Gestational Polyphenol Levels and Risk of Atopic and Respiratory Outcomes in Early-Life: Insights from The LiNA Study

Gestational Polyphenol Levels and Risk of Atopic and Respiratory Outcomes in Early-Life: Insights from The LiNA Study | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 13 January 2026 V1 Latest version Share on Gestational Polyphenol Levels and Risk of Atopic and Respiratory Outcomes in Early-Life: Insights from The LiNA Study Authors : Sergio Gómez-Olarte , Carolin Huber , Stefan Roeder , Ulrich Sack , Michael Borte , Martin Krauss , Werner Brack , Ana C. Zenclussen , and Gunda Herberth 0000-0003-0212-3509 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176830092.26806232/v1 Published Allergy Version of record Peer review timeline 279 views 121 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background Prenatal exposure to diet-derived polyphenols may shape fetal immune development and early-life atopic risk. However, evidence on this relationship is scarce and often relies on food questionnaires to assess polyphenol intake. This study aimed to examine the prospective association between levels of polyphenol markers in late pregnancy and childhood health outcomes. Methods Fourteen polyphenol markers were measured in gestational urine samples from 581 mother-child pairs of the LiNA German cohort and were associated with allergic and respiratory outcomes in children aged 3 (n=478) by multivariable regression models. Mixture and immune-driven effects were estimated using quantile g-computation and mediation analysis with the children’s Th2 cytokine blood concentrations (n=268; IL-4, IL-5, IL-10, and IL-13), respectively. Results Children prenatally exposed to the highest tertiles of the flavonoids isosakuranetin (aOR=0.45, 95% CI: 0.22-0.88), norwogonin-glucuronide (aOR=0.42, 95% CI: 0.20-0.84), and pinocembrin (aOR=0.41, 95% CI: 0.20-0.81) had lower odds of atopic dermatitis. The highest tertiles of enterolactone and hippuric acid, two microbiota-derived compounds, were also associated with reduced odds of wheezing (aOR=0.50, 95% CI: 0.31-0.80) and bronchitis (aOR=0.60, 95% CI: 0.37-0.95), respectively. The flavonoid mixture was protective against the onset of atopic dermatitis, with pinocembrin effect (weight of 33%) being partially mediated by IL-5 levels (ACME=-0.022, 95% CI: -0.055, -0.001). Hippuric acid and enterolactone contributed equally (weights of 44%) to the protective mixture effect of microbiota-derived compounds on wheezing risk. Conclusion Prenatal exposure to polyphenol-rich foods may influence the development of the child’s immune and respiratory systems, potentially reducing the risk of early-life atopic disorders. Gestational Polyphenol Levels and Risk of Atopic and Respiratory Outcomes in Early-Life: Insights from The LiNA Study Short title: Prenatal Polyphenol Exposure and Childhood Health Outcomes Authors: Sergio Gómez-Olarte a* , Carolin Huber b, c , Stefan Röder a , Ulrich Sack d , Michael Borte e , Martin Krauss b , Werner Brack b, f , Ana C. Zenclussen a, g, h , Gunda Herberth a, g* Affiliations: a Department of Environmental Immunology, Helmholtz Centre for Environmental Research – UFZ, Leipzig, Germany b Department of Exposure Science, Helmholtz Centre for Environmental Research – UFZ, Leipzig, Germany c Department of Environmental Chemistry, Eawag - Swiss Federal Institute of Aquatic Science and Technology, Duebendorf, Switzerland d Institute of Clinical Immunology, Faculty of Medicine, Leipzig University, Leipzig, Germany e Children’s Hospital, Municipal Hospital ”St. Georg”, Academic Teaching Hospital of Leipzig University, Leipzig, Germany f Department of Evolutionary Ecology & Environmental Toxicology, Faculty of Biological Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany g German Center for Child and Adolescent Health (DZKJ), Partner Site Leipzig/Dresden, Germany h Perinatal Immunology, Saxonian Incubator for Clinical Translation (SIKT), Medical Faculty, Leipzig University, Leipzig, Germany * Corresponding Authors: Gunda Herberth, PhD. Department of Environmental Immunology, Helmholtz Centre for Environmental Research – UFZ, Permoserstraße 15, 04318, Leipzig, Germany. E-mail: [email protected] Sergio Gómez-Olarte, PhD. Department of Environmental Immunology, Helmholtz Centre for Environmental Research – UFZ, Permoserstraße 15, 04318, Leipzig, Germany. E-mail: [email protected] ORCID Sergio Gómez-Olarte: https://orcid.org/0000-0002-9494-068X Carolin Huber: https://orcid.org/0000-0002-9355-8948 Stefan Röder: https://orcid.org/0000-0001-9367-663X Ulrich Sack: https://orcid.org/0000-0002-7813-0492 Martin Krauss: https://orcid.org/0000-0002-0362-4244 Werner Brack: https://orcid.org/0000-0001-9269-6524 Ana C. Zenclussen: https://orcid.org/0000-0003-3544-4552 Gunda Herberth: https://orcid.org/0000-0003-0212-3509 Acknowledgments This work was supported by the ENDOMIX project: Understanding how endocrine disruptors and chemical mixtures of concern target the immune system to trigger or perpetuate disease. ENDOMIX has received funding from the European Union’s European Health and Digital Executive Agency under grant agreement No. 101136566. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. We acknowledge Melanie Bänsch, Maik Schilde, and Michaela Loschinski for their excellent technical assistance, and thank all participants in the LiNA cohort for their valuable contributions to the study. Background Prenatal exposure to diet-derived polyphenols may shape fetal immune development and early-life atopic risk. However, evidence on this relationship is scarce and often relies on food questionnaires to assess polyphenol intake. This study aimed to examine the prospective association between levels of polyphenol markers in late pregnancy and childhood health outcomes. Methods Fourteen polyphenol markers were measured in gestational urine samples from 581 mother-child pairs of the LiNA German cohort and were associated with allergic and respiratory outcomes in children aged 3 (n=478) by multivariable regression models. Mixture and immune-driven effects were estimated using quantile g-computation and mediation analysis with the children’s Th2 cytokine blood concentrations (n=268; IL-4, IL-5, IL-10, and IL-13), respectively. Results Children prenatally exposed to the highest tertiles of the flavonoids isosakuranetin (aOR=0.45, 95% CI: 0.22-0.88), norwogonin-glucuronide (aOR=0.42, 95% CI: 0.20-0.84), and pinocembrin (aOR=0.41, 95% CI: 0.20-0.81) had lower odds of atopic dermatitis. The highest tertiles of enterolactone and hippuric acid, two microbiota-derived compounds, were also associated with reduced odds of wheezing (aOR=0.50, 95% CI: 0.31-0.80) and bronchitis (aOR=0.60, 95% CI: 0.37-0.95), respectively. The flavonoid mixture was protective against the onset of atopic dermatitis, with pinocembrin effect (weight of 33%) being partially mediated by IL-5 levels (ACME=-0.022, 95% CI: -0.055, -0.001). Hippuric acid and enterolactone contributed equally (weights of 44%) to the protective mixture effect of microbiota-derived compounds on wheezing risk. Conclusion Prenatal exposure to polyphenol-rich foods may influence the development of the child’s immune and respiratory systems, potentially reducing the risk of early-life atopic disorders. Keywords: Atopic dermatitis, polyphenol markers, quantile g-computation, Th2 cytokines, wheezing. Word count: 3,441. 1. Introduction The priming of the immune system begins early in life, possibly during the prenatal period. Therefore, maternal diet during pregnancy may shape the infant’s immune development. Over the past two decades, growing evidence has highlighted the role of dietary bioactive compounds in health trajectories 1,2 . Among them, polyphenols —a group of plant metabolites abundant in fruits, vegetables, tea, and coffee— have been associated with a reduced risk of allergies and respiratory disorders, likely due to their antioxidant and anti-inflammatory properties 3,4 . Experimental studies suggest that polyphenols modulate immune responses by regulating cytokine production, Th1/Th2 immune polarization, and dendritic cell function 5-7 . Through these mechanisms, they might modulate inflammatory processes underlying the pathogenesis of atopic dermatitis, asthma, rhinitis, and other atopic diseases. Nevertheless, most available evidence on the health effects of polyphenols derives from studies in adults, whereas data on childhood outcomes, particularly regarding prenatal exposures, remain scarce 8 . Recently, a birth cohort reported that maternal intake of resveratrol was associated with a lower risk of wheezing and allergic rhinitis in children aged 8 years 9 . Beyond this, little is known about how maternal polyphenol intake during pregnancy may influence early-life atopic and respiratory outcomes in children. Furthermore, as most studies rely on self-reported food frequency questionnaires that are intrinsically susceptible to recall and reporting biases 10,11 , objective biomarkers of polyphenol intake are needed to accurately capture prenatal exposure. In our previous work within the prospective mother-child cohort LiNA: Lifestyle and environmental factors and their influence on the Newborn Allergy risk, we conducted non-targeted and suspect screening of maternal urine samples collected during pregnancy and identified 46 food-derived metabolites with a focus on polyphenols 12 . In the present study, we investigated whether maternal polyphenol markers during pregnancy are associated with the development of atopic and respiratory outcomes in 3-year-old children. We extended the analysis beyond single exposure-outcome relationships by exploring potential mixture effects among the flavonoid and microbiota-derived marker subgroups. Besides, we conducted mediation analyses to assess whether the children’s Th2 immune response may partially explain the relationship between prenatal polyphenol exposure and the onset of atopic diseases. Altogether, this study seeks to provide novel insights into how maternal nutrition during pregnancy may shape immune development and disease risk in early childhood by integrating dietary biomarkers and longitudinal health outcome data. 2. Materials and Methods 2.1 Description of the LiNA study The study was conducted with data from the prospective birth cohort LiNA, involving 629 mother-child pairs, of which 622 correspond to mothers and 629 to children (7 twin pairs). The cohort investigates how environmental factors in the prenatal and postnatal period influence the development of the immune system and the risk of childhood diseases 13,14 . The pregnant women were recruited between May 2006 and December 2008 in Leipzig, Germany. All participants voluntarily provided written informed consent. The LiNA study was approved by the