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This commentary highlighted the background, take-home messages, and impacts of our 2007 British Journal of Nutrition paper entitled “Amino acids and immune function”. In 2003–2004, there was an outbreak of severe acute respiratory syndrome (SARS) caused by SARS coronavirus-1 (CoV-1) in Asian countries. By the mid-2000’s, clinical and experimental evidence indicated important roles for amino acids (AA) in improving innate and adaptive immunities in humans and animals. Based on our long-standing interest in AA metabolism and nutritional immunology, we decided to critically analyze advances in this nutritional field. Furthermore, we proposed a unified mechanism responsible for beneficial effects of AA and their products (including nitric oxide, glutathione, antibodies, and cytokines) on immune responses. We hoped that such integrated knowledge would be helpful for designing AA-based nutritional methods (e.g., supplementation with glutathione, arginine and glutamine) to prevent and treat SARS-like infectious diseases in the future. Our paper laid a framework for subsequent studies to quantify AA metabolism in intestinal bacteria, determine the effects of functional AA on cell-mediated and humoral immunities, and establish a much-needed database of AA composition in foodstuffs. Unexpectedly, COVID-19 (caused by SARS-CoV-2) emerged in December 2019 and has become one of the deadliest pandemics in history. Notably, glutathione, arginine and glutamine have now been exploited to effectively relieve severe respiratory symptoms of COVID-19 in affected patients. Functional AA (e.g., arginine, cysteine, glutamate, glutamine, glycine, taurine and tryptophan) and glutathione, which are all abundant in animal-sourced foodstuffs, are crucial for optimum immunity and health in humans and animals.
Mammalian neonates undergo rapid transitions from a sterile uterine environment with a continuous intravenous supply of nutrients to a microbe-rich environment with intermittent ingesting of colostrum/milk via the gut. Currently, little is known about the colostrum-induced alterations of intestinal mucosal proteins in piglets with intra-uterine growth restriction (IUGR). In this study, we sought to investigate the innate differences and effects of colostrum on alterations in small-intestinal proteomes of IUGR piglets. Two IUGR (approximately 0·9 kg) and two normal-birth weight (NBW; approximately 1·3 kg) piglets were obtained from each of six sows at birth. One half (n 12; 6 IUGR v. 6 NBW) of the selected newborn piglets were killed to obtain jejunum samples, and the other half (n 12; 6 IUGR v. 6 NBW) of the newborn piglets were allowed to suckle colostrum from their own mothers for 24 h before jejunum sample collection. On the basis of proteomic analysis, we identified thirty-one differentially expressed proteins in the jejunal mucosa between IUGR and normal neonates before or after colostrum consumption. The intestinal proteins altered by colostrum feeding play important roles in the following: (1) increasing intestinal integrity, transport of nutrients, energy metabolism, protein synthesis, immune response and, therefore, cell proliferation; and (2) decreasing oxidative stress, and therefore cell apoptosis, in IUGR neonates. However, colostrum only partially ameliorated the inferior status of the jejunal mucosa in IUGR neonates. These findings provide the first evidence in intestinal protein alterations of IUGR neonates in response to colostrum ingestion, and thus render new insights into the mechanisms responsible for impaired growth in IUGR neonates and into new nutritional intervention strategies.
Infants born with low birth weights (<2500 g, LBW), accounting for about 15 % of newborns, have a high risk for postnatal growth failure and developing the metabolic syndromes such as type 2 diabetes, CVD and obesity later in life. Improper nutrition provision during critical stages, such as undernutrition during the fetal period or overnutrition during the neonatal period, has been an important mediator of these metabolic diseases. Considering the specific physiological status of LBW infants, nutritional intervention and optimisation during early life merit further attention. In this review, the physiological and metabolic defects of LBW infants were summarised from a nutritional perspective. Available strategies for nutritional interventions and optimisation of LBW infants, including patterns of nutrition supply, macronutrient proportion, supplementation of amino acids and their derivatives, fatty acids, nucleotides, vitamins, minerals as well as hormone and microbiota manipulators, were reviewed with an aim to provide new insights into the advancements of formulas and human-milk fortifiers.
