Neonatal Immune System Research Articles

Impact of Early-Life Microbiota on Immune System Development and Allergic Disorders.

Introduction: The shaping of the human intestinal microbiota starts during the intrauterine period and continues through the subsequent stages of extrauterine life. The microbiota plays a significant role in the predisposition and development of immune diseases, as well as various inflammatory processes. Importantly, the proper colonization of the fetal digestive system is influenced by maternal microbiota, the method of pregnancy completion and the further formation of the microbiota. In the subsequent stages of a child's life, breastfeeding, diet and the use of antibiotics influence the state of eubiosis, which determines proper growth and development from the neonatal period to adulthood. The literature data suggest that there is evidence to confirm that the intestinal microbiota of the infant plays an important role in regulating the immune response associated with the development of allergic diseases. However, the identification of specific bacterial species in relation to specific types of reactions in allergic diseases is the basic problem. Background: The main aim of the review was to demonstrate the influence of the microbiota of the mother, fetus and newborn on the functioning of the immune system in the context of allergies and asthma. Methods: We reviewed and thoroughly analyzed the content of over 1000 articles and abstracts between the beginning of June and the end of August 2024. Over 150 articles were selected for the detailed study. Results: The selection was based on the PubMed National Library of Medicine search engine, using selected keywords: "the impact of intestinal microbiota on the development of immune diseases and asthma", "intestinal microbiota and allergic diseases", "the impact of intrauterine microbiota on the development of asthma", "intrauterine microbiota and immune diseases", "intrauterine microbiota and atopic dermatitis", "intrauterine microbiota and food allergies", "maternal microbiota", "fetal microbiota" and "neonatal microbiota". The above relationships constituted the main criteria for including articles in the analysis. Conclusions: In the present review, we showed a relationship between the proper maternal microbiota and the normal functioning of the fetal and neonatal immune system. The state of eubiosis with an adequate amount and diversity of microbiota is essential in preventing the development of immune and allergic diseases. The way the microbiota is shaped, resulting from the health-promoting behavior of pregnant women, the rational conduct of the medical staff and the proper performance of the diagnostic and therapeutic process, is necessary to maintain the health of the mother and the child. Therefore, an appropriate lifestyle, rational antibiotic therapy as well as the way of completing the pregnancy are indispensable in the prevention of the above conditions. At the same time, considering the intestinal microbiota of the newborn in relation to the genera and phyla of bacteria that have a potentially protective effect, it is worth noting that the use of suitable probiotics and prebiotics seems to contribute to the protective effect.

Maternal probiotic exposure enhances CD8 T cell protective neonatal immunity and modulates offspring metabolome to control influenza virus infection

ABSTRACT Maternal gut microbiota composition contributes to the status of the neonatal immune system and could influence the early life higher susceptibility to viral respiratory infections. Using a novel protocol of murine maternal probiotic supplementation, we report that perinatal exposure to Lacticaseibacillus rhamnosus (L.rh) or Bifidobacterium animalis subsp. lactis (B.lac) increases the influenza A/PR8 virus (IAV) clearance in neonates. Following either supplementation, type 1 conventional dendritic cells (cDC1) were amplified in the lymph nodes leading to an enhanced IAV antigen-experienced IFN-γ producing effector CD8 T cells in neonates and IAV-specific resident memory CD8 T cells in adulthood. This was compatible with a higher protection of the offspring upon a secondary infection. Interestingly, only mice born to L.rh supplemented mothers further displayed an increased activation of IFN-γ producing virtual memory CD8 T cells and a production of IL-10 by CD4 and CD8 T cells that could explain a better control of the lung damages upon infection. In the offspring and the mothers, no disturbance of the gut microbiota was observed but, as analyzed through an untargeted metabolomic approach, both exposures modified neonatal plasma metabolites. Among them, we further demonstrated that genistein and 3-(3-hydroxyphenyl)propionic acid recapitulate viral clearance or cDC1 activation in neonates exposed to IAV. We conclude that maternal L.rh or B.lac supplementation confers the neonates specific metabolomic modulations with a better CD8 T cell-mediated immune protection against IAV infection.

Surfactant Protein-A and its immunomodulatory roles in infant respiratory syncytial virus infection: a potential for therapeutic intervention?

