Rapid cerebral metabolic shift during neonatal sepsis is attenuated by enteral colostrum supplementation in preterm pigs
This study examined of the perturbations in systemic and cerebral metabolism caused by sepsis, and the impact of a bioactive milk diet (bovine colostrum) during bloodstream infection with the coagulase-negative staphylococci Staphylococcus epidermidis (SE). Bloodstream infection in neonate preterm piglets was found to induce a rapid metabolic shift in both plasma and cerebrospinal fluid, which was modulated by colostrum feeding. Early colostrum supplementation attenuated the increases in lactate, alanine and succinate levels in plasma and cerebrospinal fluid, caused by bloodstream infections with SE in preterm piglets. Lactate accumulation in blood and cerebrospinal fluid and plasma choline levels are biomarkers related to the level of impaired energy metabolism and the severity of cerebral damage, respectively. Hypoxia-related changes in systemic and cerebral energy metabolism were also attenuated by oral colostrum supplementation, suggesting a protective role on the regulation of inflammatory responses. These results match previous results from same animal experiment, showing reduced blood oxygen partial pressure and saturation during SE infection, which were prevented by colostrum supplementation. Sepsis is the clinical manifestation of serious infections and is a frequent cause of cause of morbidity and mortality in newborns. One of the most frequent pathogens is SE. Very preterm infants with low birth weight are especially susceptible due to their immature innate immune system and limited maternal passive immunity. The attenuating effects from colostrum may come from the wide range of anti-inflammatory and anti-microbial proteins found herein.
Human milk fortification with bovine colostrum is superior to formula-based fortifiers to prevent gut dysfunction, necrotizing enterocolitis, and systemic infection in preterm pigs
Human milk fortification is required for preterm infants to support postnatal growth and development. This study provides preclinical evidence that early fortification with bovine colostrum (BC) is superior to fortification with formula-based fortifiers (FF) in preventing gut dysfunction, NEC, and systemic infections. BC support gut function, nutrient absorption, and bacterial defense mechanisms in preterm pigs. Relative to preterm pigs fed donor human milk with BC, preterm pigs fed donor human milk with FF had higher diarrhea score, lower hexose uptake, lower lactase activity, higher gut permeability, higher NEC score, more mucosa-adherent bacteria, lower gut microbiota diversity, higher expression of intestinal cytokine and inflammation-related genes, more gut-derived bacteria in the bone marrow, lower density of mucin-containing goblet cells, slightly higher colon lactate, stomach pH, acetate, and blood neutrophil-to-lymphocyte levels. BC has been tested for preterm infants in a feasibility study and appears safe (FortiColos clinical trial: NCT03537365). It is now important to optimize the composition of the nutrient fortifiers for preterm infants fed human milk.
Nutrient fortification of human donor milk affects intestinal function and protein metabolism in preterm pigs
Nutrient fortification of human donor milk is often required to secure adequate growth and organ development for very preterm infants. Formula-based fortifiers induce intestinal dysfunction, feeding intolerance, and necrotizing enterocolitis (NEC). Bovine colostrum as fortifier for human donor milk has proved feasible and without adverse effects in pilot studies. This study provides important preclinical evidence for a diet-dependent response to nutrient fortification of human donor milk to preterm neonates. Compared to piglets receiving human donor milk fortified with formula-based fortifier, preterm piglets receiving human donor milk fortified with bovine colostrum showed higher growth, better intestinal function and protein utilization. These results suggest that bovine colostrum is superior to formula-based fortifiers in promoting intestinal maturation, nutrient metabolism, and body growth. Further studies are needed to investigate long-term effects. The relevance of bovine colostrum as nutrient fortifier for human donor milk for preterm infants should be tested.