Skeletal muscle is a major site for the oxidation of fatty acids (FA) in mammals, including humans. Using a swine model, we tested the hypothesis that dietary protein intake regulates the expression of key genes for lipid metabolism in skeletal muscle. A total of ninety-six barrows (forty-eight pure-bred Bama mini-pigs (fatty genotype) and forty-eight Landrace pigs (lean genotype)) were fed from 5 weeks of age to market weight. Pigs of fatty or lean genotype were randomly assigned to one of two dietary treatments (low- or adequate-protein diet), with twenty-four individually fed pigs per treatment. Our data showed that dietary protein levels affected the expression of genes involved in the anabolism and catabolism of lipids in the longissimus dorsi and biceps femoris muscles in a genotype-dependent manner. Specifically, Bama mini-pigs had more intramuscular fat, SFA and MUFA, as well as elevated mRNA expression levels of lipogenic genes, compared with Landrace pigs. In contrast, Bama mini-pigs had lower mRNA expression levels of lipolytic genes than Landrace pigs fed an adequate-protein diet in the growing phase. These data are consistent with higher white-fat deposition in Bama mini-pigs than in Landrace pigs. In conclusion, adequate provision of dietary protein (amino acids) plays an important role in regulating the expression of key lipogenic genes, and the growth of white adipose tissue, in a genotype- and tissue-specific manner. These findings have important implications for developing novel dietary strategies in pig production.
Tributyrin (TBU) is a good dietary source of butyrate and has beneficial effects on the maintenance of normal intestinal morphology. The present study tested the hypothesis that dietary TBU supplementation could alleviate intestinal injury in the acetic acid (ACA)-induced porcine model of colitis. A total of eighteen piglets (25 d old) were randomly allocated to one of three treatment groups (control, ACA and TBU). The control and ACA groups were fed a basal diet and the TBU group was fed the basal diet supplemented with 0·1 % TBU. On day 15 of the trial, under anaesthesia, a soft catheter was inserted into the rectum of piglets (20–25 cm from the anus), followed by administration of either saline (control group) or ACA (10 ml of 10 % ACA solution for ACA and TBU groups). On day 22 of the trial, after venous blood samples were collected, piglets were killed to obtain mid-ileum and mid-colon mucosae. Compared with the control group, the ACA group exhibited an increase (P< 0·05) in lymphocyte counts, creatinine, PGE2, and malondialdehyde concentrations and diamine oxidase and inducible NO synthase activities in the plasma and lymphocyte density in the colon and a decrease in insulin concentrations and glutathione peroxidase activity, ileal villus height:crypt depth ratios and goblet cell numbers in the colon. These adverse effects of ACA were attenuated by TBU supplementation. Moreover, TBU prevented the ACA-induced increase in caspase-3 levels while enhancing claudin-1 protein and epidermal growth factor receptor (EGFR) mRNA expression in the colonic mucosa. Collectively, these results indicate that dietary supplementation with 0·1 % TBU alleviates ACA-induced intestinal injury possibly by inhibiting apoptosis, promoting tight-junction formation and activating EGFR signalling.