The vast majority of early-life hospital admissions globally highlight respiratory syncytial virus (RSV), the leading cause of neonatal lower respiratory tract infections, as the major culprit behind the poor neonatal outcomes following respiratory infections. Unlike those of older children and adults, the immune system of neonates looks rather unique, therefore mostly counting on the innate immune system and antibodies of maternal origins. The collaborations between cells and immune compartments during infancy inclines bias toward a T-helper 2 (Th2) immune profile and thereby away from a T-helper 1 (Th1) immune response. What makes it more problematic is that RSV infection also tends to elicit a stronger Th2-biased immune response and drive an aberrant allergy-like inflammation. It is thus evident how RSV infections potentially pave the way for wheezing recurrences and childhood asthma later in life. Surfactant, the essential lung substance for normal breathing processes in mammals, has immunomodulatory properties including lung collectins such as Surfactant Protein-A (SP-A), which is the most abundant protein component of surfactant, and also Surfactant Protein-D (SP-D). Deficiency of SP-A and SP-D has been found to be associated with impaired pathogen clearance and exacerbated immune responses during infections. We therefore conducted a review of the literature to describe pathomechanisms of RSV infections during blunted neonatal immunity potentially facilitating allergy-like inflammatory events within the developing lungs and highlight the potential protective role of the humoral collectin SP-A to mitigate these in the "early in life" pulmonary immune system.

Describing Biological Vulnerability in Small, Vulnerable Newborns in Urban Burkina Faso (DenBalo): Gut Microbiota, Immune System, and Breastmilk Assembly.

Background: Small vulnerable newborns (SVNs), including those born preterm, small for gestational age, or with low birth weight, are at higher risk of neonatal mortality and long-term health complications. Early exposure to maternal vaginal microbiota and breastfeeding plays a critical role in the development of the neonatal microbiota and immune system, especially in low-resource settings like Burkina Faso, where neonatal mortality rates remain high. Objectives: The DenBalo study aims to investigate the role of maternal and neonatal factors, such as vaginal and gut microbiota, immune development, and early nutrition, in shaping health outcomes in SVNs and healthy infants. Methods: This prospective cohort observational study will recruit 141 mother-infant pairs (70 SVNs and 71 healthy controls) from four health centers in Bobo-Dioulasso, Burkina Faso. The mother-infant pairs will be followed for six months with anthropometric measurements and biospecimen collections, including blood, breast milk, saliva, stool, vaginal swabs, and placental biopsies. Multi-omics approaches, encompassing metagenomics, metabolomics, proteomics, and immune profiling, will be used to assess vaginal and gut microbiota composition and functionality, immune cell maturation, and cytokine levels at critical developmental stages. Conclusions: This study will generate comprehensive data on how microbiota, metabolomic, and proteomic profiles, along with immune system development, differ between SVNs and healthy infants. These findings will guide targeted interventions to improve neonatal health outcomes and reduce mortality, particularly in vulnerable populations.

The association of maternal COVID-19-infection during pregnancy on the neonatal immune profile and associations with later diagnosis of neurodevelopmental disorders

