The journey toward disease modification in cow milk protein allergy.

Cow milk protein allergy (CMPA) is one of the most common food allergies in the pediatric age worldwide. Prevalence, persistence, and severity of this condition are on the rise, with a negative impact on the health-related quality of life of the patients and families and on the costs related to its management. Another relevant issue is that CMPA in early life may be the first stage of the "allergic march," leading to the occurrence of other atopic manifestations later in life, especially asthma, atopic eczema, urticaria, and rhinoconjunctivitis. Thus, "disease modification" options that are able to modulate the disease course of pediatric patients affected by CMPA would be very welcomed by affected families and healthcare systems. In this review, we report the most relevant progress on this topic.

The genome of a bunyavirus cannot be defined at the level of the viral particle but only at the scale of the viral population.

Bunyaviruses are enveloped negative or ambisense single-stranded RNA viruses with a genome divided into several segments. The canonical view depicts each viral particle packaging one copy of each genomic segment in one polarity named the viral strand. Several opposing observations revealed nonequal ratios of the segments, uneven number of segments per virion, and even packaging of viral complementary strands. Unfortunately, these observations result from studies often addressing other questions, on distinct viral species, and not using accurate quantitative methods. Hence, what RNA segments and strands are packaged as the genome of any bunyavirus remains largely ambiguous. We addressed this issue by first investigating the virion size distribution and RNA content in populations of the tomato spotted wilt virus (TSWV) using microscopy and tomography. These revealed heterogeneity in viral particle volume and amount of RNA content, with a surprising lack of correlation between the two. Then, the ratios of all genomic segments and strands were established using RNA sequencing and qRT-PCR. Within virions, both plus and minus strands (but no mRNA) are packaged for each of the three L, M, and S segments, in reproducible nonequimolar proportions determined by those in total cell extracts. These results show that virions differ in their genomic content but together build up a highly reproducible genetic composition of the viral population. This resembles the genome formula described for multipartite viruses, with which some species of the order Bunyavirales may share some aspects of the way of life, particularly emerging properties at a supravirion scale.

TCMFP: a novel herbal formula prediction method based on network target's score integrated with semi-supervised learning genetic algorithms.

Traditional Chinese medicine (TCM) has accumulated thousands years of knowledge in herbal therapy, but the use of herbal formulas is still characterized by reliance on personal experience. Due to the complex mechanism of herbal actions, it is challenging to discover effective herbal formulas for diseases by integrating the traditional experiences and modern pharmacological mechanisms of multi-target interactions. In this study, we propose a herbal formula prediction approach (TCMFP) combined therapy experience of TCM, artificial intelligence and network science algorithms to screen optimal herbal formula for diseases efficiently, which integrates a herb score (Hscore) based on the importance of network targets, a pair score (Pscore) based on empirical learning and herbal formula predictive score (FmapScore) based on intelligent optimization and genetic algorithm. The validity of Hscore, Pscore and FmapScore was verified by functional similarity and network topological evaluation. Moreover, TCMFP was used successfully to generate herbal formulae for three diseases, i.e. the Alzheimer's disease, asthma and atherosclerosis. Functional enrichment and network analysis indicates the efficacy of targets for the predicted optimal herbal formula. The proposed TCMFP may provides a new strategy for the optimization of herbal formula, TCM herbs therapy and drug development.

Impact of lowering fine particulate matter from major emission sources on mortality in Canada: A nationwide causal analysis.

Emissions of fine particulate matter (PM2.5) from human activities have been linked to substantial disease burdens, but evidence regarding how reducing PM2.5 at its sources would improve public health is sparse. We followed a population-based cohort of 2.7 million adults across Canada from 2007 through 2016. For each participant, we estimated annual mean concentrations of PM2.5 and the fractional contributions to PM2.5 from the five leading anthropogenic sources at their residential address using satellite observations in combination with a global atmospheric chemistry transport model. For each source, we estimated the causal effects of six hypothetical interventions on 10-y nonaccidental mortality risk using the parametric g-formula, a structural causal model. We conducted stratified analyses by age, sex, and income. This cohort would have experienced tangible health gains had contributions to PM2.5 from any of the five sources been reduced. Compared with no intervention, a 10% annual reduction in PM2.5 contributions from transportation and power generation, Canada's largest and fifth-largest anthropogenic sources, would have prevented approximately 175 (95%CI: 123-226) and 90 (95%CI: 63-117) deaths per million by 2016, respectively. A more intensive 50% reduction per year in PM2.5 contributions from the two sources would have averted 360 and 185 deaths per million, respectively, by 2016. The potential health benefits were greater among men, older adults, and low-income earners. In Canada, where PM2.5 levels are among the lowest worldwide, reducing PM2.5 contributions from anthropogenic sources by as little as 10% annually would yield meaningful health gains.

