Infant Microbiota Communities and Human Milk Oligosaccharide Supplementation Independently and Synergistically Shape Metabolite Production and Immune Responses in Healthy Mice.

BACKGROUND: Multiple studies have demonstrated associations between the early-life gut microbiome and incidence of inflammatory and autoimmune disease in childhood. Although microbial colonization is necessary for proper immune education, it is not well understood at a mechanistic level how specific communities of bacteria promote immune maturation or drive immune dysfunction in infancy. OBJECTIVES: In this study, we aimed to assess whether infant microbial communities with different overall structures differentially influence immune and gastrointestinal development in healthy mice. METHODS: Germ-free mice were inoculated with fecal slurries from Bifidobacterium longum subspecies infantis positive (BIP) or B. longum subspecies infantis negative (BIN) breastfed infants; half of the mice in each group were also supplemented with a pool of human milk oligosaccharides (HMOs) for 14 d. Cecal microbiome composition and metabolite production, systemic and mucosal immune outcomes, and intestinal morphology were assessed at the end of the study. RESULTS: The results showed that inoculation with a BIP microbiome results in a remarkably distinct microbial community characterized by higher relative abundances of cecal Clostridium senu stricto, Ruminococcus gnavus, Cellulosilyticum sp., and Erysipelatoclostridium sp. The BIP microbiome produced 2-fold higher concentrations of cecal butyrate, promoted branched short-chain fatty acid (SCFA) production, and further modulated serotonin, kynurenine, and indole metabolism relative to BIN mice. Further, the BIP microbiome increased the proportions of innate and adaptive immune cells in spleen, while HMO supplementation increased proliferation of mesenteric lymph node cells to phorbol myristate acetate and lipopolysaccharide and increased serum IgA and IgG concentrations. CONCLUSIONS: Different microbiome compositions and HMO supplementation can modulate SCFA and tryptophan metabolism and innate and adaptive immunity in young, healthy mice, with potentially important implications for early childhood health.

Gut microbiome in the first 1000 days and risk for childhood food allergy.

OBJECTIVE: To summarize recent data on the association between gut microbiome composition and food allergy (FA) in early childhood and highlight potential host-microbiome interactions that reinforce or abrogate oral tolerance. DATA SOURCES: PubMed search of English-language articles related to FA, other atopic disease, and the gut microbiome in pregnancy and early childhood. STUDY SELECTIONS: Human studies published after 2015 assessing the relationship between the gut bacteriome and virome in the first 2 years of life and FA or food sensitization development in early childhood were prioritized. Additional human studies conducted on the prenatal gut microbiome or other atopic diseases and preclinical studies are also discussed. RESULTS: Children who developed FA harbored lower abundances of Bifidobacterium and Clostridia species and had a less mature microbiome during infancy. The early bacterial microbiome protects against FA through production of anti-inflammatory metabolites and induction of T regulatory cells and may also affect FA risk through a role in trained immunity. Infant enteric phage communities are related to childhood asthma development, though no data are available for FA. Maternal gut microbiome during pregnancy is associated with childhood FA risk, potentially through transplacental delivery of maternal bacterial metabolites, though human studies are lacking. CONCLUSION: The maternal and infant microbiomes throughout the first 1000 days of life influence FA risk through a number of proposed mechanisms. Further large, longitudinal cohort studies using taxonomic, functional, and metabolomic analysis of the bacterial and viral microbiomes are needed to provide further insight on the host-microbe interactions underlying FA pathogenesis in childhood.

Environmental Exposures may Hold the Key; Impact of Air Pollution, Greenness, and Rural/Farm Lifestyle on Allergic Outcomes.