Despite the prevalence and significant concern of COVID-19 in maternal and offspring health, little is known about the impact of COVID-19 during pregnancy on newborn immunity and neurodevelopment. This study aimed to examine 1) the relationship between maternal COVID-19 during pregnancy and newborn immune profiles and investigate the 2) associations between specific newborn immune profiles and the risk of subsequent diagnosis of a neurodevelopmental disorder (NDD) among children with prenatal exposure to COVID-19. Newborn dried bloodspots (NBS) from 545 children born at Kaiser Permanente Northern California between January 2020 and September 2021 (460 [223 males, 237 females] to COVID-19-infected [COVID+] mothers; 85 [45 males, 40 females] to COVID-19-uninfected [COVID-] mothers) were used to profile newborn immune molecules via a 42-plex cytokine/chemokine assay. Among the 460 children born to COVID+ mothers, 73 (47 males, 27 females) were later diagnosed with an NDD. In the first set of analyses examining the association between maternal COVID-19 infection during pregnancy and newborn immune profile, the results adjusted for covariates but uncorrected for multiple comparisons showed that newborns of COVID+ mothers had significantly higher levels of IL-22 (estimate [est.] = 0.16, 95 % Cl 0.01, 0.3, p = 0.04) and GM-CSF (est. = 0.27, 95 % Cl 0.09, 0.46, p = 0.004) compared to newborns of COVID- mothers. These differences were no longer statistically significant after multiple comparison adjustments. In the second analysis exploring the association between newborn profile and later diagnosis of NDD among newborns born to COVID+ mothers, the results adjusted for covariates revealed an association between higher neonatal levels of IL-22 (hazard ratio [HR] = 0.49, 95 % Cl 0.33, 0.75, p = 0.001) and lower risk of a later diagnosis of an NDD, which remained significant after multiple comparison adjustments (p = 0.04). Other neonatal cytokines/chemokines/growth factors such as sCD40L (HR = 0.7, 95 % Cl 0.57, 0.9, p = 0.009), IP-10 (HR = 0.46, 95 % Cl 0.25, 0.83, p = 0.009), MIG (HR = 0.52, 95 % Cl 0.3, 0.9, p = 0.02), FLT-3L (HR = 0.45, 95 % Cl 0.24, 0.83, p = 0.01), PDGF AB/BB (HR = 0.56, 95 % Cl 0.36, 0.99, p = 0.046), VEGF (HR = 0.57, 95 % Cl 0.34, 0.98, p = 0.04), and IL-4 (HR = 0.48, 95 % Cl 0.26, 0.93, p = 0.03) were no longer statistically significant after multiple comparison adjustments. Despite the imbalance between the number of COVID-19 exposed and unexposed newborns in this study cohort, our novel findings enhance our understanding of the potential impact of maternal COVID-19 infection during pregnancy on the developing neonatal immune system. Our findings highlight the role of immune molecules, beyond those considered to be pro-inflammatory, that may be crucial in maternal and newborn immunity against COVID-19 infection during pregnancy. Furthermore, our results suggest that reduced levels of neonatal immune molecules in newborns of COVID + mothers may be linked to an increased risk of a subsequent diagnosis of an NDD.

Neonatal Neutrophil-mediated Control of Bordetella pertussis Is Disrupted by Pertussis Toxin.

The increased susceptibility of infants and young children to some diseases has often been explained as the neonatal immune system (NIS) being incomplete and/or underdeveloped. However, our recent work demonstrated that neonatal mice could clear a Bordetella pertussis (Bp) strain lacking pertussis toxin (PTx) (BpΔptx) much more efficiently than adult mice, indicating that the NIS can be extremely effective, but this ability is highly sensitive to being blocked by PTx. In this article, we investigated immunological mechanisms by which neonates efficiently and rapidly clear BpΔptx to better understand how the NIS functions and how PTx disrupts it. Depleting neutrophils, or blocking their recruitment, inhibited pups' ability to rapidly clear BpΔptx, revealing a critical role for neutrophils. Pups deficient in complement (C3-/-) failed to recruit neutrophils and did not efficiently clear BpΔptx but recovered these abilities upon treatment with C3a. Neutrophil depletion in C3-/- pups led to further failure to control BpΔptx, suggesting that neutrophils and complement have independent roles in rapid clearance of BpΔptx. Depleting or disrupting neutrophils and complement had negligible effect on the rapid growth of wild-type Bp, indicating that PTx blocks these otherwise highly effective aspects of the NIS.

Bacterial Meningoencephalitis in Newborns.

Bacterial meningoencephalitis in newborns is a severe and life-threatening pathology, which results from meningeal infection and the subsequent involvement of the brain parenchyma. The severity of the acute onset of symptoms and the risk of neurodevelopmental adverse sequelae in children strongly depend on the timing of the infection, the immunological protection transmitted by the mother to the fetus during pregnancy, and the neonate's inflammatory and immune system response after birth. Although the incidence of neonatal meningitis and meningoencephalitis and related mortality declined in the past twenty years with the improvement of prenatal care and with the introduction of intrapartum antibiotic prophylaxis against Streptococcus beta Hemolyticus group B (Streptococcus Agalactiae) in the 1990s, bacterial meningitis remains the most common form of cerebrospinal fluid infection in pediatric patients. To date, the rate of unfavorable neurological outcomes is still from 20% to 60%, and the possibility of containing its rate strongly depends on early diagnosis, therapy, and a multidisciplinary approach, which involves neonatologists, neurologists, neuroradiologists, and physiotherapists. Neonatal meningitis remains difficult to diagnose because the responsible bacteria vary with gestational age at birth, age at presentation, and environmental context. The clinical presentation, especially in the newborn, is very ambiguous. From a clinical point of view, the definitive test for diagnosis is lumbar puncture in patients with symptoms suggestive of neurological involvement. Therefore, neuroimaging is key for raising clinical suspicion of meningitis or corroborating the diagnosis based on clinical and laboratory data. Our pictorial review offers a practical approach to neonatal meningoencephalitis by describing the epidemiology, the pathophysiology of bacterial meningoencephalitis, defining the indications and suggesting optimized protocols for neuroimaging techniques, and showing the main neuroimaging findings to reach the diagnosis and offering proper follow-up of bacterial meningitis. Moreover, we tried identifying some peculiar MRI patterns related to some bacteria.