Diet-dependent changes in the intestinal DNA methylome after introduction of enteral feeding in preterm pigs
The first nutrition can influence DNA methylation, thus affecting cellular functions by regulating gene expressions. As preterm infants has an immature gut and immune system, the first feeding and gut colonization are two important environmental factors for intestinal health and diseases. Slowly introduction of either bovine colostrum or infant formula as first enteral feeding for preterm pigs resulted in clear diet-dependent changes in the DNA methylation and/or RNA expression were associated with a variety of intestinal functions, including innate immune response, hypoxia, VEGF signaling and digestive functions. DNA methylation is heritable during cell replication and the early feeding regime may thus have long-term effects on the intestinal development and health of preterm infants. Using preterm pigs as models for preterm infants, epigenetic changes may thus mediate important effects of the first feeding on intestinal development in preterm infants.
Early microbial colonization affects DNA methylation of genes related to intestinal immunity and metabolism in preterm pigs
Preterm infants are supersensitive to invading bacteria due to their immature intestine. A comparison of the intestinal DNA methylome and microbiome between conventional and antibiotics-treated preterm pigs was used as a model for preterm infants. Oral treatment with antibiotics reduced bacterial density (∼100-fold), diversity and fermentation, improved the resistance to necrotizing enterocolitis (NEC), and changed the genome-wide DNA methylation in the distal small intestine. Also, the DNA methylation and expression of intestinal genes, related to innate immune response, phagocytosis, endothelial homeostasis and tissue metabolism differed between conventional and antibiotics-treated pigs. These findings document that the newborn immature intestine is influenced by bacterial colonization via DNA methylation changes. Such microbiota-dependent epigenetic programming of genes related to gut immunity, vascular integrity and metabolism may be critical for short- and long-term intestinal health in preterm neonate infants.
Oral supplementation with bovine colostrum prevents septic shock and brain barrier disruption during bloodstream infection in preterm newborn pigs
Early oral supplementation with bovine colostrum prevents septic shock and ameliorates brain barrier disruption and neuroinflammation during bloodstream infection in newborn preterm piglets. At 24h, colostrum supplementation reduced the abundance of Staphylococcus epidermis in both blood and cerebrospinal fluid. Furthermore, supplementation with bovine colostrum normalized arterial blood pressure and increased motor activity to the levels found in the control group. Finally, piglets fed bovine colostrum showed reduced permeability in the blood-cerebrospinal barrier and reduced levels of leukocytes in the cerebrospinal fluid, accompanied by normalized gene expression of tight junction proteins and reduced gene expression of leukocyte chemoattractants. Bovine colostrum may improve resistance against systemic infection in immature, immune-compromised preterm infants.
Minimal enteral nutrition to improve adaptation after intestinal resection in piglets and infants
Extensive intestinal resection in infants may result in intestinal failure followed by requirements for parenteral support. Due to the potential complications of parenteral nutrition, identification of the optimal minimal enteral nutrition for pediatric patients with short bowel syndrome is important. Supplementation of bovine colostrum as enteral nutrition after small intestinal resection in piglets appeared to be marginally superior to conventional formula. Bovine colostrum and formula induced similar intestinal adaptation. Both diet regimens proved superior to parenteral nutrition, confirming that early introduction of minimal enteral nutrition after intestinal resection is superior to parenteral nutrition. Further studies with a larger sample size and a longer period of enteral feedings are required to confirm the conclusion of bovine colostrum being superior to formula. Bovine colostrum also proved to be well tolerated by newly small intestinal resected preterm and term infants and without clinical adverse effects. The clinical indication for colostrum supplementation to infants subjected to intestinal resection remains to be further determined.
Bovine colostrum for preterm infants in the first days of life: A randomized controlled pilot study
Mother’s milk is the optimal diet for infants relative to human donor milk and infant formula, but for preterm infants maternal milk is often in insufficient supply. Bovine colostrum improves gut maturation, growth and resistance to necrotizing enterocolitis in preterm piglets, relative to infant formula and human donor milk. Preterm infants fed with bovine colostrum showed an increased enteral protein intake without increased feeding intolerance or any apparent clinical adverse effects. This pilot study (PreColos, phase C) demonstrates that it is feasible to give bovine colostrum to preterm infants in the first weeks of life as diet supplement for mother’s own milk. Based on these results more clincal studies are planned in order to develop a bovine colostrum based diet supplement for preterm infants.