PURPOSE OF REVIEW: There has been an increased prevalence of allergy. Due to this relatively rapid rise, changes in environmental exposures are likely the main contributor. In this review, we highlight literature from the last 3 years pertaining to the role of air pollution, greenness, and the rural/farm lifestyle and their association with the development of allergic sensitization, atopic dermatitis, food allergy, and allergic rhinitis in infancy and childhood. Because asthma has a more complex pathophysiology, it was excluded from this review. RECENT FINDINGS: Recent studies support a role for air pollution, greenness, and rural/farming lifestyle influencing atopic outcomes that continue to be defined. While many studies have examined singular environmental exposures, the interconnectedness of these exposures and others points to a need for future work to consider an individual's whole exposure. Environmental exposures' influence on atopic disease development remains an ongoing and important area of study.

Gut microbiome and breast-feeding: Implications for early immune development.

Establishment of the gut microbiome during early life is a complex process with lasting implications for an individual's health. Several factors influence microbial assembly; however, breast-feeding is recognized as one of the most influential drivers of gut microbiome composition during infancy, with potential implications for function. Differences in gut microbial communities between breast-fed and formula-fed infants have been consistently observed and are hypothesized to partially mediate the relationships between breast-feeding and decreased risk for numerous communicable and noncommunicable diseases in early life. Despite decades of research on the gut microbiome of breast-fed infants, there are large scientific gaps in understanding how human milk has evolved to support microbial and immune development. This review will summarize the evidence on how breast-feeding broadly affects the composition and function of the early-life gut microbiome and discuss mechanisms by which specific human milk components shape intestinal bacterial colonization, succession, and function.

Protein and carbohydrate content of infant formula purchased in the United States.

BACKGROUND: The protein and carbohydrate composition of formula fed infants' diets in the United States (US) has not been described. The aims of this study were to characterize these dietary exposures in infant formula purchased in the US and to estimate the proportion of formula purchased which is hypoallergenic or lactose-reduced formula. METHODS: Powdered infant formula purchase data from all major physical stores in the US prior to the COVID-19 pandemic, between 2017 and 2019, were obtained from Information Resources, Inc. Protein and carbohydrate composition and scoop sizes for each formula were obtained from manufacturers. Ready to feed liquid products, products for premature infants and products for over 1 year old were not included. RESULTS: Total volumes of term formula purchased were 216 million kg of formula powder (equivalent to 1.65 billion litres) over 3 years. Intact protein formula was 67.9% of formula purchased, 26.6% was partially hydrolysed and 5.5% was hypoallergenic (5.2% extensively hydrolysed protein; 0.3% amino acid based). Soy protein formula represented 5.1% of formula purchased. Carbohydrate content overall was 52.7% lactose, 42.3% glucose polymers and 5.0% sucrose. 23.7% of formula purchased included sucrose as a carbohydrate. Of all formula purchased, 59.0% was lactose reduced, containing a non-lactose carbohydrate. Of 'standard' formula, defined as intact protein, non-thickened, cow's milk formula, 32.3% was lactose reduced. The proportion of hypoallergenic formula purchased significantly exceeded the prevalence of cow's milk protein allergy and increased over the 3-year study period from 4.9% to 7.6% of all formula sold. CONCLUSIONS: US infants are exposed to unnecessarily high levels of non-lactose carbohydrates and hypoallergenic formula, and this may represent a significant nutritional health risk.

Predictors and biomarkers of food allergy and sensitization in early childhood.

OBJECTIVE: To review existing literature on the early risk factors for and biomarkers of food allergy (FA) and food sensitization (FS) and highlight opportunities for future research that will further the understanding of FA pathogenesis in infancy and toddlerhood. DATA SOURCES: PubMed search of English-language articles related to FA and atopic disease. STUDY SELECTIONS: Human studies with outcomes related to FA, FS, and other atopic disease in childhood were selected and reviewed. Studies published after 2015 were prioritized. RESULTS: The prevalence of FA has greatly increased in recent decades and is now a global public health concern. A complex network of early life risk factors has been associated with development of FA and FS in childhood. Food allergy has a genetic component, but recent evidence suggests that interactions between risk alleles and other environmental exposures are important for disease pathogenesis, potentially through epigenetic mechanisms. Lifestyle factors, such as delivery mode, antibiotic use, and pet exposure also influence FA risk, which may be through their effect on the early life gut microbiome. How these early life risk factors, along with route and timing of antigen exposure, collectively target the developing immune system remains an ongoing and important area of study. CONCLUSION: The current body of evidence emphasizes the first 1000 days of life as a critical period for FA development. More observational studies and adequately powered clinical trials spanning early pregnancy through childhood are needed to identify novel biomarkers and risk factors that can predict susceptibility toward or protection against FA.