The present study was carried out to determine whether N-acetylcysteine (NAC) could modulate liver injury in a lipopolysaccharide (LPS)-challenged piglet model. For this purpose, eighteen piglets were randomly assigned to the control, LPS or NAC group. Piglets in the control and LPS groups were fed a basal diet, whereas those in the NAC group were fed the basal diet supplemented with 500 mg/kg NAC. On days 10, 13 and 20 of the trial, the LPS- and NAC-treated piglets were intraperitoneally administered LPS (100 μg/kg body weight), while the control group was administered the same volume of saline. On day 20 of the trial, blood samples were obtained 3 h after LPS or saline injection. On day 21, the piglets were killed to collect liver samples. Dietary NAC supplementation attenuated LPS-induced liver histomorphological abnormalities. Compared with the control group, in the LPS-challenged piglets, the activities of alanine aminotransferase and aspartate aminotransferase and the concentrations of H2O2, TNF-α, IL-6 and PGE2 were dramatically increased in the plasma and the activity of superoxide dismutase in the plasma and that of glutathione peroxidase in the liver were significantly decreased. The LPS challenge also increased the concentration of AMP and the ratio of AMP:ATP, but decreased adenylate energy charges and the levels of ATP and ADP. These adverse effects of the LPS challenge were ameliorated by NAC supplementation. Moreover, NAC inhibited the LPS-induced increases in the abundance of liver heat shock protein 70 and NF-κB proteins. In conclusion, these results suggest that dietary NAC supplementation alleviates LPS-induced liver injury by reducing the secretion of pro-inflammatory cytokines, increasing the antioxidative capacity and improving energy metabolism.
Mechanisms linking maternal nutrient restriction (MNR) to intra-uterine growth restriction (IUGR) and programming of adult disease remain to be established. The impact of controlled MNR on maternal and fetal amino acid metabolism has not been studied in non-human primates. We hypothesised that MNR in pregnant baboons decreases fetal amino acid availability by mid-gestation. We determined maternal and fetal circulating amino acid concentrations at 90 d gestation (90dG, term 184dG) in control baboons fed ad libitum (C, n 8) or 70 % of C (MNR, n 6). Before pregnancy, C and MNR body weights and circulating amino acids were similar. At 90dG, MNR mothers had lower body weight than C mothers (P< 0·05). Fetal and placental weights were similar between the groups. MNR reduced maternal blood urea N (BUN), fetal BUN and fetal BUN:creatinine. Except for histidine and lysine in the C and MNR groups and glutamine in the MNR group, circulating concentrations of all amino acids were lower at 90dG compared with pre-pregnancy. Maternal circulating amino acids at 90dG were similar in the MNR and C groups. In contrast, MNR fetal β-alanine, glycine and taurine all increased. In conclusion, maternal circulating amino acids were maintained at normal levels and fetal amino acid availability was not impaired in response to 30 % global MNR in pregnant baboons. However, MNR weight gain was reduced, suggesting adaptation in maternal–fetal resource allocation in an attempt to maintain normal fetal growth. We speculate that these adaptive mechanisms may fail later in gestation when fetal nutrient demands increase rapidly, resulting in IUGR.
The present study was conducted to determine the adjuvant effect of arginine in mice immunised with inactivated vaccine. Mice immunised with an inactivated Pasteurella multocida vaccine and fed diets supplemented with 0·2 % (vaccine-0·2 %) or 0·5 % (vaccine-0·5 %) arginine exhibited 100 % protection from a challenge with P. multocida serotype A (CQ2) at a dose of 4·4 × 105 colony-forming units (2LD50; median lethal dose), when compared with mice receiving no arginine supplementation. Meanwhile, antibody titres in the vaccine-0·2 % arginine group were much higher than those in the vaccine-oil adjuvant group before challenge and at 36 h post-infection. Furthermore, immunisation with the inactivated vaccine and dietary supplementation with 0·2 % arginine increased serum levels of glutathione peroxidase, in comparison with immunisation with the inactivated vaccine and an oil adjuvant. Collectively, dietary arginine supplementation confers an immunostimulatory effect in mice immunised with the inactivated P. multocida vaccine. The present results also indicate that optimal supplemental doses of arginine are 0·2–0·5 % in the mouse model.
