Courtney M. Jackson

Maternal exposure to a traditional farming lifestyle during pregnancy is associated with protection against allergic disease in childhood; however, the mechanism remains unclear. Pre‐clinical work has demonstrated a role for the maternal gut microbiome in fetal immune programming. Given the diverse microbial exposure on farms, we sought to assess whether the maternal gut microbiome may mediate the relationship between maternal farm exposure and protection against offspring allergic disease. Deep shotgun metagenomic analysis of the perinatal fecal microbiome showed that women from an Old Order Mennonite traditional farming community (OOM, n = 68) harbored a more diverse gut microbiome relative to women from urban/suburban Rochester, NY (ROC, n = 55). We identified several bacterial species differentially abundant between lifestyle groups, including those from Dorea, Anaerobutyricum, Bifidobacterium , and Bacteroides genera, which translated to marked differences in microbiome functional capacity. These differences in the gut microbiome composition were accompanied by targeted metabolite findings indicating higher serum acetate and isobutyrate levels in OOM women that were positively correlated with cord plasma levels and infant systemic IgA concentrations. Among urban women, maternal microbiome composition was associated with early childhood atopic disease outcomes. Specifically, Dorea longicatena and Segatella copri were least abundant in urban mothers whose infants developed atopic disease (atopic dermatitis) or IgE‐mediated food allergy alone, respectively, and were most abundant in the OOM mothers. Together, these findings highlight the maternal gut microbiome and metabolites as potential contributors to prenatal farming lifestyle protection against early childhood allergic disease.

Human milk is a rich source of immunomodulatory factors that influence the development of the infant immune system, including susceptibility to allergic diseases. Among these components, milk antibodies have been extensively studied for their role in protecting against infections; however, their potential contribution to allergy prevention may be equally important. The mechanisms of protection include allergen exclusion, enhanced and targeted antigen presentation, immune modulation via shaping of the infant gut microbiome, and direct regulation of gut immune responses. This review summarizes current evidence on the secretion of human milk antibodies, highlights what is known and what remains unclear about their role in allergy prevention and outlines the need for further research to develop antibody‐based strategies for early allergy prevention.

The role of antibodies in protection against food allergy is debated. Here, we designed a longitudinal birth cohort study recruiting participants from an Old Order Mennonite (OOM) community, a traditional farm lifestyle considered to be at low risk for allergic diseases, and participants from urban and suburban Rochester, NY, USA, that were at higher risk for developing allergic diseases. We collected cord and peripheral blood, stool, saliva, and maternal milk samples longitudinally during pregnancy and during the first year of the infant’s life to evaluate B cell and antibody responses. Farm exposure led to an accrual of memory and immunoglobulin G–positive (IgG ⁺ ) B cells, higher titers of plasma IgG and IgA and salivary and fecal IgA in infants, and higher IgA titers in maternal milk. Moreover, OOM infants and their mothers had higher titers of plasma IgG ₄ and IgA antibodies to egg ovalbumin in maternal milk, respectively, a feature that we found to be associated with lower incidence of egg allergy. Infant systemic IgG ₄ and IgA were associated with early introduction or more frequent ingestion of lightly cooked egg, respectively, but there was also an effect independent of egg exposure. Several food antigens were detected in cord blood, with in utero exposure potentially explaining the unexpected presence of antigen-specific IgA at birth. These analyses suggest earlier maturation of B cell immunity in farming lifestyle communities.

Background: Little is known about the ontogeny of T cell immunity during infancy in farming and urban lifestyles due to the lack of immunophenotyping in such birth cohorts. Methods: Two birth cohorts (farming and urban) at differing risks and rates of allergic diseases were compared. Blood mononuclear cells were collected from infants at birth, and 6 and 12 months of age. Full spectrum flow cytometry, followed by traditional gating and the Scalable Weighted Iterative Flow‐clustering Technique (SWIFT) high‐dimensional analysis, were used to identify cell populations that differed between farming and urban infants. Additionally, single‐cell RNAseq and multiplex cytokine assays were used to assess the function of cell populations of interest. Results: Several regulatory T cell (Treg) subpopulations were elevated in farming lifestyles and in non‐atopic infants. A unique effector memory CD25 ⁺ CD127 ⁺ CD161 ⁻ CD49d ⁺ CCR4 ⁺ CRTH2 ⁺ Th2 population was elevated at 6 months in urban infants and in those who developed atopic dermatitis and/or food allergy and allergic sensitization. Although this population shared Th2 and IL‐9 skewing with Th2A cells, the population uniquely failed to express CD161, produced more IL‐2 and TNF‐α, and upregulated the differentially expressed genes (DEGs), FOXP3 and the cytokine inducible SH2‐containing protein gene ( CISH ) relative to Th2A cells. This population has been termed Th2B cells. Conclusion: We describe a unique effector memory Th2 population elevated in urban high‐risk infants, potentially implicated in the development of allergic disease.