Maternal consumption of yoghurt activating the aryl hydrocarbon receptor increases group 3 innate lymphoid cells in murine offspring.

Key progresses in the sequencing and functional annotation of microbial organisms have revolutionized research in the fields of human metabolism and food biotechnology. In particular, the gut microbiome is now recognized as an important mediator of the impact of nutrition on human metabolism. Annotated genomes of a large number of bacteria are now available worldwide, which selectively transform food through fermentation to produce specific bioactive compounds with the potential to modulate human health. A previous research has demonstrated that the maternal microbiota shapes the neonatal immune system. Similarly, this report shows that lactic acid bacteria can be selected to produce fermented food that can also modulate postnatal intestinal immunity.

Impact of Infections During Pregnancy on Transplacental Antibody Transfer.

Vaccination in pregnancy is important to protect the mother and fetus from infectious diseases. The transfer of maternal antibodies across the placenta during pregnancy can continue to protect the neonate for several months after birth while the neonatal adaptive immune system develops. Several pathogens have been shown to impair the transplacental transfer of maternal antibodies, including human immunodeficiency virus, malaria, the severe acute respiratory syndrome coronavirus 2, and cytomegalovirus. This review discusses the mechanisms contributing to decreased transplacental antibody transfer in the setting of maternal infections, such as changes in antibody glycosylation profile, maternal hypergammaglobulinemia, and placental injury. The frequency of epidemics is increasing, and pregnant people are more likely to become exposed to novel pathogens now than they were in the past. Understanding the mechanisms by which infectious diseases impair maternal-fetal antibody transfer is important for pandemic preparedness to maximize the impact of maternal vaccination for child health.

Safety and implementation of a phase 1 randomized GLA-SE-adjuvanted CH505TF gp120 HIV vaccine trial in newborns.

The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a novel glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV. HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants in South Africa aged ≤5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks. 38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, p = 0.25; 4, 40.0% systemic, p = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded. This study illustrates the feasibility of conducting trials of novel adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring. ClinicalTrials.gov NCT04607408. National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH).

The effect of intrauterine growth restriction on the developing pancreatic immune system.

Immune cells in the pancreas are known to participate in organ development. However, the resident pancreatic immune system has yet to be fully defined. Immune cells also play a role in pathology and are implicated in diseases such as diabetes induced by intrauterine growth restriction (IUGR). We hypothesized that the resident immune system is established during neonatal development and disrupted by IUGR. Using single cell RNAseq and flow cytometry we identified many immune cell populations in the near-term fetus (at embryologic day 22) and neonatal (postnatal day 1, 7, &14) islets, non-endocrine pancreas, and the spleen in the rat. Using flow cytometry, we observed the resident immune system is established during neonatal development in the pancreas and spleen. We identified 9 distinct immune populations in the pancreatic islets and 8 distinct immune populations in the spleen by single cell RNAseq. There were no sex-specific differences in the relative proportion of immune cells in the pancreas or spleen. Finally, we tested if IUGR disrupted the neonatal immune system using bilateral uterine artery ligation. We found significant changes to the percentage of CD11B+ HIS48- and CD8+ T cells in the islets and non-endocrine pancreas and in the spleen. IUGR-induced alterations were influenced by the tissue environment and the sex of the offspring. Future research to define the role of these immune cells in pancreatic development may identify disrupted pathways that contribute to the development of diabetes following IUGR.

Pathogenic mechanisms in the evolution of food allergy.