Exact Integral Formulas for False Discovery Rate and the Variance of False Discovery Proportion.

Multiple hypothesis testing is an integral component of data analysis for large-scale technologies such as proteomics, transcriptomics, or metabolomics, for which the false discovery rate (FDR) and positive FDR (pFDR) have been accepted as error estimation and control measures. The pFDR is the expectation of false discovery proportion (FDP), which refers to the ratio of the number of null hypotheses to that of all rejected hypotheses. In practice, the expectation of ratio is approximated by the ratio of expectation; however, the conditions for transforming the former into the latter have not been investigated. This work derives exact integral expressions for the expectation (pFDR) and variance of FDP. The widely used approximation (ratio of expectations) is shown to be a particular case (in the limit of a large sample size) of the integral formula for pFDR. A recurrence formula is provided to compute the pFDR for a predefined number of null hypotheses. The variance of FDP was approximated for a practical application in peptide identification using forward and reversed protein sequences. The simulations demonstrate that the integral expression exhibits better accuracy than the approximate formula in the case of a small number of hypotheses. For large sample sizes, the pFDRs obtained by the integral expression and approximation do not differ substantially. Applications to proteomics data sets are included.

Evaluation of the Therapeutical Effect of Matricaria Chamomilla Extract vs. Galantamine on Animal Model Memory and Behavior Using 18F-FDG PET/MRI.

The memory-enhancing activity of Matricaria chamomilla hydroalcoholic extract (MCE) is already being investigated by behavioral and biochemical assays in scopolamine-induced amnesia rat models, while the effects of scopolamine (Sco) on cerebral glucose metabolism are examined as well. Nevertheless, the study of the metabolic profile determined by an enriched MCE has not been performed before. The present experiments compared metabolic quantification in characteristic cerebral regions and behavioral characteristics for normal, only diseased, diseased, and MCE- vs. Galantamine (Gal)-treated Wistar rats. A memory deficit was induced by four weeks of daily intraperitoneal Sco injection. Starting on the eighth day, the treatment was intraperitoneally administered 30 min after Sco injection for a period of three weeks. The memory assessment comprised three maze tests. Glucose metabolism was quantified after the 18F-FDG PET examination. The right amygdala, piriform, and entorhinal cortex showed the highest differential radiopharmaceutical uptake of the 50 regions analyzed. Rats treated with MCE show metabolic similarity with normal rats, while the Gal-treated group shows features closer to the diseased group. Behavioral assessments evidenced a less anxious status and a better locomotor activity manifested by the MCE-treated group compared to the Gal-treated group. These findings prove evident metabolic ameliorative qualities of MCE over Gal classic treatment, suggesting that the extract could be a potent neuropharmacological agent against amnesia.

Evaluating recommendation-based dietary and physical activity strategies for prostate cancer prevention: a target trial emulation in the Health Professionals Follow-up Study.

