty acid (BCFA) concentrations in the cecum and colon of rats fed either SFD or SCF. The SFD and SCF treatments increased cecal propionate and decreased butyrate concentrations compared to Control or Pectin. Pectin resulted in increased BCFA in the cecum and colon. Supplementation of SFD and SCF had no effect on cecal microbial populations compared to Control. Consumption of SFD and SCF increased total and empty cecal weight but not colon weight. Gut histomorphology was positively affected by SFD and SCF. Increased crypt depth, goblet cell numbers, and acidic mucin were observed in both the cecum and colon of rats supplemented with SFD, SCF, and Pectin. These novel, low-digestible carbohydrates appear to be beneficial in modulating indices of hindgut morphology when supplemented in the diet of the rat.

Intestinal adaptation is stimulated by partial enteral nutrition supplemented with the prebiotic short-chain fructooligosaccharide in a neonatal intestinal failure piglet model.

BACKGROUND: Butyrate has been shown to stimulate intestinal adaptation when added to parenteral nutrition (PN) following small bowel resection but is not available in current PN formulations. The authors hypothesized that pre- and probiotic administration may be a clinically feasible method to administer butyrate and stimulate intestinal adaptation. METHODS AND MATERIALS: Neonatal piglets (48 hours old, n = 87) underwent placement of a jugular catheter and an 80% jejunoileal resection and were randomized to one of the following treatment groups: control (20% standard enteral nutrition/80% standard PN), control plus prebiotic (10 g/L short-chain fructooligosaccharides [scFOS]), control plus probiotic (1 × 10(9) CFU Lactobacillus rhamnosus GG [LGG]), or control plus synbiotic (scFOS + LGG). Animals received infusions for 24 hours, 3 days, or 7 days, and markers of intestinal adaptation were assessed. RESULTS: Prebiotic treatment increased ileal mucosa weight compared with all other treatments (P = .017) and ileal protein compared with control (P = .049), regardless of day. Ileal villus length increased in the prebiotic and synbiotic group (P = .011), regardless of day, specifically due to an increase in epithelial proliferation (P = .003). In the 7-day prebiotic group, peptide transport was upregulated in the jejunum (P = .026), whereas glutamine transport was increased in both the jejunum and colon (P = .001 and .003, respectively). CONCLUSIONS: Prebiotic and/or synbiotic supplementation resulted in enhanced structure and function throughout the residual intestine. Identification of a synergistic prebiotic and probiotic combination may enhance the promising results obtained with prebiotic treatment alone.

Bifidobacterium lactis Bb12 enhances intestinal antibody response in formula-fed infants: a randomized, double-blind, controlled trial.

BACKGROUND: Addition of probiotics to infant formula may positively affect immune function in nonexclusively breastfed infants. This study aimed to investigate the effect of infant starter formula containing the probiotic Bifidobacterium animalis subspecies lactis (Bb12) on intestinal immunity and inflammation. METHODS: Six-week-old healthy, full-term infants (n = 172) were enrolled in a prospective, randomized, double-blind, controlled clinical trial with 2 groups studied in parallel to a breastfed comparison group. Formula-fed (FF) infants were randomized to partially hydrolyzed whey formula (CON) or the same formula containing 10(6) colony-forming units (CFU) Bb12/g (PRO) for 6 weeks. Fecal secretory IgA (sIgA), calprotectin, lactate, and stool pH were assessed at baseline, 2 weeks, and 6 weeks. Anti-poliovirus-specific IgA and anti-rotavirus-specific IgA were assessed at 2 and 6 weeks. RESULTS: Among vaginally delivered FF infants, PRO consumption increased (P < .05) fecal sIgA compared to CON. Anti-poliovirus-specific IgA concentration increased (P < .05) in all infants consuming PRO, whereas anti-rotavirus-specific IgA tended to increase (P = .056) with PRO consumption in cesarean-delivered infants. Anthropometrics and tolerance did not differ significantly between FF infants. CONCLUSIONS: Infants consuming formula with Bb12 produced feces with detectable presence of Bb12 and augmented sIgA concentration. Furthermore, cesarean-delivered infants consuming Bb12 had heightened immune response, as evidenced by increased anti-rotavirus- and anti-poliovirus-specific IgA following immunization. These results demonstrate that negative immune-related effects of not breastfeeding and cesarean delivery can be mitigated by including Bb12 in infant formula, thereby providing infants a safe, dietary, immune-modulating bacterial introduction.