Perinatal inflammatory stress is associated with early life morbidity and lifelong consequences for pulmonary health. Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25 to 40% of preterm births. Severe chorioamnionitis with preterm birth is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may markedly alter the development of the lung. Here, we used intra-amniotic lipopolysaccharide (LPS) challenge to induce experimental chorioamnionitis in a prenatal rhesus macaque ( Macaca mulatta ) model that mirrors structural and temporal aspects of human lung development. Inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure, particularly the close association and coordinated differentiation of alveolar type 1 pneumocytes and specialized alveolar capillary endothelium. Single-cell RNA sequencing analysis defined a multicellular alveolar signaling niche driving alveologenesis that was extensively disrupted by perinatal inflammation, leading to a loss of gas exchange surface and alveolar simplification, with notable resemblance to chronic lung disease in newborns. Blockade of the inflammatory cytokines interleukin-1β and tumor necrosis factor–α ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells, restoring structural integrity and key signaling networks in the developing alveolus. These data provide new insight into the pathophysiology of developmental lung injury and suggest that modulating inflammation is a promising therapeutic approach to prevent fetal consequences of chorioamnionitis.

There has been an increased prevalence of several allergic manifestations such as food allergy, atopic eczema, allergic rhinitis and asthma. Several explanations have been proposed why this has occurred, but one of the main contributing factors may be the gradual loss of microbial exposures over time in regions where allergy is prevalent. Such exposures occur in individuals who practise a traditional farming lifestyle and are protected against allergy. Infant consumption of human milk, more commonly practised in these farming communities, may provide an alternative in combatting allergy, as it known to be beneficial to infant health. In this review, we cover human milk and its role in shaping the gut microbiome promoting the growth of beneficial bacteria like Bifidobacterium, as well as the downstream impact of the farming lifestyle, human milk and Bifidobacterium has on developing infant immunity.

Respiratory complications are the major cause of morbidity and mortality among preterm infants, which is partially prevented by the administration of antenatal corticosteroids (ACS). Most very preterm infants are exposed to chorioamnionitis, but short- and long-term effects of ACS treatment in this setting are not well defined. In low-resource settings, ACS increased neonatal mortality by perhaps increasing infection. We report that treatment with low-dose ACS in the setting of inflammation induced by intraamniotic lipopolysaccharide (LPS) in rhesus macaques improves lung compliance and increases surfactant production relative to either exposure alone. RNA sequencing shows that these changes are mediated by suppression of proliferation and induction of mesenchymal cellular death via TP53. The combined exposure results in a mature-like transcriptomic profile with inhibition of extracellular matrix development by suppression of collagen genes COL1A1 , COL1A2 , and COL3A1 and regulators of lung development FGF9 and FGF10 . ACS and inflammation also suppressed signature genes associated with proliferative mesenchymal progenitors similar to the term gestation lung. Treatment with ACS in the setting of inflammation may result in early respiratory advantage to preterm infants, but this advantage may come at a risk of abnormal extracellular matrix development, which may be associated with increased risk of chronic lung disease.

Accumulation of activated neutrophils at the feto-maternal interface is a defining hallmark of intrauterine inflammation (IUI) that might trigger an excessive immune response during pregnancy. Mechanisms responsible of this massive neutrophil recruitment are poorly investigated. We have previously showed that intraamniotic injection of LPS in rhesus macaques induced a neutrophil predominant inflammatory response similar to that seen in human IUI. Here, we demonstrate that anti-TNF antibody (Adalimumab) inhibited ~80% of genes induced by LPS involved in inflammatory signaling and innate immunity in chorio-decidua neutrophils. Consistent with the gene expression data, TNF-blockade decreased LPS-induced neutrophil accumulation and activation at the feto-maternal interface. We also observed a reduction in IL-6 and other pro-inflammatory cytokines but not prostaglandins concentrations in the amniotic fluid. Moreover, TNF-blockade decreased mRNA expression of inflammatory cytokines in the chorio-decidua but not in the uterus, suggesting that inhibition of TNF-signaling decreased the inflammation in a tissue-specific manner within the uterine compartment. Taken together, our results demonstrate a predominant role for TNF-signaling in modulating the neutrophilic infiltration at the feto-maternal interface during IUI and suggest that blockade of TNF-signaling could be considered as a therapeutic approach for IUI, the major leading cause of preterm birth.

Neutrophil infiltration of the chorioamnion-decidua tissue at the maternal-fetal interface (chorioamnionitis) is a leading cause of prematurity, fetal inflammation, and perinatal mortality. We induced chorioamnionitis in preterm rhesus macaques by intraamniotic injection of LPS. Here, we show that, during chorioamnionitis, the amnion upregulated phospho-IRAK1–expressed neutrophil chemoattractants CXCL8 and CSF3 in an IL-1–dependent manner. IL-1R blockade decreased chorio-decidua neutrophil accumulation, neutrophil activation, and IL-6 and prostaglandin E2 concentrations in the amniotic fluid. Neutrophils accumulating in the chorio-decidua had increased survival mediated by BCL2A1 , and IL-1R blockade also decreased BCL2A1 ⁺ chorio-decidua neutrophils. Readouts for inflammation in a cohort of women with preterm delivery and chorioamnionitis were similar to findings in the rhesus macaques. IL-1 is a potential therapeutic target for chorioamnionitis and associated morbidities.