The 2018 World Cancer Research Fund/American Institute for Cancer Research recommends sustained strategies of physical activity and diet for cancer prevention, but evidence for long-term prostate cancer risk is limited. Using observational data from 27,859 men in the Health Professionals Follow-up Study, we emulated a target trial of recommendation-based physical activity and dietary strategies and 26-year risks of prostate cancer, adjusting for risk factors via the parametric g-formula. Compared with no intervention, limiting sugar-sweetened beverages showed a 0.4% (0.0-0.9%) lower risk of lethal (metastatic or fatal) disease and 0.5% (0.1-0.9%) lower risk of fatal disease. Restricting consumption of processed foods showed a 0.4-0.9% higher risk of all prostate cancer outcomes. Estimated risk differences for clinically significant disease were close to null for strategies involving fruits and non-starchy vegetables, whole grains and legumes, red meat, and processed meat, as well as under a joint strategy of physical activity and diet. Compared with a "low adherence" strategy, maintaining recommended physical activity levels showed a 0.4% (0.1-0.8%) lower risk of lethal and 0.5% (0.2-0.8%) lower risk of fatal disease. Adhering to specific components of current physical activity and dietary recommendations may help to prevent lethal and fatal prostate cancer over 26 years.

Analysis of the relative frequencies of the multipartite BNYVV genomic RNAs in different plants and tissues.

Multipartite virus genomes are composed of two or more segments, each packaged into an independent viral particle. A potential advantage of multipartitism is the regulation of gene expression through changes in the segment copy number. Soil-borne beet necrotic yellow vein virus (BNYVV) is a typical example of multipartism, given its high number of genomic positive-sense RNAs (up to five). Here we analyse the relative frequencies of the four genomic RNAs of BNYVV type B during infection of different host plants (Chenopodium quinoa, Beta macrocarpa and Spinacia oleracea) and organs (leaves and roots). By successfully validating a two-step reverse-transcriptase digital droplet PCR protocol, we show that RNA1 and -2 genomic segments always replicate at low and comparable relative frequencies. In contrast, RNA3 and -4 accumulate with variable relative frequencies, resulting in distinct RNA1 : RNA2 : RNA3 : RNA4 ratios, depending on the infected host species and organ.

Network pharmacology prediction and molecular docking analysis reveal the mechanism of modified Bushen Yiqi formulas on chronic obstructive pulmonary disease.

BACKGROUND: The present study aimed to explore the mechanism of the modified Bushen Yiqi formula (MBYF) in the treatment of chronic obstructive pulmonary disease (COPD) based on network pharmacology and molecular docking. METHODS: First, the active ingredients and corresponding targets in MBYF were mined through the Traditional Chinese Medicine Systems Pharmacology database. Subsequently, Online Mendelian Inheritance in Man, DrugBank, and GeneCard were used to screen COPD-related targets. Cytoscape was used to construct a network of candidate components of MBYF in COPD treatment. The overlapping targets of COPD and MBYF were used to treat COPD, and then CytoHubba and CytoNAC plug-ins in Cytoscape were used for topology analysis to build the core network. In addition, core targets were used for Gene Ontology analysis and enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes. Finally, AutoDock Vina software was used to conduct a molecular docking study on the core active ingredients and core targets to verify the above network pharmacological analysis. RESULTS: Seventy-nine active components of MBYF were screened and 261 corresponding targets were found. At the same time, 1307 related targets corresponding to COPD were screened and 111 overlapping targets were matched. By bioinformatics analysis, 10 core targets were identified, and subsequently, enrichment analysis revealed 385 BP, two CC, eight MF and 78 related signaling pathways. The binding of the core active components in MBYF to the core target was further verified by molecular docking, and all showed good binding. CONCLUSIONS: The active components of MBYF, such as quercetin, kaempferol, luteolin, and baicalein, may be the material basis for the treatment of chronic obstructive pulmonary disease. They affect the expression of inflammatory cells and inflammatory factors, protein phosphorylation, and smooth muscle hyperplasia through tumor necrosis factor, interleukin-17, mitogen-activated protein kinase, nuclear factor-kappa B and other signaling pathways.

Breastfeeding is associated with enhanced intestinal gluconeogenesis in infants.

BACKGROUND: Breastfeeding (BF) confers metabolic benefits to infants, including reducing risks of metabolic syndrome such as obesity and diabetes later in life. However, the underlying mechanism is not yet fully understood. Hence, we aim to investigate the impacts of BF on the metabolic organs of infants. METHODS: Previous literatures directly studying the influences of BF on offspring's metabolic organs in both animal models and humans were comprehensively reviewed. A microarray dataset of intestinal gene expression comparing infants fed on breastmilk versus formula milk was analyzed. RESULTS: Reanalysis of microarray data showed that BF is associated with enhanced intestinal gluconeogenesis in infants. This resembles observations in other mammalian species showing that BF was also linked to increased gluconeogenesis. CONCLUSIONS: BF is associated with enhanced intestinal gluconeogenesis in infants, which may underpin its metabolic advantages through finetuning metabolic homeostasis. This observation seems to be conserved across species, hinting its biological significance.