The present study determined whether α-ketoglutarate (AKG) might affect the expression of AMP-activated protein kinase (AMPK) and energy status in the intestinal mucosa of piglets challenged with Escherichia coli lipopolysaccharide (LPS). A total of eighteen piglets (weaned at 21 d of age) were allocated to one of three treatments: (1) non-challenged (control); (2) LPS-challenged (LPS); (3) LPS+1 % AKG (LPS+AKG). Piglets in the control and LPS groups were fed a maize- and soyabean meal-based diet, and the LPS+AKG group was fed the basal diet supplemented with 1 % AKG. On days 10, 12, 14 and 16 of the trial, piglets in the LPS and LPS+AKG groups were challenged with LPS (80 μg/kg body weight), whereas piglets in the control group received the same volume of sterile saline. Pigs were euthanised 24 h after the last administration of LPS or saline to obtain intestinal mucosae for biochemical analysis. Compared with the control group, LPS administration decreased (P < 0·05) the oxidation of AKG, oleic acid, glutamine and glucose in enterocytes, decreased concentrations of ATP in the duodenal and jejunal mucosae and decreased adenylate energy charge (AMP:ATP ratio) in the jejunal and ileal mucosae. Additionally, LPS treatment reduced (P < 0·05) mucosal concentrations of phosphorylated AMPK in the jejunum and ileum as well as acetyl-CoA carboxylase in all segments of the small intestine. The adverse effects of LPS were reversed by AKG. Collectively, these results indicate that dietary supplementation with 1 % AKG beneficially modulates the AMPK signalling pathway to improve energy status in the small intestine of LPS-challenged piglets.
Oral administration of l-arginine has been reported to prevent gut disease in human infants. However, little is known about the effects of dietary arginine supplementation on intestinal development of weaned piglets. In the present study, twenty 21-d-old castrated piglets with 5·3 (sem 0·13) kg body weight (BW) were weaned from sows, individually housed and randomly assigned to one of the two maize- and soyabean meal-based diets supplemented with 0 or 1 % l-arginine. After consuming the diets for 7 d, six pigs were randomly selected from each group to obtain various tissues. Compared with control pigs, dietary supplementation with 1 % l-arginine did not affect feed intake but enhanced (P < 0·05) the relative weight of the small intestine (+33 %), daily BW gain (+38 %) and feed efficiency (+28 %). The villus height of the duodenum, jejunum and ileum in arginine-supplemented piglets was 21, 28 and 25 % greater (P < 0·05) than in the non-supplemented control group. Arginine supplementation increased (P < 0·05) protein levels for vascular endothelial growth factor (VEGF) in duodenal, jejunal and ileal mucosae by 14, 39 and 35 %, respectively. Compared with the control group, dietary supplementation with 1 % l-arginine increased (P < 0·05) plasma concentrations of arginine and insulin (+36 %), and decreased (P < 0·05) plasma concentrations of cortisol ( − 33 %), NH3 ( − 21 %) and urea ( − 19 %). These results indicate that arginine supplementation enhances intestinal growth, development and expression of VEGF in early-weaned pigs fed a maize- and soyabean meal-based diet. The findings may have important implications for neonatal pigs under stressful or diseased conditions.
A deficiency of dietary protein or amino acids has long been known to impair immune function and increase the susceptibility of animals and humans to infectious disease. However, only in the past 15 years have the underlying cellular and molecular mechanisms begun to unfold. Protein malnutrition reduces concentrations of most amino acids in plasma. Findings from recent studies indicate an important role for amino acids in immune responses by regulating: (1) the activation of T lymphocytes, B lymphocytes, natural killer cells and macrophages; (2) cellular redox state, gene expression and lymphocyte proliferation; and (3) the production of antibodies, cytokines and other cytotoxic substances. Increasing evidence shows that dietary supplementation of specific amino acids to animals and humans with malnutrition and infectious disease enhances the immune status, thereby reducing morbidity and mortality. Arginine, glutamine and cysteine precursors are the best prototypes. Because of a negative impact of imbalance and antagonism among amino acids on nutrient intake and utilisation, care should be exercised in developing effective strategies of enteral or parenteral provision for maximum health benefits. Such measures should be based on knowledge about the biochemistry and physiology of amino acids, their roles in immune responses, nutritional and pathological states of individuals and expected treatment outcomes. New knowledge about the metabolism of amino acids in leucocytes is critical for the development of effective means to prevent and treat immunodeficient diseases. These nutrients hold great promise in improving health and preventing infectious diseases in animals and humans.
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