The early development of the neonatal immune system is profoundly influenced by exposure to dietary and microbial antigens, which shapes mucosal tolerance. Successful oral tolerance induction is crucially dependent on microbially imprinted immune cells, most notably the RORγt+ regulatory T (Treg) and antigen presenting cells and is essential for preventing food allergy (FA). The development of FA can be envisioned to result from disruptions at key checkpoints (CKPTs) that govern oral tolerance induction. These include gut epithelial sensory and effector circuits that when dysregulated promote pro-allergic gut dysbiosis. They also include microbially imprinted immune regulatory circuits that are disrupted by dysbiosis and pro-allergic immune responses unleashed by the dysregulation of the aforementioned cascades. Understanding these checkpoints is essential for developing therapeutic strategies to restore immune homeostasis in FA.

Maternal influences on offspring food allergy.

The prevalence of allergies has been globally escalating. While allergies could appear at any age, they often develop in early life. However, the significant knowledge gap in the field is the mechanisms by which allergies affect certain people but not others. Investigating early factors and events in neonatal life that have a lasting impact on determining the susceptibilities of children to develop allergies is a significant area of the investigation as it promotes the understanding of neonatal immune system that mediates tolerance versus allergies. This review focuses on the research over the recent 10 years regarding the potential maternal factors that influence offspring allergies with a view to food allergy, a potentially life-threatening cause of anaphylaxis. The role of breast milk, maternal diet, maternal antibodies, and microbiota that have been suggested as key maternal factors regulating offspring allergies are discussed here. We also suggest future research area to expand our knowledge of maternal-offspring interactions on the pathogenesis of food allergy.

The Significance of Prebiotics and Immuno-Nutrients for Assuring the Developmental Milestones in Toddlerhood

The immune system development of children is influenced by the mother's nutritional state throughout pregnancy as well as the nutrients the unborn kid is exposed to through nursing and other meals. Micronutrients that are important for the development of the immune system in neonates include iron, zinc, and vitamins A, C, D, and E. both probiotics and prebiotics are essential for maintaining a healthy gut microbiota and a robust immune system. While probiotics directly add beneficial bacteria to the gut, prebiotics serve as food for these bacteria, enhancing their growth and activity. Together, they play a vital role in supporting immune function and overall health. Prebiotics also play a significant role in this process by acting as fertilizers to encourage the growth of healthy bacteria in the stomach. Micronutrient deficiencies (MNDs) have an effect on the developing immune system; therefore, a meeting of specialists was arranged to talk about preventative and mitigating strategies. Immunological responses are largely determined by nutrition, and malnutrition is the leading cause of immunodeficiency worldwide. Protein-energy deprivation is associated with a significant decline in cell-mediated immunity, phagocyte activity, complement system, secretory immunoglobulin an antibody concentration, and cytokine production. Certain nutrient deficits cause altered immune responses, even in cases when the deficiency is fairly mild. The immune responses are significantly influenced by micronutrients such as folic acid, zinc, selenium, iron, copper, and vitamins A, C, E, and B-6. Additionally, overeating and obesity reduce immunity. Low birth weight babies' cell-mediated immunity is permanently compromised; this can be somewhat restored by adding more zinc to their diets. Prebiotics are inactive dietary ingredients that, when combined with immuno-nutrients, benefit the host by encouraging the growth and/or activity of a certain kind of bacteria in the colon. Government, development partners, non-governmental organizations, and academia must collaborate to increase the availability of basic and effective nutrition interventions, as well as those that address more stifling issues. These interventions include exclusive breastfeeding, appropriate supplemental feeding, micronutrient supplementation for children, adolescents, pregnant women, and lactating women, managing severe acute malnutrition and deworming, and hygiene interventions. The entire healthcare system needs to be revitalized in order to get over the obstacles that exist at the levels of policy, governance, and service delivery and to create demand for the services at the household level. Priority should also be devoted to stabilizing food prices and managing nutrition following natural disasters.

Characterising glycosaminoglycans in human breastmilk and their potential role in infant health.

Human breastmilk is composed of many well researched bioactive components crucial for infant nutrition and priming of the neonatal microbiome and immune system. Understanding these components gives us crucial insight to the health and wellbeing of infants. Research surrounding glycosaminoglycans (GAGs) previously focused on those produced endogenously; however, recent efforts have shifted to understanding GAGs in human breastmilk. The structural complexity of GAGs makes detection and analysis complicated therefore, research is time consuming and limited to highly specialised teams experienced in carbohydrate analysis. In breastmilk, GAGs are present in varying quantities in four forms; chondroitin sulphate, heparin/heparan sulphate, dermatan sulphate and hyaluronic acid, and are hypothesised to behave similar to other bioactive components with suspected roles in pathogen defense and proliferation of beneficial gut bacteria. Chondroitin sulphate and heparin, being the most abundant, are expected to have the most impact on infant health. Their decreasing concentration over lactation further indicates their role and potential importance during early life.