SPOOC (Sensor for Periodic Observation of Choline): An Integrated Lab-on-a-Spoon Platform for At-Home Quantification of Choline in Infant Formula.

Choline is an essential micronutrient for infants' brain development and health. To ensure that infants receive the needed daily dose of choline, the U.S. Food and Drug Administration (FDA) has set requirements for choline levels in commercialized infant formulas. Unfortunately, not all families can access well-regulated formulas, leading to potential inadequacies in choline intake. Economic constraints or difficulties in obtaining formulas, exacerbated by situations like COVID-19, prompt families to stretch formulas. Accurate measurement of choline in infant formulas becomes imperative to guarantee that infants receive the necessary nutritional support. Yet, accessible tools for this purpose are lacking. An innovative integrated sensor for the periodic observation of choline (SPOOC) designed for at-home quantification of choline in infants' formulas and milk powders is reported. This system is composed of a choline potentiometric sensor and ionic-liquid reference electrode developed on laser-induced graphene (LIG) and integrated into a spoon-like device. SPOOC includes a micro-potentiometer that conducts the measurements and transmits results wirelessly to parents' mobile devices. SPOOC demonstrated rapid and accurate assessment of choline levels directly in pre-consuming infant formulas without any sample treatment. This work empowers parents with a user-friendly tool for choline monitoring promoting informed nutritional decision-making in the care of infants.

Modulation of innate immunity related genes resulting in prophylactic antimicrobial and antiviral properties.

BACKGROUND: The innate immunity acts during the early phases of infection and its failure in response to a multilayer network of co-infections is cause of immune system dysregulation. Epidemiological SARS-CoV-2 infections data, show that Influenza Virus (FLU-A-B-C) and Respiratory Syncytial Virus (RSV) are co-habiting those respiratory traits. These viruses, especially in children (mostly affected by 'multi-system inflammatory syndrome in children' [MIS-C] and the winter pandemic FLU), in the aged population, and in 'fragile' patients are causing alteration in immune response. Then, bacterial and fungal pathogens are also co-habiting the upper respiratory traits (e.g., Staphylococcus aureus and Candida albicans), thus contributing to morbidity in those COVID-19 affected patients. METHODS: Liquid chromatography coupled with high-resolution mass spectrometry using the quadrupole orbital ion trap analyser (i.e., UHPLC-Q-Orbitrap HRMS) was adopted to measure the polyphenols content of a new nutraceutical formula (Solution-3). Viral infections with SARS-CoV-2 (EG.5), FLU-A and RSV-A viruses (as performed in BLS3 authorised laboratory) and real time RT-PCR (qPCR) assay were used to test the antiviral action of the nutraceutical formula. Dilution susceptibility tests have been used to estimate the minimum inhibitory and bactericidal concentration (MIC and MBC, respectively) of Solution-3 on a variety of microorganisms belonging to Gram positive/ negative bacteria and fungi. Transcriptomic data analyses and functional genomics (i.e., RNAseq and data mining), coupled to qPCR and ELISA assays have been used to investigate the mechanisms of action of the nutraceutical formula on those processes involved in innate immune response. RESULTS: Here, we have tested the combination of natural products containing higher amounts of polyphenols (i.e., propolis, Verbascum thapsus L., and Thymus vulgaris L.), together with the inorganic long chain polyphosphates 'polyPs' with antiviral, antibacterial, and antifungal behaviours, against SARS-CoV-2, FLU-A, RSV-A, Gram positive/ negative bacteria and fungi (i.e., Candida albicans). These components synergistically exert an immunomodulatory action by enhancing those processes involved in innate immune response (e.g., cytokines: IFNγ, TNFα, IL-10, IL-6/12; chemokines: CXCL1; antimicrobial peptides: HBD-2, LL-37; complement system: C3). CONCLUSION: The prophylactic antimicrobial success of this nutraceutical formula against SARS-CoV-2, FLU-A and RSV-A viruses, together with the common bacteria and fungi co-infections as present in human oral cavity, is expected to be valuable.