Institutional Review Board of the University of Leipzig (file ref. No. 046-2006). Mothers and children were monitored by annual follow-ups, with biological sample collection (blood and urine) and detailed self-reported standardized questionnaires. For the present study, cytokine and IgE were quantified in the children’s blood samples at age 3 years, and polyphenol markers were detected in first-morning void urine samples from the third trimester of pregnancy as previously described 12 (Supporting Methods). Lifetime prevalence of children’s health outcomes (atopic dermatitis, wheezing, and bronchitis) and the relevant covariates were defined using longitudinal questionnaire data from pregnancy to the 3-year follow-up. 2.2 Measurement of polyphenol markers The suspect and non-targeted screening for polyphenols is described in Huber et al., 2024 12 and Supporting Methods. In brief, urine samples from 581 women in the 34 th -36 th week of pregnancy were analyzed by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Measured signal intensities of the annotated polyphenols (Schymanski level 2a: confirmation by tandem spectral library comparison) 15 with a detection rate (DR) 2.3 Quantification of food allergen-specific IgE and Th2 cytokines IgE specific for food allergens (fx5) was quantified in the serum of children aged 3 years using the Phadia ImmunoCAP System (Thermo Fisher Scientific, Freiburg, Germany). The allergen sources tested in the fx5 panel comprised hen’s egg, cow’s milk, wheat, fish, peanut, and soy. Food sensitization was defined based on the fx5 allergen-specific IgE serum concentration >0.35 kU/L 16 . For cytokine measurements, heparinized blood from children aged 3 years was prepared within 6 h of drawing. Whole blood samples (500 μL) were incubated for 4 h at 37°C with the mitogen phytohemagglutinin (PHA, 50 μg/mL; Sigma Aldrich, Hamburg, Germany). Thereafter, the samples were diluted 1:1 with RPMI 1640 medium without supplements and then centrifuged. Collected cell-free supernatants were stored at −80°C until analysis. Concentrations of the Th2 cytokines IL-4, IL-5, IL-10, and IL-13 were quantified using a cytometric bead array (BD CBA Human Soluble Flex Set system; Becton Dickinson, Heidelberg, Germany), according to the manufacturer’s instructions ( Table S2 ). 2.4 Health outcomes and covariates Information on physician-diagnosed health outcomes until the age of 3 years, including atopic dermatitis, wheezing, and bronchitis, was obtained annually from questionnaires: “Has a physician diagnosed your child with allergic or atopic dermatitis/eczema or neurodermatitis in the past year?” “Has a physician diagnosed your child with wheezing in the past year?” Has a physician diagnosed your child with bronchitis in the past year?” The lifetime prevalence of the outcomes was calculated considering annual reports. Children were classified as food allergen-sensitized when their fx5 values were above 0.35 kU/L. To control for potential confounding, known environmental and lifestyle variables, including smoking/environmental tobacco smoke (ETS) exposure during pregnancy, breastfeeding up to 6 months, cat keeping, parental atopy history, parental education level, and child sex, were retrieved from questionnaires and included as covariates in the statistical models (directed acyclic graph, Fig. S2 ). 2.5 Statistical analyses The Chi-square or Fisher’s exact test (n >5) was used to compare the parameter distribution between the entire LiNA cohort and the analyzed subcohorts. Statistical significance was defined using p- values <0.05. Missing data on the covariates smoking (n=2) and breastfeeding (n=18) were completed using multiple imputation (m=20) by chained equations with logistic regression models. Given the semiquantitative nature of the food marker measurements, polyphenol values were categorized into tertiles (T). We also examined the collinearity across the exposure matrix based on Spearman’s rank correlation coefficients, as polyphenols often derive from common food sources (e.g., vegetables and fruits). The association of individual and subgroups of polyphenol markers, including mixtures of flavonoids and microbiota-derived compounds, with health outcomes was investigated using multivariable logistic regression and quantile g-computation models 17 . Health outcomes exhibiting borderline or statistically significant associations with at least one polyphenol of interest (output of single models) were selected for the mixture analyses. In addition, the average causal mediation effect (ACME) of Th2 cytokines on the relationship between flavonoid polyphenols and atopic outcomes was estimated by independent mediation analyses. The applied modelling parameters are described in the Supporting Methods. Statistical analyses and plots, including the correlation matrix, imputations, quantile g-computation models, and mediation analyses, were computed with the R software (v4.4.1) using the packages “corrplot” (v0.95) 18 , “mice” (v3.18) 19 , “qgcomp” (v2.18) 20 , and “mediation” (v4.5) 21 , respectively. 