State of the Art: Intrapartum Antibiotics in Cesarean Section—The Infant Microbiota and Allergic Diseases

(Acta Obstet Gynecol Scand. 2023;102:811–820) Recent changes in guidelines for administering maternal antibiotics for cesarean deliveries (CD) have increased neonatal exposure to antibiotics. Potential long-term effects of this exposure are relatively unknown; recent evidence in other fields has indicated a long-lasting impact of antibiotic exposure on gut microbiota composition, which raises concerns about the effects of antibiotics on the fragile and new gut microbiota of neonates around the time of birth. This review assessed the current guidelines and applications for CD antibiotics, as well as discussed the importance of neonatal intestinal microbiota and the potential consequences of antibiotic prophylaxis in the development of the neonatal immune system and allergic disease.

Maternal supplementation with n-3 fatty acids affects placental lipid metabolism, inflammation, oxidative stress, the endocannabinoid system, and the neonate cytokine concentrations in dairy cows

BackgroundThe placenta plays a crucial role in supporting and influencing fetal development. We compared the effects of prepartum supplementation with omega-3 (n-3) fatty acid (FA) sources, flaxseed oil (FLX) and fish oil (FO), on the expression of genes and proteins related to lipid metabolism, inflammation, oxidative stress, and the endocannabinoid system (ECS) in the expelled placenta, as well as on FA profile and inflammatory response of neonates. Late-pregnant Holstein dairy cows were supplemented with saturated fat (CTL), FLX, or FO. Placental cotyledons (n = 5) were collected immediately after expulsion, and extracted RNA and proteins were analyzed by RT-PCR and proteomic analysis. Neonatal blood was assessed for FA composition and concentrations of inflammatory markers.ResultsFO increased the gene expression of fatty acid binding protein 4 (FABP4), interleukin 10 (IL-10), catalase (CAT), cannabinoid receptor 1 (CNR1), and cannabinoid receptor 2 (CNR2) compared with CTL placenta. Gene expression of ECS-enzyme FA-amide hydrolase (FAAH) was lower in FLX and FO than in CTL. Proteomic analysis identified 3,974 proteins; of these, 51–59 were differentially abundant between treatments (P ≤ 0.05, |fold change| ≥ 1.5). Top canonical pathways enriched in FLX vs. CTL and in FO vs. CTL were triglyceride metabolism and inflammatory processes. Both n-3 FA increased the placental abundance of FA binding proteins (FABPs) 3 and 7. The abundance of CNR1 cannabinoid-receptor-interacting-protein-1 (CNRIP1) was reduced in FO vs. FLX. In silico modeling affirmed that bovine FABPs bind to endocannabinoids. The FLX increased the abundance of inflammatory CD44-antigen and secreted-phosphoprotein-1, whereas prostaglandin-endoperoxide synthase 2 was decreased in FO vs. CTL placenta. Maternal FO enriched neonatal plasma with n-3 FAs, and both FLX and FO reduced interleukin-6 concentrations compared with CTL.ConclusionMaternal n-3 FA from FLX and FO differentially affected the bovine placenta; both enhanced lipid metabolism and modulated oxidative stress, however, FO increased some transcriptional ECS components, possibly related to the increased FABPs. Maternal FO induced a unique balance of pro- and anti-inflammatory components in the placenta. Taken together, different sources of n-3 FA during late pregnancy enhanced placental immune and metabolic processes, which may affect the neonatal immune system.

Maternal immunization and vitamin A sufficiency impact sow primary adaptive immunity and passive protection to nursing piglets against porcine epidemic diarrhea virus infection.