Farming lifestyle and human milk: Modulation of the infant microbiome and protection against allergy.

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.

Infant gut microbiome is enriched with Bifidobacterium longum ssp. infantis in Old Order Mennonites with traditional farming lifestyle.

BACKGROUND: Growing up on traditional, single-family farms is associated with protection against asthma in school age, but the mechanisms against early manifestations of atopic disease are largely unknown. We sought determine the gut microbiome and metabolome composition in rural Old Order Mennonite (OOM) infants at low risk and Rochester, NY urban/suburban infants at high risk for atopic diseases. METHODS: In a cohort of 65 OOM and 39 Rochester mother-infant pairs, 101 infant stool and 61 human milk samples were assessed by 16S rRNA gene sequencing for microbiome composition and qPCR to quantify Bifidobacterium spp. and B. longum ssp. infantis (B. infantis), a consumer of human milk oligosaccharides (HMOs). Fatty acids (FAs) were analyzed in 34 stool and human 24 milk samples. Diagnoses and symptoms of atopic diseases by 3 years of age were assessed by telephone. RESULTS: At a median age of 2 months, stool was enriched with Bifidobacteriaceae, Clostridiaceae, and Aerococcaceae in the OOM compared with Rochester infants. B. infantis was more abundant (p < .001) and prevalent, detected in 70% of OOM compared with 21% of Rochester infants (p < .001). Stool colonized with B. infantis had higher levels of lactate and several medium- to long/odd-chain FAs. In contrast, paired human milk was enriched with a distinct set of FAs including butyrate. Atopic diseases were reported in 6.5% of OOM and 35% of Rochester children (p < .001). CONCLUSION: A high rate of B. infantis colonization, similar to that seen in developing countries, is found in the OOM at low risk for atopic diseases.

Vitamin D and iron status in children with food allergy.

BACKGROUND: Children with food allergy are at specific risk for nutritional deficiencies. OBJECTIVE: To retrospectively determine prevalence of vitamin D and iron deficiencies in children with or without food allergy (FA). METHODS: We compared the markers of vitamin D and iron status of 0 to 17-year-olds with cow's milk allergy (CMA) (n = 77), those with other FAs (n = 70), and those with atopy without FA (n = 87) at an academic pediatric allergy practice. Multiple linear regression analyses were performed to determine the impact of CMA and other FAs on vitamin D levels and iron markers. RESULTS: Vitamin D deficiency was detected in one-fourth and insufficiency in one-third of children with CMA and other FAs and in those with atopic diseases but no FA, respectively. Vitamin D levels were associated with vitamin D supplementation and consumption of breast milk, cow's milk, infant formula, or plant-based milk beverage, but not with CMA or other FAs. Older children with FA who did not consume any cow's milk or alternative milk beverage were at highest risk for vitamin D insufficiency. Children with CMA have a higher rate of iron deficiency anemia (8%) than children with other FAs (1%) or those with no FA (5%, P < .001); however, suboptimal levels of transferrin saturation and iron were detected in up to one-third of children with CMA or other FAs. CONCLUSION: Vitamin D deficiency and insufficiency is common in children with atopy overall, but children with CMA are at higher risk for iron deficiency anemia. Intensive nutritional counseling and nutrient intake monitoring, specifically for vitamin D and iron in those avoiding cow's milk, are necessary to optimize nutritional status.

