Milk Osteopontin for Gut, Immunity and Brain Development in Preterm Pigs

Deficient levels of milk osteopontin (OPN) in infant formula may partly account for developmental differences between infants fed formula or maternal milk. We hypothesized that a milk diet supplemented with bovine milk OPN improves gut, immunity and brain development and tested this in a preterm pig model. Preterm pigs delivered by cesarean section (90% gestation) were fed raw bovine milk (CON, n = 19) or the same diet supplemented with a physiologically relevant dose of OPN (46 mg/(kg·d), n = 16). Endpoints related to clinical outcomes, systemic immunity and neurocognitive development were assessed during the study and gut tissues were collected at Day 19. Growth pattern, early motor development and most systemic immune parameters were similar between OPN and CON pigs. The OPN pigs had higher villus-to-crypt ratios than CON pigs and higher monocyte and lymphocyte counts on Day 8. Gut digestive and absorptive functions and cognitive performance (T-maze test) were similar between OPN and CON pigs. In conclusion, dietary supplementation with OPN above basal bovine milk levels induced minor improvements in gut structure and systemic immunity without any effects on cognitive performance. The minimal levels of OPN in infant formula to secure optimal adaptation in the immediate neonatal period remain to be determined.

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Gut and immune effects of bioactive milk factors in preterm pigs exposed to prenatal inflammation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00042.2019 ◽

2019 ◽

Vol 317 (1) ◽

pp. G67-G77 ◽

Cited By ~ 6

Author(s):

Shuqiang Ren ◽

Yan Hui ◽

Sandra Goericke-Pesch ◽

Stanislava Pankratova ◽

Witold Kot ◽

...

Keyword(s):

Preterm Birth ◽

Digestive Enzyme ◽

Bovine Milk ◽

Intestinal Epithelial ◽

Immune Parameters ◽

Gut Immunity ◽

Prenatal Inflammation ◽

Bioactive Ingredients ◽

Digestive Enzyme Activities

Prenatal inflammation may predispose to preterm birth and postnatal inflammatory disorders such as necrotizing enterocolitis (NEC). Bioactive milk ingredients may help to support gut maturation in such neonates, but mother’s milk is often insufficient after preterm birth. We hypothesized that supplementation with bioactive ingredients from bovine milk [osteopontin (OPN), caseinoglycomacropeptide (CGMP), colostrum (COL)] supports gut, immunity, and NEC resistance in neonates born preterm after gram-negative infection before birth. Using preterm pigs as a model for preterm infants, fetal pigs were given intraamniotic injections of lipopolysaccharide (LPS; 1 mg/fetus) and delivered 3 days later (90% gestation). For 5 days, groups of LPS-exposed pigs were fed formula (FOR), bovine colostrum (COL), or formula enriched with OPN or CGMP. LPS induced intraamniotic inflammation and postnatal systemic inflammation but limited effects on postnatal gut parameters and NEC. Relative to FOR, COL feeding to LPS-exposed pigs showed less diarrhea, NEC severity, reduced gut IL-1β and IL-8 levels, greater gut goblet cell density and digestive enzyme activities, and blood helper T-cell fraction. CGMP improved neonatal arousal and gut lactase activities and reduced LPS-induced IL-8 secretion in intestinal epithelial cells (IECs) in vitro. Finally, OPN tended to reduce diarrhea and stimulated IEC proliferation in vitro. No effects on villus morphology, circulating cytokines, or colonic microbiota were observed among groups. In conclusion, bioactive milk ingredients exerted only modest effects on gut and systemic immune parameters in preterm pigs exposed to prenatal inflammation. Short-term, prenatal exposure to inflammation may render the gut less sensitive to immune-modulatory milk effects. NEW & NOTEWORTHY Prenatal inflammation is a risk factor for preterm birth and postnatal complications including infections. However, from clinical studies, it is difficult to separate the effects of only prenatal inflammation from preterm birth. Using cesarean-delivered preterm pigs with prenatal inflammation, we documented some beneficial gut effects of bioactive milk diets relative to formula, but prenatal inflammation appeared to decrease the sensitivity of enteral feeding. Special treatments and diets may be required for this neonatal population.

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Nutrient Restriction has Limited Short-Term Effects on Gut, Immunity, and Brain Development in Preterm Pigs

Journal of Nutrition ◽

10.1093/jn/nxaa030 ◽

2020 ◽

Vol 150 (5) ◽

pp. 1196-1207 ◽

Cited By ~ 1

Author(s):

Agnethe May Ahnfeldt ◽

Ole Bæk ◽

Yan Hui ◽

Charlotte Holme Nielsen ◽

Karina Obelitz-Ryom ◽

...