Animal models of chemotherapy-induced mucositis: translational relevance and challenges
A common adverse side effect of chemotherapy for cancer patients is chemotherapy-induced mucositis (CIM) that has severe consequences for the patient. This makes it highly relevant to develop translational animal models to help understand treatment toxicities and to manage adverse effects of chemotherapy. Rodent CIM models allow well-controlled, in-depth studies while pig CIM models more easily make clinically relevant treatment regimens possible. Such models have indicated new preventive interventions, including supplementation with natural bioactive diet, nutrients and growth factor peptides, as well as manipulations of the gut microbiota. One example of translational animal models are pig models with CIM fed bovine colostrum. The diet proved beneficial as it increase the digestive function and decreased the gastrointestinal injury. Animal models show some limitations, but the scientific evidence from animal studies improves the general biological understanding of CIM and thereby provides a foundation for new treatments.
Necrotizing enterocolitis - classification and two initial steps towards prevention
The current state of knowledge on necrotizing enterocolitis in preterm infants include gaps about the pathology, but many contributing factors are well documented. Treatment is either medical or surgical, but a better understanding of the pathology and a more valid diagnosis would be beneficial. Microbiota in the feeding tubes for preterm infants may be a contributing factor. Prevention of necrotizing enterocolitis is thus most an important research topic. Results from the first two phases (A and B) of the Precolos study showed that bovine colostrum used for preterm infants in the first days of life as diet supplementation to mother’s own milk proved feasible. No adverse effects were observed. Earlier studies revealed that bovine colostrum was superior to human donor milk and infant formula in stimulating gut immunity and digestive functions. All together, these results valid the use of bovine colostrum as feasible diet supplement for preterm infants and act as step stone for further clinical research.
A stepwise, pilot study of bovine colostrum to supplement the first enteral feeding in preterm infants (PreColos): study protocol and initial results
The optimal feeding for preterm infants during the first weeks of life when mother’s own milk is insufficient is still debated. New evidence from studies on the preterm piglets reveal that whole bovine colostrum may be both feasible and beneficial. This paper describes the study protocol for the first pilot study (PreColos) that investigate intact bovine colostrum as the first enteral feed for preterm infants, and provides the results from the first two phases in the project. Supplementation of bovine colostrum was well tolerated, and no clinical adverse effects were observed. Phase C was initiated based on the safety evaluation of phase A and B.
Feeding premature neonates: Kinship and species in translational neonatology
It is essential for the process of ‘translating’ research from experimental animal laboratory to human clinical trials that kinship (biogenetic proximity) is established between the animal model and the human patient counterpart. In the Danish research center NEOMUNE, premature piglets are fed bovine colostrum to model the effects of this new diet in premature infants. During the daily practice, the piglets and the researchers form ‘interspecies-milk-kinships’, enhancing the ‘translatability’ of the results. Parents of premature infants tend to perceive the animality of bovine colostrum and the background information obtained in piglets, when presented with the option to supplements mother’s own milk with bovine colostrum. It is important to emphasize the ‘species flexibility’ of premature beings in the translational process in the field of neonatology research as it profoundly shapes the dialog.
Spray dried, pasteurized bovine colostrum protects against gut dysfunction and inflammation in preterm pigs
Feeding bovine colostrum instead of infant formula to newborn preterm pigs improves their gut maturation and function and protects against necrotizing enterocolitis. Using preterm pigs as animal model to preterm infants, bovine colostrum makes a good nutrient supply when mother’s milk is insufficient. Before use on preterm infant, it is important to know if the milk processing affects the bioactivity and the efficacy of a bovine colostrum product. This was studied by feeding infant formula or raw, spray-dried or pasteurized bovine colostrum to preterm piglets. All preterm pigs fed bovine colostrum had reduced necrotizing enterocolitis severity relative to preterm pigs fed infant formula. Spray drying and pasteurization showed some effect on bovine colostrum proteins, but did not reduce the trophic and anti-inflammatory effects of bovine colostrum on the immature intestine.