Food allergy in at-risk adolescents with asthma: A key area for focus.

BACKGROUND: Asthma affects more than 6.2 million children in the United States and is a major source of chronic disease burden. Concurrent food allergy (FA) may be a risk factor for worse asthma outcomes. OBJECTIVE: To estimate the prevalence of FA among a cohort of adolescents with persistent asthma and assess whether FA is an independent risk factor for asthma morbidity. METHODS: We included 342 adolescents aged 12 to 16 years with persistent asthma from the Rochester city school district who participated in the School-Based Asthma Care for Teens trial between 2014 and 2018. Multivariable models were used to estimate the association between FA and asthma morbidity. RESULTS: Overall, 29% of adolescents with asthma reported having a FA. Although there were no statistically significant differences in daytime asthma symptoms, teens with FA had higher fractional exhaled nitric oxide (47.5 vs 33.9 P = .002) and reported more days with activity limitation owing to asthma (3.1 vs 2.3 days/2 weeks, P = .03) compared with teens without FA. Less than half (42%) of adolescents with FA had an epinephrine autoinjector. CONCLUSION: This study found FA to be common among this cohort of adolescents with asthma. Although FA was not related to asthma symptom severity, adolescents with FA had higher fractional exhaled nitric oxide and more activity limitation, and most did not have epinephrine autoinjectors. A history of FA and lack of epinephrine autoinjector may increase near-fatal outcomes in adolescents with asthma. Preventive measures in addition to standard asthma treatments are warranted for these teens.

SARS-CoV-2 and human milk: What is the evidence?

The novel coronavirus SARS-CoV-2 has emerged as one of the most compelling and concerning public health challenges of our time. To address the myriad issues generated by this pandemic, an interdisciplinary breadth of research, clinical and public health communities has rapidly engaged to collectively find answers and solutions. One area of active inquiry is understanding the mode(s) of SARS-CoV-2 transmission. Although respiratory droplets are a known mechanism of transmission, other mechanisms are likely. Of particular importance to global health is the possibility of vertical transmission from infected mothers to infants through breastfeeding or consumption of human milk. However, there is limited published literature related to vertical transmission of any human coronaviruses (including SARS-CoV-2) via human milk and/or breastfeeding. Results of the literature search reported here (finalized on 17 April 2020) revealed a single study providing some evidence of vertical transmission of human coronavirus 229E; a single study evaluating presence of SARS-CoV in human milk (it was negative); and no published data on MERS-CoV and human milk. We identified 13 studies reporting human milk tested for SARS-CoV-2; one study (a non-peer-reviewed preprint) detected the virus in one milk sample, and another study detected SARS-CoV-2 specific IgG in milk. Importantly, none of the studies on coronaviruses and human milk report validation of their collection and analytical methods for use in human milk. These reports are evaluated here, and their implications related to the possibility of vertical transmission of coronaviruses (in particular, SARS-CoV-2) during breastfeeding are discussed.

Immunomodulatory effects of breast milk on food allergy.

OBJECTIVE: To summarize the literature on immunomodulatory effects of breast milk on sensitization and possible mechanisms of action. DATA SOURCES: Animal and human studies in PubMed that assessed breastfeeding or breast milk composition in food allergy. STUDY SELECTIONS: All recent studies and some older key publications focusing on this topic. RESULTS: Human milk composition is highly variable among mothers, which can affect the developing infant immune system. Human milk also affects the infant gut microbiome, which is associated with food allergy. High levels of human milk immune factors (IgA, cytokines, oligosaccharides) are associated with reduced risk of food allergy in the infant; it remains uncertain whether these are directly protective or biomarkers of transferred protection. Animal studies highlight potential mechanisms of protection provided by antigens, transforming growth factor ß, and immunocomplexes, yet their relevance is poorly understood in humans. The role of food antigens in human milk in initial sensitization or tolerance induction is unclear. CONCLUSION: The protection against allergy development provided by human milk may be attributable to the effect on the infant gut microbiome or direct effects on immune system. Studies evaluating the effect of breastfeeding and human milk composition on food allergy are needed.

