Complement in breast milk modifies offspring gut microbiota to promote infant health.

Breastfeeding offers demonstrable benefits to newborns and infants by providing nourishment and immune protection and by shaping the gut commensal microbiota. Although it has been appreciated for decades that breast milk contains complement components, the physiological relevance of complement in breast milk remains undefined. Here, we demonstrate that weanling mice fostered by complement-deficient dams rapidly succumb when exposed to murine pathogen Citrobacter rodentium (CR), whereas pups fostered on complement-containing milk from wild-type dams can tolerate CR challenge. The complement components in breast milk were shown to directly lyse specific members of gram-positive gut commensal microbiota via a C1-dependent, antibody-independent mechanism, resulting in the deposition of the membrane attack complex and subsequent bacterial lysis. By selectively eliminating members of the commensal gut community, complement components from breast milk shape neonate and infant gut microbial composition to be protective against environmental pathogens such as CR.

A distinct clade of Bifidobacterium longum in the gut of Bangladeshi children thrives during weaning.

The gut microbiome has an important role in infant health and development. We characterized the fecal microbiome and metabolome of 222 young children in Dhaka, Bangladesh during the first two years of life. A distinct Bifidobacterium longum clade expanded with introduction of solid foods and harbored enzymes for utilizing both breast milk and solid food substrates. The clade was highly prevalent in Bangladesh, present globally (at lower prevalence), and correlated with many other gut taxa and metabolites, indicating an important role in gut ecology. We also found that the B. longum clades and associated metabolites were implicated in childhood diarrhea and early growth, including positive associations between growth measures and B. longum subsp. infantis, indolelactate and N-acetylglutamate. Our data demonstrate geographic, cultural, seasonal, and ecological heterogeneity that should be accounted for when identifying microbiome factors implicated in and potentially benefiting infant development.

Mobile genetic elements from the maternal microbiome shape infant gut microbial assembly and metabolism.

The perinatal period represents a critical window for cognitive and immune system development, promoted by maternal and infant gut microbiomes and their metabolites. Here, we tracked the co-development of microbiomes and metabolomes from late pregnancy to 1 year of age using longitudinal multi-omics data from a cohort of 70 mother-infant dyads. We discovered large-scale mother-to-infant interspecies transfer of mobile genetic elements, frequently involving genes associated with diet-related adaptations. Infant gut metabolomes were less diverse than maternal but featured hundreds of unique metabolites and microbe-metabolite associations not detected in mothers. Metabolomes and serum cytokine signatures of infants who received regular-but not extensively hydrolyzed-formula were distinct from those of exclusively breastfed infants. Taken together, our integrative analysis expands the concept of vertical transmission of the gut microbiome and provides original insights into the development of maternal and infant microbiomes and metabolomes during late pregnancy and early life.

Fc Characteristics Mediate Selective Placental Transfer of IgG in HIV-Infected Women.

The placental transfer of maternal IgG is critical for infant protection against infectious pathogens. However, factors that modulate the placental transfer of IgG remain largely undefined. HIV-infected women have impaired placental IgG transfer, presenting a unique "disruption model" to define factors that modulate placental IgG transfer. We measured the placental transfer efficiency of maternal HIV and pathogen-specific IgG in US and Malawian HIV-infected mothers and their HIV-exposed uninfected and infected infants. We examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, IgG subclass, and glycan signatures and their association with placental IgG transfer efficiency. Maternal IgG characteristics, such as binding to placentally expressed Fc receptors FcγRIIa and FcγRIIIa, and Fc region glycan profiles were associated with placental IgG transfer efficiency. Our findings suggest that Fc region characteristics modulate the selective placental transfer of IgG, with implications for maternal vaccine design and infant health.

Site-specific development and progressive maturation of human tissue-resident memory T cells over infancy and childhood.

Infancy and childhood are critical life stages for generating immune memory to protect against pathogens; however, the timing, location, and pathways for memory development in humans remain elusive. Here, we investigated T cells in mucosal sites, lymphoid tissues, and blood from 96 pediatric donors aged 0-10 years using phenotypic, functional, and transcriptomic profiling. Our results revealed that memory T cells preferentially localized in the intestines and lungs during infancy and accumulated more rapidly in mucosal sites compared with blood and lymphoid organs, consistent with site-specific antigen exposure. Early life mucosal memory T cells exhibit distinct functional capacities and stem-like transcriptional profiles. In later childhood, they progressively adopt proinflammatory functions and tissue-resident signatures, coincident with increased T cell receptor (TCR) clonal expansion in mucosal and lymphoid sites. Together, our findings identify staged development of memory T cells targeted to tissues during the formative years, informing how we might promote and monitor immunity in children.