Bovine colostrum improves neonatal growth, digestive function, and gut immunity relative to donor human milk and infant formula in preterm piglets
Mother’s milk is the optimal first diet for infants, but donor human milk or infant formula is used when supply is limited. Preterm pigs fed with colostrum show higher body growth, intestinal transit time and reduced diarrhea and gut permeability, relative to pigs fed with donor human milk or infant formula. They also show a more developed and mature colon. Pigs fed on donor human milk showed intermediate values, while pigs fed on infant formula showed the lowest values. Also, >50% of pigs fed on infant formula showed severe necrotizing enterocolitis, while only subclinical intestinal lesions were found in pigs fed bovine colostrum or donor human milk. Using preterm piglets as model for preterm infants, bovine colostrum is feasible as diet supplement to preterm infants when supply of mother’s milk is limited.
Doxorubicin-induced gut toxicity in piglets fed bovine milk and colostrum
A common adverse effect of cancer treatment is chemotherapy-induced intestinal toxicity, showing clinical signs as diarrhea and weight loss. Bovine colostrum is rich in immunoglobulins and bioactive proteins and is crucial for the development of the gastrointestinal system and the immune system in calves. In this study, preweaned piglets were given the chemotherapy medication Doxorubicin to induce intestinal toxicity. When fed with bovine colostrum afterwards, piglets had lower diarrhea severity and reduced intestinal toxicity relative to piglets fed on enriched bovine milk. Using preterm pigs as model for preterm infant, the results indicate that bovine colostrum is feasible as supplemental diet for children in chemotherapy, as it could help protect the intestines from chemotherapy-induced toxicity.
Milk diets influence doxorubicin-induced intestinal toxicity in piglets
Chemotherapy-induced intestinal toxicity is a common adverse effect of cancer treatment, showing clinical signs as diarrhea and weight loss. Bovine colostrum is crucial for the development of the gastrointestinal system and immune system in calves. This study tested if the immunomodulatory effects of bovine colostrum could reduce the severity of chemotherapy-induced complications. Preterm piglets were given the chemotherapy medication Doxorubicin, and were fed either infant formula or bovine colostrum. All piglets given Doxorubicin developed diarrhea, growth deficits and leukopenia, but those fed bovine colostrum showed less pronounced intestinal toxicity than those fed infant formula. Using preterm piglet as a model, bovine colostrum to be a beneficial supplementary diet for children in chemotherapy.
Limited effects of preterm birth and the first enteral nutrition on cerebellum morphology and gene expression in piglets
Preterm pigs show many signs of immaturity that are characteristic of preterm infants. This includes a neurodevelopmental growth and maturation with a pre- and postnatal growth spurt for the brain that is comparable in timing with that of infants. They show delayed memory and learning and reduced volume of white and grey matter. Early initiation of enteral nutrition had limited structural or molecular effects indicating that pig cerebellar development is more related to postconceptional age than by an inappropriate response to environmental factors at birth or after such as enteral feeding, gut bacterial colonization, inflammation, dysmetabolism, or hypoxia after preterm birth. In contrast to the brain, the gut is always affected immediately after birth, preterm or term, partly mediated by the exposure to nutritional and microbiota triggers. The limited effect from enteral nutrition on the brain development may be caused by the very short feeding period that may have been insufficient to affect cerebellar development and should thus be studied further.
Delayed growth, motor function and learning in preterm pigs during early postnatal life
Preterm birth interrupts normal fetal growth with consequences for postnatal growth and organ development. Many physiological deficits adapt and disappear with advancing postnatal age, but some may persist into childhood. The preterm pig is a recognized model for preterm infants in neonatal gastroenterology and nutrition, but also in relation to physiological and neural development. This study show that preterm birth induces growth deficits, neurodevelopmental delay, and defects in several organ systems at least until 1 month of life. Many normal functional impairments following preterm delivery adapt within the first postnatal days (e.g. physical activity, motor control), while others remain present for a longer period (e.g. balance, coordination, exploration, learning). Several of the physiological characteristics of immaturity disappeared by the fourth week, but some neurodevelopmental deficits remained. No differences were found between fed total parental nutrition and minimal enteral nutrition with bovine colostrum.