Anaphylaxis risk factors for hospitalization and intensive care: A comparison between adults and children in an upstate New York emergency department.

Background: Anaphylaxis is an acute, systemic allergic reaction that can be life threatening, and with an increasing incidence and costs associated with hospitalization and intensive care. Objective: To assess the risk factors for hospitalization by comparing pediatric and adult patients. Methods: We performed a retrospective chart review for patients with anaphylactic reactions who presented to the Albany Medical Center emergency department between 2005 and 2012. Results: We identified 267 anaphylactic reactions in 258 patients (143 adults). Of those, 128 (48%) were not coded as anaphylaxis despite fulfilling diagnostic criteria. Foods were the most common trigger both in adults and children. Factors associated with increased odds of hospitalization (intensive care unit [ICU] and hospital floor combined) included a severity score of 3 in both children (odds ratio [OR] 41.86 [95% confidence interval {CI}, 2.9-602.48], p = 0.006) and adults (OR 32.52 [95% CI, 6.28-168.35], p < 0.001), and those who received multiple doses of epinephrine in children (OR 15.36 [95% CI, 1.9-121.4], p = 0.009) and adults (OR 11.49 [95% CI, 3.08-44.13], p < 0.001). Patient characteristics associated with ICU admission in children and adults combined included Medicare and/or Medicaid insurance (OR 4.96 [95% CI, 1.14-21.67], p = 0.023), cutaneous symptoms (OR 0.19 [95% CI, 0.04-0.79], p = 0.23), and cardiovascular symptoms (OR 5.8 [95% CI, 1.16-28.87], p = 0.032). Conclusion: Anaphylaxis remains underrecognized and improperly treated in the emergency department. Severity of symptoms and receiving multiple doses of epinephrine were associated with hospitalization in both children and adults. Medicare and/or Medicaid insurance, and cardiovascular or cutaneous symptoms were characteristics associated with ICU admission in our cohort.

Mechanistic correlates of clinical responses to omalizumab in the setting of oral immunotherapy for milk allergy.

BACKGROUND: In our recent clinical trial, the addition of omalizumab to oral immunotherapy (OIT) for milk allergy improved safety, but no significant clinical benefit was detected. OBJECTIVE: We sought to investigate mechanisms by which omalizumab modulates immunity in the context of OIT and to identify baseline biomarkers that predict subgroups of patients most likely to benefit from omalizumab. METHODS: Blood was obtained at baseline and multiple time points during a placebo-controlled trial of OIT for milk allergy in which subjects were randomized to receive omalizumab or placebo. Immunologic outcomes included measurement of basophil CD63 expression and histamine release and casein-specific CD4+ regulatory T-cell proliferation. Biomarkers were analyzed in relationship to measurements of safety and efficacy. RESULTS: Milk-induced basophil CD63 expression was transiently reduced in whole blood samples from both omalizumab- and placebo-treated subjects. However, IgE-dependent histamine release increased in washed cell preparations from omalizumab- but not placebo-treated subjects. No increase in regulatory T-cell frequency was evident in either group. Subjects with lower rates of adverse reactions, regardless of arm, experienced better clinical outcomes. Pre-OIT basophil reactivity positively associated with occurrence of symptoms during OIT, whereas the baseline milk IgE/total IgE ratio correlated with the likelihood of achieving sustained unresponsiveness. A combination of baseline basophil and serologic biomarkers defined a subset of patients in which adjunctive therapy with omalizumab was associated with attainment of sustained unresponsiveness and a reduction in adverse reactions. CONCLUSIONS: Combining omalizumab therapy with milk OIT led to distinct alterations in basophil reactivity but not T-cell responses. Baseline biomarkers can identify subjects most likely to benefit from adjunctive therapy with omalizumab.