3. Results 3.1 Characteristics of LiNA study participants The present explorative study evaluates the association of maternal food markers during pregnancy with 3-year-old children’s allergic and respiratory health outcomes. Since detected food markers were primarily polyphenols, the term ‘polyphenol marker’ is used onwards for simplicity reasons. Children aged 3 with maternal polyphenol measurements in pregnancy and longitudinal information on health outcomes and covariates, as well as cytokine and IgE quantification, were included in the study. As shown in the flow chart ( Fig. S1 ), two subcohorts of the LiNA cohort (n=622) were included in the analyses: mother-child pairs with polyphenol marker and outcome data (n=478) and mother-child pairs with polyphenol marker, outcome, and IgE/cytokine data at age of 3 (n=268). The sociodemographic characteristics and health outcomes of participants from the entire cohort and subcohorts were similar ( p >0.05) ( Table 1 ), which rules out potential selection bias. Maternal age at delivery was mainly between 30-35 years, nearly 80% of children were breastfed, and parental education levels were rather high. The 3-year lifetime prevalence was about 15-17% for atopic dermatitis, 40% for wheezing, and 50% for bronchitis ( Table 1 ), whereas the prevalence of food sensitization was 14%. The distribution of the children’s fx5 and cytokine concentrations is presented in Table S2 . 3.2 Polyphenol marker distribution and selection Out of 46 polyphenol markers measured in the maternal urine samples from pregnancy 12 , 14 compounds with DR >70% were selected for further statistical analyses. Measurements for both parent compound and glucuronide metabolite of enterolactone, isosakuranetin, and daidzein were available, but only values of non-conjugated forms were retried to the exposure dataset due to their strong correlation. By limiting the analysis to high DR biomarkers, we could reliably capture consistent food intake patterns and larger exposure variability across the study population. The selected polyphenol markers are flavonoids of different subclasses, such as flavone, anthocyanin, dihydrochalcone, and isoflavone, as well as microbiota-derived metabolites like enterolactone and urolithin ( Table S3 ). The distributions of the polyphenol marker levels are shown in Fig. 1A . As the non-targeted measurements were not quantified due to a lack of appropriate analytical standards, peak intensities were treated as semiquantitative markers of exposure 22 . Riboflavin and enterolactone had the highest DRs (>98% of samples) in the exposure set, whereas the plant flavonoids naringenin, cyanidin-glycoside, and homoeriodictyol displayed the largest DR (>79%) among the polyphenol compounds. Some polyphenols were strongly positively correlated, e.g., isosakuranetin and homoeriodictyol ( r =0.97) or negatively correlated, e.g., naringenin and enterolactone ( r =-0.83) ( Fig. 1B ). 3.3 Association of polyphenol markers with atopic and respiratory outcomes Firstly, we investigated the association of individual polyphenol markers with allergic (atopic dermatitis and food sensitization) and respiratory (wheezing and bronchitis) outcomes using multivariable logistic regression models adjusted for covariates. Both crude and adjusted models showed a statistically significant relationship between high levels of two fruit flavonoids, isosakuranetin and norwogonin-glucuronide, in pregnancy and reduced odds of atopic dermatitis (aOR=0.45, 95% CI: 0.22-0.88 and aOR=0.42, 95% CI: 0.20-0.84) at the age of 3 ( Table 2/S4 ). This indicates that 3-year-old children in the highest exposure tertile (T3) for these polyphenols had a 55-58% lower risk of developing atopic dermatitis compared with those in the lowest tertile (T1). Similarly, high levels of the plant flavonoid pinocembrin were significantly associated with a lower risk of atopic dermatitis onset (aOR=0.41, 95% CI: 0.20-0.81). We found no associations between the polyphenol markers and sensitization to food allergens ( Table 2/S4 ). Furthermore, the regression analysis between prenatal polyphenol markers and respiratory outcomes revealed that 3-year-old children in the highest exposure tertile (T3) of isosakuranetin and enterolactone had reduced odds of wheezing (aOR=0.50, 95% CI: 0.31-0.80 and aOR=0.60, 95% CI: 0.37-0.95) compared with those in the lowest tertile (T1). Interestingly, medium and high levels of hippuric acid (tertiles T2/3 vs. T1) detected in pregnancy were significantly associated with lower odds of bronchitis (aOR=0.61, 95% CI: 0.39-0.96/aOR=0.58, 95% CI: 0.37-0.90), suggesting a dose-dependent effect ( Table 3/S5 ). 3.4 Potential protective effects of polyphenol mixtures Next, we examined whether prenatal co-exposure to flavonoids may influence the lifetime prevalence of atopic dermatitis, food sensitization, or wheezing, in both positive and negative directions. The quantile g-computation analyses of 9 flavonoid markers yielded overall negative point estimates ( Fig. 2 ), but only the model for atopic dermatitis showed a statistically significant inverse association with the flavonoid mixture (aOR=0.50, 95% CI: 0.27-0.92; p =0.027). This suggests that a one-tertile increase in co-exposure to flavonoids, excluding phloretin and cyanidin-glycoside (positive weights), reduced the odds of childhood atopic dermatitis by about half. The main contributors to the joint protective effect against atopic dermatitis were pinocembrin (33%), norwogonin-glucuronide (23%), and isosakuranetin (14%). Notably, the compounds cyanidin-glycoside and pinocembrin displayed persistent positive and negative associations with the evaluated outcomes, respectively ( Fig. 2 ). In addition, co-exposure to the microbiota-derived polyphenols was significantly associated with lower odds of wheezing (aOR=0.68, 95% CI: 0.48-0.96; p =0.029), with hippuric acid and enterolactone contributing equally (weights of 44%) to the mixture effect ( Fig. S3 ). 