Bovine colostrum modulates myeloablative chemotherapy-induced gut toxicity in piglets
Chemotherapy frequently induces intestinal toxicity, resulting in poor treatment outcomes and increased mortality. The severity of such intestinal toxicity may be diet dependent. Bovine colostrum is rich in immunoglobulins and bioactive proteins and is crucial for the development of the gastrointestinal system and the immune system in calves. Intake of bovine colostrum as diet supplement could reduce adverse effects of chemotherapy. This study tested if bovine colostrum provides better gut protection than artificial milk replacer does in preweaned piglets. The piglets received myeloablative treatment and were fed either bovine colostrum or artificial milk replacer. All piglets receiving chemotherapy showed intestinal toxicity, but those fed bovine colostrum showed less vomiting, higher intestinal function and lower tissue inflammation. Using preterm piglets as model for preterm infant, the results indicate that children receiving chemotherapy may benefit from intake of bovine colostrum as diet supplement.
Introducing enteral feeding induces intestinal subclinical inflammation and respective chromatin changes in preterm pigs
Enteral feeding is likely to induce subclinical inflammation in a premature intestine and increase the susceptibility for necrotizing enterocolitis. When tested in preterm pigs as enteral supplement to parental nutrition, infant formula showed higher levels of damage than bovine colostrum, the latter only showing minimal effect. Using preterm pigs as a model for preterm infants, bovine colostrum is feasible as enteral feeding as it minimizes severe adverse effects resulting from enteral feeding. This study document the relation between diet and intestinal epithelium inflammation, and characterize the intestinal epithelial response on the gene-expression and chromatin level prior to the development of any clinical signs of NEC. It also describes how the first small amounts of enteral feeds can shape the epigenetic landscape in the gut, influencing the transcription of genes in the premature intestinal epithelium and how these changes might influence the susceptibility for NEC development.
Early gradual feeding with bovine colostrum improves gut function and NEC resistance to infant formula in preterm pigs
Mother’s milk is often not available in sufficient amounts for preterm infants, so the diet is supplemented by either donor human milk or infant formula. No precise feeding guidelines exists yet on the use of diet supplements for preterm infants. Preterm piglets were fed with total parental nutrition or slowly advancing volumes of infant formula or bovine colostrum as supplementary nutrition. The results showed that feeding infant formula induced intestinal dysfunction whereas bovine colostrum supported gut maturation. Using preterm pigs as animal model for preterm infants, this study provides important information about future feeding guidelines for diet supplements to preterm infants, such as infant formula and bovine colostrum.
Effect of bovine colostrum feeding in comparison with milk replacer and natural feeding on the immune responses and colonization of enterotoxigenic Escherichia coli in the intestinal tissue of piglets
Preterm infants is best nourished with mother’s milk, but it is often insufficient and food supplies as donor human milk or infant formula is added to the diet. Calves are utterly dependent on the cow’s milk as it a vital contribution to their immune system and gastrointestinal system. Preterm piglets were fed with bovine colostrum, milk replacer or maternal milk from the sow to test the effect of diet on the intestinal immune system and presence of the enterotoxigenic Escherichia coli in the intestinal tissue. Piglets fed on sow’s milk and bovine colostrum showed the same reduced colonization by E. coli in the intestinal tissue and a modulated intestinal immune system relative to piglets fed on milk replacer. The frequency of diarrhea was higher in piglets fed with milk replacer and they showed a lower IgG concentration. Using preterm pigs as a model for preterm infants, this study points to the feasibility of bovine colostrum as diet supplement for preterm infants.