Microbiological survey and genomic analysis of Cronobacter sakazakii strains isolated from US households and retail foods.

Cronobacter species are opportunistic pathogens that are capable of causing morbidity and mortality, particularly in infants. Although the transmission dynamics involved in Cronobacter infections remain largely unknown, contaminated powdered infant formula (PIF) has been linked to 30% of Cronobacter sakazakii cases involving invasive illness in infants. As several lines of evidence have implicated the domestic environment in PIF contamination, we undertook a microbiological survey of homes (N = 263) across the US. Cronobacter spp. and C. sakazakii were isolated from 36.1% and 24.7% of US homes, respectively, with higher recovery rates observed for floor and kitchen surfaces. Multi-locus sequence typing indicated that the dominant strain was C. sakazakii ST4, the sequence type most commonly associated with neonatal meningitis. For comparison purposes, retail foods (N = 4,009) were also surveyed, with the highest contamination frequencies (10.1%-26.3%) seen for nut products, seeds, and grains/baked goods/flours. The sequence type profile of isolates recovered from homes mirrored that of isolates recovered from retail foods, with increased representation of ST1, ST4, ST13, ST17, and ST40. Analysis of 386 whole genomic sequences revealed significant diversity. Redundancies were only observed for isolates recovered from within the same domicile, and there were no identical matches with sequences archived at the NCBI pathogen database. Genes coding for putative virulence and antibiotic resistance factors did not segregate with clinically significant sequence types. Collectively, these findings support the possibility that contamination events occurring within the home should not be overlooked as a contributor to community-onset Cronobacter infections. IMPORTANCE: Cronobacter sakazakii is an opportunistic pathogen that can cause significant morbidity and mortality in neonates. Its transmission dynamics are poorly understood, though powered infant formula (PIF) is thought to be the major transmission vehicle. How the PIF becomes contaminated remains unknown. Our survey shows that roughly 1/4 of US homes are contaminated with Cronobacter sakazakii, particularly in the kitchen setting. Our analyses suggest that the domestic environment may contribute to contamination of PIF and provides insights into mitigating the risk of transmission.

Prevalence and risk factors for milk allergy overdiagnosis in the BEEP trial cohort.

BACKGROUND: Cow's milk allergy (CMA) overdiagnosis in young children appears to be increasing and has not been well characterised. We used a clinical trial population to characterise CMA overdiagnosis and identify individual-level and primary care practice-level risk factors. METHODS: We analysed data from 1394 children born in England in 2014-2016 (BEEP trial, ISRCTN21528841). Participants underwent formal CMA diagnosis at ≤2 years. CMA overdiagnosis was defined in three separate ways: parent-reported milk reaction; primary care record of milk hypersensitivity symptoms; and primary care record of low-allergy formula prescription. RESULTS: CMA was formally diagnosed in 19 (1.4%) participants. CMA overdiagnosis was common: 16.1% had parent-reported cow's milk hypersensitivity, 11.3% primary care recorded milk hypersensitivity and 8.7% had low-allergy formula prescription. Symptoms attributed to cow's milk hypersensitivity in participants without CMA were commonly gastrointestinal and reported from a median age of 49 days. Low-allergy formula prescriptions in participants without CMA lasted a median of 10 months (interquartile range 1, 16); the estimated volume consumed was a median of 272 litres (26, 448). Risk factors for CMA overdiagnosis were high practice-based low-allergy formula prescribing in the previous year and maternal report of antibiotic prescription during pregnancy. Exclusive formula feeding from birth was associated with increased low-allergy formula prescription. There was no evidence that practice prescribing of paediatric adrenaline auto-injectors or anti-reflux medications, or maternal features such as anxiety, age, parity and socioeconomic status were associated with CMA overdiagnosis. CONCLUSION: CMA overdiagnosis is common in early infancy. Risk factors include high primary care practice-based low-allergy formula prescribing and maternal report of antibiotic prescription during pregnancy.