Effects of prebiotic-containing infant formula on gastrointestinal tolerance and fecal microbiota in a randomized controlled trial.

BACKGROUND: Prebiotic-containing infant formula may beneficially affect gastrointestinal tolerance and commensal microbiota composition. OBJECTIVE: Assess gastrointestinal tolerance and fecal microbiota, pH, and short-chain fatty acid (SCFA) concentrations of infants consuming formula with or without prebiotics. DESIGN: Full-term formula-fed infants were studied to a breastfed comparison group (BF). Formula-fed infants (FF) were randomized to consume a partially hydrolyzed whey formula with (PRE) or without (CON) 4 g/L of galacto-oligosaccharides and fructo-oligosaccharides (9:1). Fecal bacteria, pH, and SCFA were assessed at baseline, 3 weeks, and 6 weeks. Caregivers of patients recorded stool characteristics and behavior for 2 days before the 3- and 6-week visits. RESULTS: Feces from infants fed PRE had a higher absolute number (P = .0083) and proportion (P = .0219) of bifidobacteria than CON-fed infants and did not differ from BF. BF had a higher proportion of bifidobacteria than CON (P = .0219) and lower number of Clostridium difficile than FF (P = .0087). Feces from formula-fed infants had higher concentrations of acetate (P < .001), butyrate (P < .001), propionate (P < .001), and total SCFAs (P = .0230) than BF; however, fecal pH was lower (P = .0161) in PRE and BF than CON. Prebiotic supplementation did not alter stool patterns, tolerance, or growth. BF had more frequent stools that were yellow (P < .0001) and more often liquid than FF (P < .0001). CONCLUSIONS: Infant formula containing the studied oligosaccharides was well tolerated, increased abundance and proportion of bifidobacteria, and reduced fecal pH in healthy infants.

Quest for excellence: inspiration from the ileum.

The occasion of the American Society for Parenteral and Enteral Nutrition 33rd Presidential Address was used to glean wisdom and inspiration from the ileum. Not only is this intestinal segment so central to the chief organ involved in specialized nutrition support, but it is a complex, yet elegant system that: (1) is interdisciplinary with actions coordinated to achieve a common goal; (2) looks to the future by mentoring the next generation of leaders; (3) constantly seeks evidence of its effectiveness and accordingly adjusts its practice; and (4) strategically forges synergistic partnerships with other habitants within its environment. As relevant within many other realms, it remains true that much can be learned from looking within.

Emerging therapies for intestinal failure.

Given the immeasurable human distress and health care burden associated with intestinal failure, medical therapies aimed at intestinal rehabilitation are needed. Following massive small-bowel resection, the residual intestine is known to adapt structurally and functionally in an attempt to compensate for the resected portion. However, parenteral nutrition may be associated with many short- and long-term complications, including prevention of intestinal adaptation and promotion of mucosal atrophy due to lack of stimulus provided by oral or enteral nutrition. However, data herein demonstrate that the addition of butyrate, a short-chain fatty acid produced in the colon by dietary fiber fermentation, stimulates intestinal adaptation when added to parenteral nutrition, indicating that current solutions could be formulated to optimize intestinal adaptation and to reduce dependence of individuals with intestinal failure receiving long-term parenteral nutrition regimens.

Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL-4 and Th2 polarization.

Peripheral activation of the immune system by infectious agents triggers the brain-cytokine system causing sickness behaviors which profoundly impact well-being. Dietary fiber is a beneficial foodstuff that, from a gastrointestinal tract perspective, exists in both insoluble and soluble forms. We show that a diet rich in soluble fiber protects mice from endotoxin-induced sickness behavior by polarizing mice Th2 when compared to a diet containing only insoluble fiber. Mice fed soluble fiber became less sick and recovered faster from endotoxin-induced sickness behaviors than mice fed insoluble fiber. In response to intraperitoneal endotoxin, mice fed soluble fiber had up-regulated IL-1RA and reduced IL-1beta and TNF-alpha in the brain as compared to mice fed insoluble fiber. Importantly, mice fed soluble fiber had a basal increase in IL-4 in the ileum and spleen which was absent in MyD88 knockout mice. Con-A stimulated splenocytes from mice fed soluble fiber showed increased IL-4 and IL-5 and decreased IL-2, IL-12 and IFN-gamma when compared to mice fed insoluble fiber. Likewise, endotoxin-stimulated macrophages from mice fed soluble fiber demonstrated decreased IL-1beta, TNF-alpha, IFN-gamma, IL-12 and nitrate and increased IL-1RA, arginase 1 and Ym1 when compared to mice fed insoluble fiber. Finally, the behavioral protection afforded by feeding mice soluble fiber was reduced in IL-4 knockout mice, as was the impact of soluble fiber on Con-A stimulated splenocytes and endotoxin activated macrophages. These data show that a diet rich in soluble fiber protects against endotoxin-induced sickness behavior by polarizing mice Th2 and promoting alternative activation of macrophages.