Porcine epidemic diarrhea virus (PEDV) causes a highly contagious enteric disease with major economic losses to swine production worldwide. Due to the immaturity of the neonatal piglet immune system and given the high virulence of PEDV, improving passive lactogenic immunity is the best approach to protect suckling piglets against the lethal infection. We tested whether oral vitamin A (VA) supplementation and PEDV exposure of gestating and lactating VA-deficient (VAD) sows would enhance their primary immune responses and boost passive lactogenic protection against the PEDV challenge of their piglets. We demonstrated that PEDV inoculation of pregnant VAD sows in the third trimester provided higher levels of lactogenic protection of piglets as demonstrated by >87% survival rates of their litters compared with <10% in mock litters and that VA supplementation to VAD sows further improved the piglets' survival rates to >98%. We observed significantly elevated PEDV IgA and IgG antibody (Ab) titers and Ab-secreting cells (ASCs) in VA-sufficient (VAS)+PEDV and VAD+VA+PEDV sows, with the latter maintaining higher Ab titers in blood prior to parturition and in blood and milk throughout lactation. The litters of VAD+VA+PEDV sows also had the highest serum PEDV-neutralizing Ab titers at piglet post-challenge days (PCD) 0 and 7, coinciding with higher PEDV IgA ASCs and Ab titers in the blood and milk of their sows, suggesting an immunomodulatory role of VA in sows. Thus, sows that delivered sufficient lactogenic immunity to their piglets provided the highest passive protection against the PEDV challenge. Maternal immunization during pregnancy (± VA) and VA sufficiency enhanced the sow primary immune responses, expression of gut-mammary gland trafficking molecules, and passive protection of their offspring. Our findings are relevant to understanding the role of VA in the Ab responses to oral attenuated vaccines that are critical for successful maternal vaccination programs against enteric infections in infants and young animals.

Oxylipin profile of human milk and human milk-derived extracellular vesicles

BackgroundSmall Extracellular Vesicles (sEVs) are nano-sized vesicles that are present in all biofluids including human milk (HM) playing a crucial role in cell-to-cell communication and the stimulation of the neonatal immune system. Oxylipins, which are bioactive lipids formed from polyunsaturated fatty acids, have gained considerable attention due to their potential role in mitigating disease progression and modulating the inflammatory status of breastfed infants. This study aims at an in-depth characterization of the oxylipin profiles of HM and, for the first time, of HM-derived sEVs (HMEVs) employing an ad-hoc developed and validated ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. ResultsThe UPLC-MS/MS method covered a panel of 13 oxylipins for quantitation and 93 oxylipins for semi-quantitation. In 200 μL of HM and HMEV isolates of 15 individuals, 42 out of 106 oxylipins were detected in either HM or HMEVs, with 38 oxylipins being detected in both matrices. Oxylipins presented distinct profiles in HM and HMEVs, suggesting specific mechanisms responsible for the encapsulation of target molecules in HMEVs. Ten and eight oxylipins were quantified with ranges between 0.03 – 73 nM and 0.30 pM–0.07 nM in HM and HMEVs, respectively. The most abundant oxylipins found in HMEVs were docosahexaenoic acid derivatives (17-HDHA and 14-HDHA) with known anti-inflammatory properties, and linoleic acid derivatives (9-10-DiHOME and 12,13-DiHOME) in HM samples. Significance and noveltyThis is the first time a selective, relative enrichment of anti-inflammatory oxylipins in HMEVs has been described. Future studies will focus on the anti-inflammatory and pro-healing capacity of oxylipins encapsulated in HMEVs, with potential clinical applications in the field of preterm infant care, specifically the prevention of severe intestinal complications including necrotizing enterocolitis.

Immature neutrophils in cord blood exert increased expression of genes associated with antimicrobial function.

The immune systems of both the mother and the newborn face significant challenges during birth. Proper immune regulation after birth is essential for the survival of neonates. Numerous studies have demonstrated that the neonatal immune system is relatively immature, particularly in its adaptive arm, placing the primary responsibility for immune surveillance on innate immunity. Given the significant role of neutrophils in protecting the neonate after birth, we conducted a study investigating the properties of neutrophils in newborn cord blood using various methodological approaches. Our findings demonstrate the presence of immature low-density neutrophils in the cord blood, which are likely responsible for the observed elevated expression of genes coding for proteins essential to antimicrobial response, including myeloperoxidase, neutrophils elastase, and defensins. We propose that these cells function normally and support the protection of newborns early after birth. Furthermore, our results suggest that the mode of delivery might significantly influence the programming of neutrophil function. The presented findings emphasize the importance of distinct neutrophil subpopulations in neonatal immunity and their potential impact on early postnatal health.