Plasma Sphingomyelins and Carnitine Esters of Infants Consuming Whole Goat or Cow Milk-Based Infant Formulas or Human Milk.

BACKGROUND: Infant formulas are typically manufactured using skimmed milk, whey proteins, and vegetable oils, which excludes milk fat globule membranes (MFGM). MFGM contains polar lipids, including sphingomyelin (SM). OBJECTIVE: The objective of this study was comparison of infant plasma SM and acylcarnitine species between infants who are breastfed or receiving infant formulas with different fat sources. METHODS: In this explorative study, we focused on SM and acylcarnitine species concentrations measured in plasma samples from the TIGGA study (ACTRN12608000047392), where infants were randomly assigned to receive either a cow milk-based infant formula (CIF) with vegetable oils only or a goat milk-based infant formula (GIF) with a goat milk fat (including MFGM) and vegetable oil mixture to the age ≥4 mo. Breastfed infants were followed as a reference group. Using tandem mass spectrometry, SM species in the study formulas and SM and acylcarnitine species in plasma samples collected at the age of 4 mo were analyzed. RESULTS: Total SM concentrations (∼42 µmol/L) and patterns of SM species were similar in both formulas. The total plasma SM concentrations were not different between the formula groups but were 15 % (CIF) and 21% (GIF) lower in the formula groups than in the breastfed group. Between the formula groups, differences in SM species were statistically significant but small. Total carnitine and major (acyl) carnitine species were not different between the groups. CONCLUSIONS: The higher total SM concentration in breastfed than in formula-fed infants might be related to a higher SM content in human milk, differences in cholesterol metabolism, dietary fatty acid intake, or other factors not yet identified. SM and acylcarnitine species composition in plasma is not closely related to the formula fatty acid composition. This trial was registered at Australian New Zealand Clinical Trials Registry as ACTRN12608000047392.

Cyclic Formula Feeding Among Infants Participating in the Special Supplemental Nutrition Program for Women, Infants, and Children.

BACKGROUND: Low-income households often experience a cyclic pattern in food availability, with acute food shortages at month end. Variations in the monthly feeding of infant formula are understudied. OBJECTIVES: This study aimed to compare the amount and frequency of formula consumed at the beginning and end of the monthly Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) assistance cycle and test associations with total energy intake and other feeding practices among infants aged 7-11 mo. METHODS: This study was conducted between May 2020 and April 2021 in the southeastern United States and involved mothers of infants participating in WIC's fully formula package. Mothers were interviewed and 24-h feeding recalls were conducted at the beginning and end of the month. We defined month beginning as 5 d following the first WIC formula purchase and month end as 5 d before the next monthly cycle. Fifty mother-infant dyads participated in single or multiple monthly cycles, totaling 98 monthly cycles. Generalized linear mixed-effects modeling was used to test differences in formula feeding at month beginning and end. RESULTS: Most participants (84%) were African American or Latino and >90% purchased all formula within 2-3 d of the WIC issuance. The energy intake from formula at month beginning was significantly higher than at month end (67.63% and 57.85%, respectively; P = 0.002), with no differences in total energy intake. The odds of infants being fed cow milk and fruit juices/drinks increased from month beginning to end (P < 0.05). CONCLUSIONS: Infants in low-income households are at risk of experiencing a cyclic feeding pattern characterized by higher formula feeding at month beginning and an increase in feeding of nonrecommended drinks at month end. The WIC program policy could review educational and distribution options to reduce cyclic formula feeding and clarify caregivers' understanding of infants' formula needs. Household-level investigations into formula management and determinants of cyclic feeding are warranted.

High Concentrations of Immunoglobulin G Against Cow Milk Proteins and Frequency of Cow Milk Consumption Are Associated With the Development of Islet Autoimmunity and Type 1 Diabetes-The Trial to Reduce Insulin-dependent Diabetes Mellitus (IDDM) in the Genetically at Risk (TRIGR) Study.