3.5 Interleukin-5 may partially mediate pinocembrin-atopic dermatitis association As Th2 cytokine signaling is a key driver of atopic disorders, we conducted mediation analyses to elucidate whether IL-4, IL-5, IL-10, or IL-13 levels may influence the observed associations between polyphenol markers and atopic dermatitis onset. The mediation analysis was restricted to isosakuranetin, norwogonin-glucuronide, and pinocembrin, since they were significantly associated with atopic dermatitis ( Table 2 ). The adjusted mediator model showed that IL-5 indirect pathway (ACME) had a statistically significant effect on the association between pinocembrin and atopic dermatitis (-0.022, 95% CI: -0.055, -0.001, p =0.042), and mediated 21% of the total effect (95% CI: -0.520, 1.302, p =0.109). Nonetheless, the total effect of IL-5 on the outcome model was only borderline significant (-0.101, 95% CI: -0.201, 0.009, p =0.079), which may be attributed to the smaller sample size when comparing T3 to T1 (n=178) ( Fig. 3B ). Although the mediator models for IL-14, IL-10, and IL-13 did not reveal further significant indirect effects in the causal pathway linking atopic dermatitis with isosakuranetin and norwogonin-glucuronide, the total and direct (ADE) effects of the latter compound remained consistently significant ( Fig. 3B ). 4. Discussion The present study investigates the potential association between maternal polyphenol levels in pregnancy and childhood outcomes from the prospective cohort LiNA. We conducted the exposure assessment by measuring urine biomarkers using non-target LC-HRMS that, unlike self-reported food frequency questionnaires, can capture polyphenol bioavailability, metabolism, and inter-individual variations. Our data revealed that high exposure levels to some flavonoids, including pinocembrin, norwogonin-glucuronide, and isosakuranetin, might protect against the onset of atopic dermatitis and wheezing within the first 3 years of life. These three compounds were also the main contributors to the protective effect of a flavonoid mixture on atopic dermatitis, while pinocembrin’s relationship with this outcome appears to be partially mediated by IL-5. In addition, we found an inverse association between two microbiota-derived compounds, enterolactone and hippuric acid, and respiratory outcomes. Altogether, these findings suggest that exposure to the analyzed polyphenols during late pregnancy may modulate immune development, thereby reducing the risk for atopic disorders in early-life. To date, the published evidence linking dietary intake of specific polyphenols, such as resveratrol and isoflavones, with allergic diseases is limited and often contradictory 3 . Moreover, the few studies that have investigated prenatal polyphenol levels in relation to childhood outcomes conducted the exposure assessment using food questionnaire data 8,23-25 . For instance, the EDEN French cohort found an association between gestational resveratrol levels and lower risk of wheezing and allergic rhinitis at age 8; yet, this study did not observe any association with atopic dermatitis or food allergies 9 . On the contrary, soy isoflavone intake during pregnancy had a protective effect against food sensitization in 1 to 2-month-old infants from a Japanese cohort 26 . Besides, some intervention studies have suggested that polyphenol intake could provide beneficial health effects on childhood allergic outcomes 27-29 . To the best of our knowledge, no prospective birth cohort has evaluated the atopic protective effect of the flavonoid markers identified in LiNA mother-child pairs. In line with our findings, a recent cross-sectional analysis of the USA National Health and Nutrition Examination Survey (NHANES) found that adults exposed to high levels of enterolactone had a lower risk of asthma and wheezing 30 . The biological plausibility of the association between polyphenols and allergies has been assessed in vivo , particularly for resveratrol, quercetin, cocoa flavanols, and green tea tannins 3,31 . In the present analysis of the LiNA cohort, we identified isosakuranetin and pinocembrin as potential biomarkers of protection against childhood atopic dermatitis and wheezing. Experimental studies have validated the capacity of plant flavonoids to downregulate atopic-related pathways. For instance, phytochemicals like quercetin and kaempferol displayed anti-histaminic properties and modulated IgE production, Th2 responses, and airway inflammation in vitro and in vivo 32-34 . Among the less studied citrus flavanones 35-37 , isosakuranetin has been shown to downregulate the pro-inflammatory CXCL2/ NF-κB signaling pathway in an osteoarthritis mouse model 38 . Similarly, the propolis-derived compound pinocembrin 39-41 diminished airway inflammation in OVA-sensitized mice via inhibition of the NF-κB pathway, thereby controlling allergic asthma signs 42 . Mechanistically, pinocembrin could reduce the production of Th2 cytokines (e.g., IL-4, IL-5, and IL-13) and OVA-specific IgE in the serum of sensitized animals, along with histamine release in vitro by IgE-sensitized basophils 43 . This indirect evidence renders a likely biological pathway