Keyword(s):

Brain Development ◽

Preterm Infants ◽

Bovine Milk ◽

Nutrition Support ◽

Physiological Adaptation ◽

Preterm Neonates ◽

Negative Consequences ◽

Large White ◽

Brain Functions ◽

Gut Immunity

ABSTRACT Background Extrauterine growth restriction (EUGR) in preterm infants is associated with higher morbidity and impaired neurodevelopment. Early nutrition support may prevent EUGR in preterm infants, but it is not known if this improves organ development and brain function in the short and long term. Objective Using pigs as models for infants, we hypothesized that diet-induced EUGR impairs gut, immunity, and brain development in preterm neonates during the first weeks after birth. Methods Forty-four preterm caesarean-delivered pigs (Danish Landrace × Large White × Duroc, birth weight 975 ± 235 g, male:female ratio 23:21) from 2 sows were fed increasing volumes [32–180 mL/(kg·d)] of dilute bovine milk (EUGR group) or the same diet fortified with powdered bovine colostrum for 19 d (CONT group, 50–100% higher protein and energy intake than the EUGR group). Results The EUGR pigs showed reduced body growth (−39%, P < 0.01), lower plasma albumin, phosphate, and creatine kinase concentrations (−35 to 14%, P < 0.05), increased cortisol and free iron concentrations (+130 to 700%, P < 0.05), and reduced relative weights of the intestine, liver, and spleen (−38 to 19%, all P < 0.05). The effects of EUGR on gut structure, function, microbiota, and systemic immunity were marginal, although EUGR temporarily increased type 1 helper T cell (Th1) activity (e.g. more blood T cells and higher Th1-related cytokine concentrations on day 8) and reduced colon nutrient fermentation (lower SCFA concentration; −45%, P < 0.01). Further, EUGR pigs showed increased relative brain weights (+19%, P < 0.01), however, memory and learning, as tested in a spatial T-maze, were not affected. Conclusion Most of the measured organ growth, and digestive, immune, and brain functions showed limited effects of diet-induced EUGR in preterm pigs during the first weeks after birth. Likewise, preterm infants may show remarkable physiological adaptation to deficient nutrient supply during the first weeks of life although early life malnutrition may exert negative consequences later.

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Infant Formula Based on Milk Fat Affects Immune Development in Both Normal Birthweight and Fetal Growth Restricted Neonatal Piglets

Nutrients ◽

10.3390/nu13103310 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3310

Author(s):

Ole Bæk ◽

Karina Skadborg ◽

Tik Muk ◽

Charlotte Amdi ◽

Peter M. H. Heegaard ◽

...

Keyword(s):

Infant Formula ◽

Vegetable Oil ◽

Milk Fat ◽

Inflammatory Responses ◽

Lipid Fraction ◽

Bovine Milk ◽

Neutrophil Function ◽

Immune Development ◽

Immune Parameters

Infant formulas offer an alternative to breast milk for both normal birth weight (NBW) and immunocompromised intrauterine growth restricted (IUGR) infants. Although the lipid fraction in formulas is often derived from vegetable oils, it is unclear if this alters immunological outcomes relative to milk fats or whether these effects differ between IUGR and NBW infants. We hypothesized that replacing vegetable oil with bovine milk fat in infant formula would improve immune development in IUGR and NBW neonates. Two-day old piglets were selected (NBW, n = 18, IUGR, n = 18) and each group of animals were fed formula based on either vegetable oil (VEG) or bovine milk fat (MILK). Animals were reared until day 23/24 and systemic immune parameters were evaluated. Milk-fat feeding decreased blood neutrophil counts and improved neutrophil function while transiently reducing leucocytes’ expression of genes related to adaptive and innate immunity as well as energy metabolism, following in vitro stimulation by live Staphylococcus epidermidis (whole blood, 2 h). However, there were only a few interactions between milk-fat type and birthweight status. Thus, piglets fed milk-fat-based formula had improved neutrophil maturation and suppressed pro-inflammatory responses, compared to those fed vegetable-oil-based formula.