BACKGROUND: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) (NCT00179777) found no difference type 1 diabetes risk between hydrolyzed and regular infant formula. However, cow milk consumption during childhood is consistently linked to type 1 diabetes risk in prospective cohort studies. OBJECTIVES: Our primary aim was to study whether humoral immune responses to cow milk and cow milk consumption are associated with type 1 diabetes in TRIGR children. METHODS: TRIGR comprised 2159 children with genetic susceptibility to type 1 diabetes born between 2002 and 2007 in 15 countries. Children were randomly assigned into groups receiving extensively hydrolyzed casein or a regular cow milk formula and followed up until age 10 y. Type 1 diabetes-related autoantibodies and antibodies to cow milk proteins were analyzed. Infant formula intake was measured by structured dietary interviews and milk consumption with a food frequency questionnaire. Associations of milk antibodies and milk consumption with risk to develop type 1 diabetes were analyzed using Cox survival model. RESULTS: Cow milk antibody concentrations both in cord blood [hazards ratio (HR) for islet autoimmunity: 1.30; 95% CI: 1.05, 1.61; HR for type 1 diabetes: 1.32; 95% CI: 1.02, 1.71] and longitudinally from birth to 3 years (HR for islet autoimmunity: 1.39; 95% CI: 1.07, 1.81; HR for type 1 diabetes: 1.43; 95% CI: 1.04, 1.96) were associated with increased risk of developing type 1 diabetes. The amount of regular infant formula was associated with reduced islet autoimmunity risk in the regular infant formula group (HR: 0.92; 95% CI: 0.85, 0.99). Furthermore, frequent liquid milk consumption after infancy was associated with increased risk of islet autoimmunity or type 1 diabetes. CONCLUSIONS: Elevated cow milk antibody concentrations and high consumption of liquid milk after infancy are related to type 1 diabetes development in children with an increased genetic susceptibility to type 1 diabetes. Enhanced antibody concentrations to cow milk may provide a biomarker of immune system prone to develop islet autoimmunity. This trial was registered at clinicaltrials.gov as NCT00179777.

Neonatal Gut and Immune Responses to ß-Casein Enriched Formula in Piglets.

BACKGROUND: ß-casein is the main casein constituent in human milk (HM) and a source of bioactive peptides for the developing gastrointestinal tract and immune system. Infant formulas contain less ß-casein than HM, but whether different concentrations of ß-casein affect tolerability and gut and immune maturation in newborns is unknown. OBJECTIVES: Using near-term piglets as a model for newborn infants, we investigated whether increasing the ß-casein fraction in bovine-based formula is clinically safe and may improve gut and immune maturation. METHODS: Three groups of near-term pigs (96% gestation) were fed formula with bovine casein and whey protein (ratio 40:60): 1) standard skim milk casein (BCN-standard, 35% ß-casein of total casein, n = 18); 2) ß-casein enrichment to HM concentrations (BCN-medium, 65%, n = 19); and 3) high ß-casein enrichment (BCN-high, 91%, n = 19). A reference group was fed 100% whey protein concentrate (WPC) as protein (WPC, n = 18). Intestinal and immune parameters were assessed before and after euthanasia on day 5. RESULTS: Clinical variables (mortality, activity, body growth, and diarrhea) were similar among the groups, and no differences in intestinal or biochemical parameters were observed between BCN-standard and BCN-medium pigs. However, pigs receiving high amounts of ß-casein (BCN-high) had lower small intestine weight and tended to have more intestinal complications (highest gut pathology score, permeability, and interleukin-8) than the other groups, particularly those receiving no casein (WPC pigs). Blood lymphocyte, thrombocyte, and reticulocyte counts were increased with higher ß-casein, whereas eosinophil counts were reduced. In vitro blood immune cell responses were similar among groups. CONCLUSIONS: ß-casein enrichment of bovine-based formula to HM concentrations is clinically safe, as judged from newborn, near-term pigs, whereas no additional benefits to gut maturation were observed. However, excessive ß-casein supplementation, beyond concentrations in HM, may potentially induce gut inflammation together with increased blood cell populations relative to natural ß-casein concentrations or pure whey-based formula.