for the observed association between pinocembrin and atopic dermatitis. Although it has been demonstrated that pinocembrin ameliorates imiquimod-induced psoriasis-like dermatitis 44 , a chronic autoimmune disease, future research must explore its underlying action mechanisms in allergic skin settings. In this regard, our findings suggested that IL-5, an eosinophil growth factor modulated by NF-κB signaling 45 , may be a likely mediator of pinocembrin’s anti-allergenic effects. Furthermore, we found an inverse association between the secondary metabolite of norwogonin, often detected following the intake of herbal teas and plant-based foods 46,47 , and atopic dermatitis. While isosakuranetin and pinocembrin modulate upstream immune pathways (e.g., NF-κB signaling), norwogonin may control inflammatory responses and hypoxia-induced injury by scavenging reactive oxygen species and promoting antioxidant enzymatic activities, at least in vitro 48 . Nevertheless, it has also been shown that wogonin, a structurally related compound, can diminish OVA-specific IgE and Th2 cytokine levels in vivo 49 , as well as eosinophil infiltration of the nasal mucosa in OVA-sensitized mice with allergic rhinitis 50 . Therefore, the potential anti-allergic effect of norwogonin requires further validation in atopic dermatitis mouse models. Taken together, this experimental evidence and our findings suggest that mixtures of pinocembrin, norwogonin, and isosakuranetin could diminish atopic-driven damage of the skin barrier through complementary mechanisms, which may target type 2 inflammation and oxidative stress, two major features of the disease pathogenesis 51 . Interestingly, the remaining flavonoid markers (or their chemically related compounds) with low weights on the joint effect, including homoeriodictyol, naringenin, and daidzein, have been shown to decrease Th2 responses and skin inflammation in vitro and in atopic dermatitis mouse models 52-56 . Two microbiota-derived polyphenols detected in the LiNA cohort mothers, enterolactone and hippuric acid, had inverse associations with the respiratory outcomes and accounted for 88% of the mixture effect on wheezing. While enterolactone results from the biotransformation of plant lignans mostly found in seeds, whole grains, and legumes 57 , hippuric acid has been proposed as a marker of overall polyphenol intake and gut microbial catabolism 58,59 . The link between enterolignans and atopic disorders is rather complex. Secoisolariciresinol diglucoside could ameliorate allergic rhinitis symptoms in mice through its microbial conversion to enterodiol, but not when it was subsequently oxidized to enterolactone 60 . Conversely, enterolactone controlled atopic dermatitis by reducing skin inflammation and Th2 responses in a contact hypersensitivity mouse model 61 . Yet, both compounds seem to modulate NF-κB signaling and exhibit antioxidant activity in vitro 62,63 . Thus, in line with our mixture analysis, the immune mechanisms underlying the physiological effects of enterolactone, especially when combined with hippuric acid, on respiratory allergies should be further examined. On the other hand, although hippuric acid levels have not been directly linked to bronchitis, they positively correlate with gut microbiome diversity 64 , a key determinant of immune tolerance during pregnancy 65 . In this sense, our findings underscore a knowledge gap on how mothers’ gut microbiome-diet interactions might influence childhood health. Our study has several strengths that support the robustness of the observed associations. Maternal polyphenol exposure was assessed using a non-targeted LC-HRMS approach that provides a sensitive measure of free and conjugated metabolites. The prospective design of the LiNA cohort assures the temporality of causal inferences and decreases the risk of potential confounding. By including children’s Th2 cytokine markers in the mediation analysis, we could explore possible mechanisms underlying the effects of maternal diet on allergy development. Nonetheless, some limitations must also be acknowledged. Polyphenol metabolites were detected in a single urine sample from the third trimester of pregnancy, possibly overlooking their variability across other gestational periods. The subcohort with immune markers was relatively small, which could limit the statistical power of mediation analyses and increase uncertainty around effect estimates. Although health outcomes were evaluated using standardized questionnaires, some degree of parental misreporting cannot be excluded. Lastly, as the LiNA cohort represents a specific Central European population, the generalizability of our findings to settings with different food exposure profiles may be limited. Altogether, this study combines a polyphenol exposure assessment with immune biomarker and longitudinal outcome data to convey novel evidence on how maternal diet may shape fetal immune development. Our results underscore the need for further studies that integrate maternal diet, gut microbiome function, and immune programming to strengthen causal inference. Understanding how prenatal exposure to polyphenols influences childhood outcomes is essential to inform nutritional guidelines and early-life intervention strategies. Author Contributions SGO: Conceptualization, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing. CH: Investigation, Validation. SR: Data curation, Methodology. MB: Investigation, Resources. MK: Funding acquisition, Project administration. WB: Resources. ACZ: Funding acquisition, Project administration, Writing – review & editing. GH: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. All authors critically revised the manuscript and approved the final version for publication. Conflicts of Interest The authors declare no conflicts of interest. Tables Table 1. Description of sociodemographic characteristics and outcomes of mother-child pairs in the entire LiNA cohort with polyphenol measurements at pregnancy (n=581/622) and in the 3-year follow-up (n=478), and the subcohort with polyphenol data and IgE/cytokine quantification (n=268) in children aged 3. Maternal age at delivery (years) 0.812 35 100 (17%) 167 (35%) 90 (34%) Smoking/ETS exposure during pregnancy 0.417 No 470 (83%) 407 (86%) 234 (88%) Yes 98 (17%) 69 (14%) 33 (12%) Missing 13 2 1 Breastfeeding (up to 6 months) 0.356 No 121 (22%) 94 (20%) 61 (23%) Yes 417 (78%) 366 (80%) 200 (77%) Missing 43 18 7 Cat keeping 0.876 No 476 (82%) 392 (82%) 221 (82%) Yes 105 (18%) 86 (18%) 47 (18%) Family history of atopy 0.615 None 192 (33%) 159 (33%) 83 (31%) One parent 274 (47%) 229 (48%) 127 (47%) Both parents 115 (20%) 90 (19%) 58 (22%) Parental school education e 0.728 Low 16 (2.8%) 5 (1.0%) 2 (0.7%) Medium 128 (22%) 103 (22%) 64 (24%) High 437 (75%) 370 (77%) 202 (75%) Child sex 0.851 Male 303 (52%) 246 (51%) 136 (51%) Female 278 (48%) 232 (49%) 132 (49%) Outcome prevalence at year 3 f Atopic dermatitis 0.436 No 440 (86%) 408 (85%) 223 (83%) Yes 74 (14%) 70 (15%) 45 (17%) Wheezing 0.401 No 314 (61%) 295 (62%) 157 (59%) Yes 200 (39%) 183 (38%) 111 (41%) Bronchitis 0.258 No 258 (50%) 240 (50%) 123 (46%) Yes 256 (50%) 238 (50%) 145 (54%) a Mothers of the entire LiNA cohort with complete questionnaire and maternal food marker data at pregnancy/birth, n=581/622. b Mother-child pairs of the 3-year follow-up with complete questionnaire data and food marker measurements at pregnancy. c Subcohort of mother-child pairs of the 3-year follow-up with complete questionnaire data, food marker measurements at pregnancy, and children’s blood protein quantification. d The Chi-square or Fisher’s exact test (n e Parental education was defined based on the number of schooling years: ≤ 9 years (low), 10 years (medium), and ≥12 years (high). f The first column displays the children of the 3-year follow-up (n=514) with complete questionnaire data. Table 2. Results of logistic regression models on the association between polyphenol markers in pregnancy with atopic dermatitis (n=478) and food sensitization (n=268) in 3-year-old children. Polyphenol marker Tertile Atopic dermatitis Food sensitization b aOR (95% CI) a p -value aOR (95% CI) a p -value Fruit flavonoids Naringenin Medium 0.87 (0.47 - 1.59) 0.648 1.04 (0.45 - 2.39) 0.931 High 0.56 (0.28 - 1.08) 0.087 0.64 (0.25 - 1.58) 0.344 Cyanidin glycoside Medium 1.38 (0.76 - 2.53) 0.287 0.86 (0.38 - 1.95) 0.725 High 0.61 (0.30 - 1.22) 0.168 0.60 (0.23 - 1.45) 0.262 Homoeriodictyol Medium 1.28 (0.70 - 2.34) 0.426 1.02 (0.46 - 2.28) 0.959 High 0.56 (0.27 - 1.11) 0.100 0.42 (0.15 - 1.11) 0.088 Isosakuranetin Medium 0.90 (0.50 - 1.63) 0.731 1.56 (0.69 - 3.60) 0.287 High 0.45 (0.22 - 0.88) 0.023 0.98 (0.39 - 2.41) 0.965 Phloretin Medium 1.15 (0.59 - 2.24) 0.683 1.33 (0.56 - 3.24) 0.523 High 1.32 (0.69 - 2.56) 0.404 1.29 (0.53 - 3.19) 0.574 Norwogonin-glucuronide Medium 1.03 (0.57 - 1.88) 0.912 1.22 (0.50 - 3.09) 0.663 High 0.42 (0.20 - 0.84) 0.017 1.53 (0.64 - 3.83) 0.346 Plant flavonoids Pinocembrin Medium 0.79 (0.43 - 1.44) 0.441 0.69 (0.30 - 1.58) 0.386 High 0.41 (0.20 - 0.81) 0.012 0.49 (0.19 - 1.17) 0.117 Daidzein Medium 0.94 (0.50 - 1.76) 0.834 1.48 (0.60 - 3.91) 0.407 High 0.63 (0.32 - 1.22) 0.174 1.26 (0.49 - 3.40) 0.638 8-prenylnaringenin Medium 1.08 (0.57 - 2.06) 0.803 0.43 (0.15 - 1.11) 0.097 High 0.92 (0.48 - 1.73) 0.786 0.81 (0.36 - 1.75) 0.585 Microbiota-derived polyphenols Enterolactone Medium 0.97 (0.47 - 1.98) 0.930 0.55 (0.19 - 1.53) 0.262 High 1.57 (0.83 - 3.03) 0.169 1.77 (0.78 - 4.18) 0.178 Hippuric acid Medium 1.63 (0.85 - 3.17) 0.147 0.74 (0.30 - 1.78) 0.505 High 1.32 (0.68 - 2.58) 0.418 0.96 (0.41 - 2.24) 0.930 Urolithin Medium 1.21 (0.64 - 2.33) 0.557 2.10 (0.82 - 5.71) 0.129 High 0.98 (0.51 - 1.89) 0.961 2.41 (0.98 - 6.41) 0.062 Vitamin & plant polyphenol Riboflavin Medium 0.89 (0.48 - 1.68) 0.725 1.04 (0.44 - 2.46) 0.931 High 0.72 (0.37 - 1.38) 0.323 0.78 (0.31 - 1.90) 0.579 34-dimethoxycinnamicacid Medium 0.82 (0.43 - 1.56) 0.552 1.39 (0.57 - 3.45) 0.467 High 0.80 (0.42 - 1.49) 0.475 1.28 (0.54 - 3.11) 0.580 a Models that compares the medium and high tertiles with the low tertile of polyphenol markers, adjusted for smoking/ETS exposure during pregnancy, breastfeeding up to 6 months, cat keeping, parental atopy history, parental education level, and child sex. b Defined according to fx5 IgE levels >0.35 kU/L. The odds ratios (ORs) in bold font are statistically significant: p <0.05. Table 3. Results of logistic regression models on the association between polyphenol markers in pregnancy and respiratory outcomes in 3-year-old children (n=478). Polyphenol marker Tertile Wheezing Bronchitis aOR (95% CI) a p -value aOR (95% CI) a p -value Fruit flavonoids Naringenin Medium 0.81 (0.51 - 1.29) 0.381 0.83 (0.53 - 1.29) 0.409 High 1.24 (0.79 - 1.96) 0.355 1.17 (0.75 - 1.82) 