Physical activity level is impaired and diet dependent in preterm newborn pigs
Preterm infants show delayed development of motor function after birth, which may relate to functional immaturity of the gut and brain. Early feeding may stimulate gut growth and neonatal physical activity. Calves are dependent on the colostrum provided by the cow to develop a functional gut system. In this study, preterm pigs were fed enteral on sow’s milk only or bovine colostrum, infant formula, or human milk as diet supplement to sow’s milk or as total diet component. The best results came from feeding sow’s milk, bovine colostrum or human milk, the latter two also increasing necrotizing enteritis resistance, relative to formula. The effects may come from maturation of digestive, metabolic and neurological functions by the first enteral feeding. The results points to the feasibility of bovine colostrum as diet supplement to preterm infants, when mother’s milk is in limited supply.
Clinical applications of bovine colostrum therapy: a systematic review
Bovine colostrum is the first milk that cows produce after parturition and contains high levels of growth factors and immunomodulatory components that are crucial for the final development of gut system and immune system in calves. Healthy and diseased individuals may benefit from consuming bovine colostrum as food supplements it may provide gastrointestinal and immunological benefits. Further studies are required before recommendations can be made for clinical application. Based on fifty-one studies this review gives a systematic and critical evaluation of the current state of knowledge on bovine colostrum and usage as diet supplement.
Amniotic fluid and colostrum as potential diets in the critical care of preterm infants
Mother’s milk is the optimal diet for preterm infants, but is often in limited supply. Donor human milk or infant formula is often used as diet supply. Bovine colostrum is rich in immunoglobulins and bioactive proteins and may thus be beneficial as diet supplement for preterm infants and improve gut functions. Preterm pigs were fed sow’s milk or bovine colostrum in small advancing doses for 5 days. Preterm pigs fed bovine colostrum showed higher body weight gain, while incidence of necrotizing enterocolitis and diarrhea and gut development did not differ between groups. Using preterm pigs as model for preterm infants, bovine colostrum is feasible as diet supplement when mother’s milk is in limited supply.
Bovine colostrum improves intestinal function following formula-induced gut inflammation in preterm pigs
The optimal diet for preterm infants is mother’s milk, but as it is insufficient, diet supplies are necessary. Such are infant formula and donor human milk, but infant formula may induce inflammatory responses and predispose to necrotizing enterocolitis. Calves depend on the colostrum produced by the cow to develop a functioning gastrointestinal system. Preterm pigs were fed with infant formula, bovine colostrum or infant formula followed by bovine colostrum. Preterm pigs fed on colostrum only or after infant formula showed lower necrotizing enterocolitis severity and higher gut growth relative to preterm pigs fed only on infant formula. Thus, bovine colostrum restored the intestinal functions after the initial formula-induced inflammation. Using preterm pigs as model for preterm infants, the results point to the feasibility of bovine colostrum as diet supply when mother’s milk is limited.
Raw bovine milk improves gut responses to feeding relative to infant formula in preterm piglets
The quality of the first milk is crucial for the intestinal maturation and resistance to necrotizing enterocolitis in preterm neonates. Bovine colostrum is rich in immunoglobulins and bioactive proteins and is crucial for the development of the gastrointestinal system and the immune system in calves. Preterm pigs were fed with sow’s milk supplemented with bovine milk, bovine colostrum, infant formula or whole milk powder. Preterm pigs fed bovine milk had significantly improved intestinal structure and function, and suffered less necrotizing enterocolitis than the other pigs. In preterm pigs fed bovine colostrum the results further improved. All three products of intact bovine milk (milk, colostrum and milk powder) showed better effects than infant formula. Using preterm pigs as model for preterm infants, the results point to the feasibility of bovine colostrum as diet supply when mother’s milk is limited.
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Råmælk fra køer skal hjælpe for tidligt fødte børn
Dansk forskningscenter vil styrke præmature børn med optimeret ernæring
Råmælk fra køer skal hjælpe for tidligt-fødte børn (NEOCOL)
Mælk og mikrobiota til nyfødtes udvikling (NEOMUNE)
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