Protein Ingredient Quality within Infant Formulas Impacts Plasma Amino Acid Concentrations in Neonatal Minipiglets.

BACKGROUND: Infant formulas (IFs), the only adequate substitute to human milk, are complex matrices that require numerous ingredients and processing steps that may impact protein digestion and subsequent amino acid (AA) absorption. OBJECTIVES: The objective was to understand the impact of the protein ingredient quality within IFs on postprandial plasma AA profiles. METHODS: Four isonitrogenous and isocaloric IFs were produced at a semi-industrial scale using whey proteins from different origins (cheese compared with ideal whey) and denaturation levels (IF-A, -B, -C), and caseins with different supramolecular organizations (IF-C, -D). Ten Yucatan minipiglets (12- to 27-d-old) were used as a human infant model and received each IF for 3 d according to a Williams Latin square followed by a 2-d wash-out period. Jugular plasma was regularly sampled from 10 min preprandial to 4 h postprandial on the third day to measure free AAs, urea, insulin, and glucose concentrations. Data were statistically analyzed using a mixed linear model with diet (IFs), time, and sex as fixed factors and piglet as random factor. RESULTS: IFs made with cheese whey (IF-A and -B) elicited significantly higher plasma total and essential AA concentrations than IFs made with ideal whey (IF-C and -D), regardless of the pre- and postprandial times. Most of the differences observed postprandially were explained by AA homeostasis modifications. IFs based on cheese whey induced an increased plasma concentration of Thr due to both a higher Thr content in these IFs and a Thr-limiting degrading capability in piglets. The use of a nonmicellar casein ingredient led to reduced plasma content of AA catabolism markers (IF-D compared with IF-C). CONCLUSIONS: Overall, our results highlight the importance of the protein ingredient quality (composition and structure) within IFs on neonatal plasma AA profiles, which may further impact infant protein metabolism.

Iron absorption from an iron-fortified follow-up formula with and without the addition of a synbiotic or a human-identical milk oligosaccharide: a randomized cross-over stable isotope study in young Thai children.

BACKGROUND: Previous studies showed that pre- and probiotics may enhance iron absorption. Probiotics combined with prebiotics (synbiotics), including human-identical milk oligosaccharides (HiMO), are commonly added to infant and follow-up formula (FUF). Whether these additions enhance iron absorption from iron-fortified commercial milk formula is uncertain. OBJECTIVE: We determined the effect of adding: 1) a synbiotic (galacto-oligosaccharides (GOS)+Limosilactobacillus reuteri [L. reuteri]), or 2) the HiMO 2'-fucosyllactose (2'FL) to iron-fortified FUF on iron absorption in young Thai children. METHODS: In a randomized, controlled, single-blinded (participants) cross-over study, 82 Thai children aged 8-14 months were enrolled to consume single servings (235ml) of FUF with isotopically labelled ferrous sulfate (2.2 mg iron) with: 1) the synbiotic (400 mg/100 ml GOS and L. reuteri DSM 17938); 2) the 2'FL (100 mg/100 ml); and 3) without synbiotic and without 2'FL (control) in random order and a 3-day wash-out period between administrations. Fractional iron absorption (FIA[%]) was assessed by measuring erythrocyte incorporation of isotopic labels 14 days (n=26) and 28 days (n=76) after consumption of the last test FUF. RESULTS: Median (IQR) FIA from iron-fortified FUF with the synbiotic (8.2[5.2, 12.9]%) and with 2'FL (8.4[5.5, 14.1]%) did not differ from the control FUF (8.1[4.8,14.7]%) (synbiotic vs. control, P=0.24; 2'FL vs. control, P=0.95). FIA from all FUF did not differ when measured after 14 and 28 days of erythrocyte incorporation (Time, P=0.368; FUF, P=0.435; Time x FUF, P=0.937). Fecal pH and hemoglobin were negatively associated with FIA. CONCLUSION: In young Thai children, the addition of a synbiotic (GOS+L. reuteri) or 2'FL to iron-fortified FUF did not impact FIA from a single serving. The trial was registered at ClinicalTrial.gov as NCT04774016. The study was registered at clinicaltrials.gov as NCT04774016.