0.498 Cyanidin glycoside Medium 0.81 (0.51 - 1.30) 0.388 0.83 (0.53 - 1.29) 0.411 High 1.29 (0.82 - 2.03) 0.268 1.09 (0.70 - 1.70) 0.697 Homoeriodictyol Medium 1.04 (0.65 - 1.66) 0.868 1.02 (0.65 - 1.59) 0.944 High 1.13 (0.71 - 1.78) 0.611 1.00 (0.64 - 1.56) 0.992 Isosakuranetin Medium 0.78 (0.49 - 1.22) 0.275 0.80 (0.51 - 1.25) 0.319 High 0.50 (0.31 - 0.80) 0.004 0.80 (0.51 - 1.25) 0.330 Phloretin Medium 0.68 (0.43 - 1.08) 0.107 1.04 (0.67 - 1.64) 0.849 High 0.72 (0.45 - 1.14) 0.158 1.07 (0.68 - 1.68) 0.758 Norwogonin-glucuronide Medium 1.28 (0.81 - 2.03) 0.290 0.77 (0.49 - 1.20) 0.251 High 0.98 (0.61 - 1.56) 0.924 0.76 (0.48 - 1.18) 0.223 Plant flavonoids Pinocembrin Medium 0.81 (0.51 - 1.29) 0.381 0.83 (0.53 - 1.29) 0.409 High 1.24 (0.79 - 1.96) 0.355 1.17 (0.75 - 1.82) 0.498 Daidzein Medium 0.81 (0.51 - 1.30) 0.388 0.83 (0.53 - 1.29) 0.411 High 1.29 (0.82 - 2.03) 0.268 1.09 (0.70 - 1.70) 0.697 8-prenylnaringenin Medium 1.04 (0.65 - 1.66) 0.868 1.02 (0.65 - 1.59) 0.944 High 1.13 (0.71 - 1.78) 0.611 1.00 (0.64 - 1.56) 0.992 Microbiota-derived polyphenols Enterolactone Medium 0.78 (0.49 - 1.25) 0.302 0.78 (0.49 - 1.23) 0.286 High 0.60 (0.37 - 0.95) 0.030 0.72 (0.46 - 1.13) 0.150 Hippuric acid Medium 0.76 (0.47 - 1.20) 0.234 0.61 (0.39 - 0.96) 0.035 High 0.65 (0.41 - 1.03) 0.066 0.58 (0.37 - 0.90) 0.017 Urolithin Medium 1.27 (0.80 - 2.03) 0.308 1.18 (0.75 - 1.86) 0.476 High 0.88 (0.55 - 1.40) 0.594 1.00 (0.64 - 1.56) 0.992 Vitamin & plant polyphenol Riboflavin Medium 1.04 (0.65 - 1.67) 0.856 0.89 (0.56 - 1.40) 0.603 High 1.06 (0.67 - 1.69) 0.804 1.03 (0.66 - 1.62) 0.888 34-dimethoxycinnamicacid Medium 1.19 (0.74 - 1.90) 0.470 1.11 (0.71 - 1.74) 0.655 High 1.12 (0.71 - 1.76) 0.632 1.11 (0.71 - 1.72) 0.645 a Models that compares the medium and high tertiles with the low tertile of polyphenol markers, adjusted for smoking/ETS exposure during pregnancy, breastfeeding up to 6 months, cat keeping, parental atopy history, parental education level, and child sex. The odds ratios (ORs) in bold font are statistically significant: p <0.05. Figures Figure 1. ( A ) Box plot that presents the distribution of 14 polyphenol markers measured in urine during pregnancy, with red dots denoting extreme values. The compounds are ordered from left to right by detection rate (DR, highest to lowest) within each polyphenol group, as denoted by box color. Note that peak intensities were used as semiquantitative indicators of exposure, but are not directly comparable across polyphenol markers. ( B ) Pairwise Spearman’s rank correlation matrix of food marker levels. In the color spectrum, blue and red shades show positive and negative correlations between the compounds. The asterisk (*) denotes statistically significant correlations ( p <0.05). Figure 2. Quantile g-computation analysis on the association between a mixture of 9 flavonoids measured in pregnancy and health outcomes in children aged 3. The three models were fitted using co-exposures categorized into tertiles (T1-T3) and adjusted for smoking/ETS exposure during pregnancy, breastfeeding up to 6 months, cat keeping, parental atopy history, parental education level, and child sex. The plots display the relative contribution (weights) of each compound to the overall mixture effect, with bars indicating the direction (positive or negative) of the partial effect. A darker bar shading denotes a stronger overall association with the outcome. The point estimates (adjusted OR and 95% CI) and p -values for each outcome are shown in the table. Figure 3. ( A ) Flow chart of the mediation analysis applied to assess the indirect effect of Th2 cytokines (IL-4, IL-5, IL-10, and IL-13) on the association between flavonoid levels and atopic dermatitis in mother-child pairs at the 3-year follow-up. 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Information & Authors Information Version history V1 Version 1 13 January 2026 Peer review timeline Published Allergy Version of Record 3 Apr 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords atopic dermatitis biomarkers epidemiology interleukins nutrition pediatrics Authors Affiliations Sergio Gómez-Olarte Helmholtz-Zentrum fur Umweltforschung UFZ View all articles by this author Carolin Huber Helmholtz-Zentrum fur Umweltforschung UFZ View all articles by this author Stefan Roeder Helmholtz-Zentrum fur Umweltforschung UFZ View all articles by this author Ulrich Sack Universitat Leipzig Medizinische Fakultat View all articles by this author Michael Borte Klinikum Sankt Georg gGmbH View all articles by this author Martin Krauss Helmholtz-Zentrum fur Umweltforschung UFZ View all articles by this author Werner Brack Helmholtz-Zentrum fur Umweltforschung UFZ View all articles by this author Ana C. Zenclussen Helmholtz-Zentrum fur Umweltforschung UFZ View all articles by this author Gunda Herberth 0000-0003-0212-3509 [email protected] Helmholtz-Zentrum fur Umweltforschung UFZ View all articles by this author Metrics & Citations Metrics Article Usage 279 views 121 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Sergio Gómez-Olarte, Carolin Huber, Stefan Roeder, et al. Gestational Polyphenol Levels and Risk of Atopic and Respiratory Outcomes in Early-Life: Insights from The LiNA Study. Authorea . 13 January 2026. DOI: https://doi.org/10.22541/au.176830092.26806232/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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