Impaired Tumor-Necrosis-Factor-α-driven Dendritic Cell Activation Limits Lipopolysaccharide-Induced Protection from Allergic Inflammation in Infants.

Infants have a higher risk of developing allergic asthma than adults. However, the underlying mechanism remains unknown. We show here that sensitization of mice with house-dust mites (HDMs) in the presence of low-dose lipopolysaccharide (LPS) prevented T helper 2 (Th2) cell allergic responses in adult, but not infant, mice. Mechanistically, adult CD11b+ migratory dendritic cells (mDCs) upregulated the transcription factor T-bet in response to tumor necrosis factor-α (TNF-α), which was rapidly induced after HDM + LPS sensitization. Consequently, adult CD11b+ mDCs produced interleukin-12 (IL-12), which prevented Th2 cell development by promoting T-bet upregulation in responding T cells. Conversely, infants failed to induce TNF-α after HDM + LPS sensitization. Therefore, CD11b+ mDCs failed to upregulate T-bet and did not secrete IL-12 and Th2 cell responses normally developed in infant mice. Thus, the availability of TNF-α dictates the ability of CD11b+ mDCs to suppress allergic Th2-cell responses upon dose-dependent endotoxin sensitization and is a key mediator governing susceptibility to allergic airway inflammation in infant mice.

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.

Physician-patient racial concordance and newborn mortality.

The racial gap in infant mortality is a pressing public-health concern, and [B. N. Greenwood et al., Proc. Natl. Acad. Sci. U.S.A. 117, 21194-21200 (2020), 10.1073/pnas.1913405117] suggest that Black newborns are more likely to survive if cared for by Black physicians after birth, even in models that control for numerous variables, including hospital and physician fixed effects, and the 65 most common comorbidities affecting newborns (as described by International Classification of Disease codes). We acquired the data used in the study, covering Florida hospital discharges from 1992 through the third quarter of 2015, to replicate and extend the analysis. We find that the magnitude of the concordance effect is substantially reduced after controlling for diagnoses indicating very low birth weight (<1,500 g), which are a strong predictor of neonatal mortality but not among the 65 most common comorbidities. In fact, the estimated effect is near zero and statistically insignificant in the expanded specifications that control for very low birth weight and include hospital and physician fixed effects.

Fibrinogen inhibits sonic hedgehog signaling and impairs neonatal cerebellar development after blood-brain barrier disruption.

Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage.

Antiracism and positive intergenerational (infant) outcomes: A county-level examination of low birth weight and infant mortality.

Racism is associated with negative intergenerational (infant) outcomes. That is, racism, both perceived and structural, is linked to critical, immediate, and long-term health factors such as low birth weight and infant mortality. Antiracism-resistance to racism such as support for the Black Lives Matter (BLM) movement-has been linked to positive emotional, subjective, and mental health outcomes among adults and adolescents. To theoretically build on and integrate such past findings, the present research asked whether such advantageous health correlations might extend intergenerationally to infant outcomes? It examined a theoretical/correlational process model in which mental and physical health indicators might be indirectly related to associations between antiracism and infant health outcomes. Analyses assessed county-level data that measured BLM support (indexed as volume of BLM marches) and infant outcomes from 2014 to 2020. As predicted, in the tested model, BLM support was negatively correlated with 1) low birth weight (Ncounties = 1,445) and 2) mortalities (Ncounties = 409) among African American infants. Given salient, intergroup, policy debates tied to antiracism, the present research also examined associations among White Americans. In the tested model, BLM marches were not meaningfully related to rates of low birth weight among White American infants (Ncounties = 2,930). However, BLM support was negatively related to mortalities among White American infants (Ncounties = 862). Analyses controlled for structural indicators of income inequality, implicit/explicit bias, voting behavior, prior low birth weight/infant mortality rates, and demographic characteristics. Theory/applied implications of antiracism being linked to nonnegative and positive infant health associations tied to both marginalized and dominant social groups are discussed.