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Nano-HPLC-HRMS Analysis to Evaluate Leptin Level in Milk Samples: A Pilot Study

Applied Sciences ◽

10.3390/app10176135 ◽

2020 ◽

Vol 10 (17) ◽

pp. 6135

Author(s):

Federica Dal Bello ◽

Enrica Mecarelli ◽

Daniela Gastaldi ◽

Francesco Savino ◽

Claudio Medana

Keyword(s):

Pilot Study ◽

Breast Milk ◽

Infant Formula ◽

Analytical Method ◽

Critical Role ◽

Bovine Milk ◽

Human Breast Milk ◽

Human Breast ◽

Milk Samples ◽

Limit Of Quantitation

Leptin is a 16 kDa lipophilic protein hormone secreted by adipocytes and its most significant function is to inform the brain with negative feedback that regulates food intake. Recently the protein found in human breast milk was related to breast feeding and onset of obesity, and the evidence of a low probability to develop pediatric obesity in children fed with breast milk was also confirmed. Since leptin could have a critical role, its quantitation both in human breast, bovine milk and in infant formula products is interesting. For this reason, we developed an analytical method based on immunoaffinity purification followed by an analysis with nano-High Pressure Liquid Chromatography coupled with High Resolution Mass Spectrometry analyzer (nano-HPLC-HRMS) to identify and quantify leptin in milk samples and performed a pilot study using samples of human breast milk, bovine milk and infant formulas. With an obtained lower limit of quantitation (LLOQ) of 100 ng mL−1 we quantified leptin in human breast milk finding an average of 6.70 ng mL−1. Our results show that leptin was under LLOQ both in bovine milk and in infant formula products. In conclusion, the developed analytical method here described was suitable to quantify leptin in milk samples with a good sensitivity and selectivity, and without the use of radioactive reagents.

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Improved Neurodevelopmental Outcomes Associated with Bovine Milk Fat Globule Membrane and Lactoferrin in Infant Formula: A Randomized, Controlled Trial

The Journal of Pediatrics ◽

10.1016/j.jpeds.2019.08.030 ◽

2019 ◽

Vol 215 ◽

pp. 24-31.e8 ◽

Cited By ~ 7

Author(s):

Fei Li ◽

Steven S. Wu ◽

Carol Lynn Berseth ◽

Cheryl L. Harris ◽

James D. Richards ◽

...

Keyword(s):

Randomized Controlled Trial ◽

Infant Formula ◽

Milk Fat ◽

Controlled Trial ◽

Bovine Milk ◽

Neurodevelopmental Outcomes ◽

Milk Fat Globule Membrane ◽

Randomized Controlled ◽

Milk Fat Globule ◽

Fat Globule

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Intestinal transport of manganese from human milk, bovine milk and infant formula in rats

Life Sciences ◽

10.1016/0024-3205(84)90449-1 ◽

1984 ◽

Vol 35 (24) ◽

pp. 2415-2419 ◽

Cited By ~ 6

Author(s):

W.Y. Chan ◽

J.M. Bates ◽

O.M. Rennert ◽

A. Mahmood ◽

R. Torres-Pinedo

Keyword(s):

Human Milk ◽

Infant Formula ◽

Bovine Milk ◽

Intestinal Transport

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Comparative biological availability of manganese from extrinsically labelled milk diets using sucking rats as a model

British Journal Of Nutrition ◽

10.1079/bjn19860009 ◽

1986 ◽

Vol 55 (1) ◽

pp. 49-58 ◽

Cited By ~ 3

Author(s):

M. Hassan Raghib. ◽

Chan Wai-Yee ◽

M. Owen Rennert

Keyword(s):

Human Milk ◽

Digestive Tract ◽

Infant Formula ◽

Bovine Milk ◽

Neonatal Rats ◽

Biological Availability ◽

Gastric Intubation ◽

Old Rats ◽

Mn Concentrations

1. Very little is known about the biological availability of manganese from human milk and other infant milk diets. To determine the relative Mn availability, and to examine whether the age and the duration of previous fasting affect Mn absorption, sucking rats were given human milk, bovine milk and infant formula (regular Similac; Ross Laboratories, Columbus, OH) extrinsically labelled with 54Mn.2. Milk diets were given by gastric intubation and the radioactivity of the carcass, liver and digestive tract was measured 3 h after feeding.3. The concentration of endogenous Mn was lowest in human milk (7–10 μg/l) and highest in rat milk (140–165 μg/l). Increasing the non-radioactive total Mn concentrations of either human milk or bovine milk up to 150 μg/l did not affect the absorption of 54Mn by 10-d-old rats.4. No significant (P> 0.05) difference in 54Mn absorption was found among the three milk diets (human milk, bovine milk, infant formula) in 8- to 11-d-old rats. However, significantly more (P< 0.05) 54Mn was absorbed from human milk and infant formula than from bovine milk when 13-d-old rats were used.5. 54Mn radioactivity detected in carcasses of 8-, 9-, 10- and 11-d-old rats ranged from 25 to 27% of the dose from various milk diets. The activities of 54Mn in the carcasses of 13-d-old rats were 15, 11, and 16% of the dose from human milk, bovine milk and infant formula respectively.6. The trend of 54Mn incorporation into liver was similar to that of the carcass and over 60% of the absorbed 54Mn was incorporated into the liver regardless of the type of milk used.7. Absorption of 54Mn from extrinsically labelled rat milk using 9- or 10-d-old sucking rats was similar to its absorption from infant formula.8. The absorption of 54Mn from the three milk diets decreased with age of the neonatal rats and 54Mn absorption from human milk, bovine milk, infant formula as well as rat milk was affected similarly by duration of previous fasting.