Fructan supplementation and infection affect food intake, fever, and epithelial sloughing from Salmonella challenge in weanling puppies.

Our objective was to examine the effects of fructan supplementation on the immune response of weanling puppies subjected to bacterial challenge. Previous studies in bacterial challenged neonatal piglets have reported benefits of fructan supplementation. Thirty hound-cross puppies (12 wk of age) were used in a 2 x 3 factorial randomized complete block design. Following a 7-d baseline period, puppies were assigned to diets containing: 1) no prebiotic, 2) 1% short-chain fructooligosaccharides (scFOS), or 3) 1% inulin. After 14 d on treatment diet, dogs received an oral gavage of: 1) Salmonella typhimurium DT104 (5 x 10(8) colony forming units) or 2) 0.9% saline. Food intake, fecal and activity scores, body temperature, body weight, blood chemistry, intestinal nutrient transport, intestinal morphology and pathology, and gut microbiota were measured. Food intake decreased (P < 0.01) and body temperature increased (P < 0.05) in infected puppies. However, the decrease in food intake was less (P < 0.05) in those consuming fructans. Infected puppies consuming fructans also had decreased (P = 0.05) severity of enterocyte sloughing than those fed the control diet. Ileal Na+-dependent glucose transport was decreased (P = 0.02) in infected vs. noninfected puppies consuming CON, whereas no changes occurred in fructan-supplemented animals. Puppies consuming inulin also had increased fecal acetate (P = 0.03) and total short-chain fatty acid (P = 0.06) concentrations than scFOS-fed puppies and controls. Finally, puppies fed inulin had an increase (P = 0.05) in Lactobacillus concentrations compared with scFOS and CON. In summary, fructan supplementation appeared to attenuate some of the negative responses associated with Salmonella challenge and may provide protection against infection in weanling puppies.

Development of the infant intestine: implications for nutrition support.

The incidence of preterm births has continued to increase over the past 25 years, and therefore the optimal feeding of these infants is an important clinical concern. This review focuses on intestinal development and physiology, with a particular emphasis on developmentally immature functions of the preterm intestine and the resulting implications for nutrition therapies used to feed the preterm infant.

Formula-feeding reduces lactose digestive capacity in neonatal pigs.

The intestine of newborn pigs develops rapidly during the first days postpartum. We investigated if feeding milk replacer (infant formula) as an alternative to colostrum has compromising effects on nutrient digestive function in the neonatal period. Nineteen piglets born at term were assigned to one of four treatments: (1) newborn controls; (2) natural suckling for 24 h; (3) tube-fed formula for 24 h; (4) tube-fed porcine colostrum for 24 h. All three fed groups showed significant increases in small-intestinal and colonic weights, villous heights and widths, maltase and aminopeptidase A activities, and decreases in dipeptidylpeptidase IV activity, relative to newborn pigs. Following oral boluses of mannitol, lactose or galactose, formula-fed pigs showed significantly reduced plasma levels of mannitol and galactose compared with colostrum-fed pigs. Activity of intestinal inducible NO synthase and plasma levels of cortisol were significantly increased, whereas intestinal constitutive NO synthase and alpha-tocopherol were decreased in formula-fed pigs compared with colostrum-fed pigs. Although formula-fed pigs only showed minor clinical signs of intestinal dysfunction and showed similar intestinal trophic responses just after birth, as those fed colostrum, lactose digestive capacity was markedly reduced. We conclude that formula-feeding may exert detrimental effects on intestinal function in neonates. Formula-induced subclinical malfunction of the gut in pigs born at term was associated with altered NO synthase activity and antioxidative capacity.