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Micronutrient and Glucose-Related Biomarkers Until 24 Mo of Age in Infants Receiving Formula With Added Bovine Milk Fat Globule Membrane Through the First Year of Life: An RCT

Current Developments in Nutrition ◽

10.1093/cdn/nzab046_059 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 762-762

Author(s):

Angela Jaramillo-Ospina ◽

Rosario Toro-Campos ◽

Teresa Murguia-Peniche ◽

Jennifer Wampler ◽

Steven Wu ◽

...

Keyword(s):

Infant Formula ◽

Milk Fat ◽

Serum Iron ◽

Bovine Milk ◽

The Body ◽

Model Assessment ◽

Milk Fat Globule Membrane ◽

Milk Fat Globule ◽

Fat Globule ◽

The Impact

Abstract Objectives Bovine milk fat globule membrane (bMFGM) added in routine infant formula supports normal growth and safety through 24 mo of age in term infants. The impact on micronutrients and glucose-related biomarkers is assessed here. Methods In this double-blind, randomized, controlled trial, formula-fed infants were enrolled (<120 days of age) and randomized to receive a standard cow´s milk-based infant formula (SF, n = 174) or a similar formula with added whey protein-lipid concentrate (5 g/L; bMFGM; EF n = 173); exclusively breastfed infants were enrolled as a reference (HM, n = 235). In 50% of infants (chosen at random), parents agreed to blood collection (2–4 h fasting) at baseline, 6, 12, and 24 mo of age. Serum micronutrients (zinc, iron, ferritin, transferrin receptor) and glucose-related biomarkers (glucose, insulin, HOMA-IR [Homeostatic Model Assessment-Insulin Resistance], IGF-1) were analyzed. Results At baseline, significant differences in markers of iron status (serum iron, ferritin) and glucose-related biomarkers (glucose, HOMA-IR, and IGF-1) were detected between HM and study formula groups. At 6 and 12 mo, no differences in any measure were detected between study formula groups. Serum iron and ferritin at 12 mo as well as glucose-related biomarkers at 6 mo (insulin, HOMA-IR, IGF-1) and 12 mo (IGF-1 only) were lower in the HM vs study formula groups. By 24 mo, micronutrients and glucose-related biomarkers were similar between study formula groups (with the exception of significantly lower serum iron in the SF group); for HM vs study formula groups, differences included significantly lower zinc and IGF-1. Conclusions Patterns of micronutrients and glucose-related biomarkers were similar through two years of age in infants who received formula through one year. This study add to the body of data available for glucose-related biomarkers in children at two years of age and younger. Funding Sources The study was funded by Mead Johnson Nutrition (MJN). TMP, SSW, and JLW are currently, and CLB was previously employed by MJN.

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Compositional and Functional Considerations for Bovine-, Caprine- and Plant-Based Infant Formulas

Dairy ◽

10.3390/dairy2040054 ◽

2021 ◽

Vol 2 (4) ◽

pp. 695-715

Author(s):

Margaret E. Byrne ◽

James A. O’Mahony ◽

Tom F. O’Callaghan

Keyword(s):

Infant Formula ◽

Bovine Milk ◽

Detailed Examination ◽

Nutritional Requirements ◽

Protein Functionality ◽

Infant Formulas ◽

Rice Protein ◽

Protein Sources ◽

Caprine Milk ◽

Bioactive Ingredients

Breastmilk is the optimal source of nutrition for infants. However, in circumstances where breastfeeding is not possible or feasible, infant formula provides an essential alternative to fulfil the nutritional requirements of the developing infant. Traditionally, the manufacture of infant formula has involved utilisation of bovine milk as a base ingredient, formulated with other nutrients and bioactive ingredients to closely match the composition of human breastmilk. While it is the most widely available type of formula on the market, bovine-based infant formula is not suitable for all infants, and therefore alternatives such as those based on caprine milk, soy and rice protein are becoming increasingly available. This review provides a detailed examination of the composition of infant formula prepared from bovine milk, caprine milk, soy, and rice protein sources. Available literature on nutrient bio-accessibility and aspects of protein functionality relevant to infant formula is discussed.

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