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Introduction: Short chain fatty acids (SCFAs) are the main intestinal intermediate and end products of metabolism of dietary fibers/polyphenols by the gut microbiota. The aim of this study was to evaluate the biological implication of stool SCFA profiles determined in the first year of life on the clinical presentation of allergic outcomes in childhood., Methods: From the Growing Up in Singapore Toward healthy Outcomes (GUSTO) cohort, a sub-cohort of 75 participants was recruited. Scheduled questionnaire data was collected for cumulative prevalence of physician-diagnosed eczema, wheezing with the use of nebuliser, and allergen sensitization till the age of 8 years. Stool samples collected at week 3 and months 3, 6 and 12 were quantitated for 9 SCFAs using LC/MS/MS. SCFA data were grouped into lower (below the 25th ) and higher (above the 75th percentiles) categories. Generalized Linear Mixed Models was employed to analyse longitudinal association between SCFAs and atopy-related outcomes., Results: Children with lower stool butyric acid levels (≤25th percentile) over the first 3 time points had higher odds ratio (OR) for wheezing (adjOR = 14.6), eczema (adjOR = 13.2), food sensitization (adjOR = 12.3) and combined outcomes of both wheezing and eczema (adjOR = 22.6) till age 8 years, compared to those with higher levels (≥75 percentile). Additionally, lower longitudinal levels of propionic acid (≤25th percentile) over 4 time points in first year of life was associated with recurrent wheezing (≥2 episodes) till 8 years (adjOR = 7.4) (adj p < 0.05)., Conclusion: Our results suggest that relatively low levels of gut SCFAs in early life are associated with increased susceptibility to atopic-related outcomes in childhood., Competing Interests: CL and JK are employees of Danone Nutricia Research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cheng, Chan, Yap, Huang, Kioh, Tham, Loo, Shek, Karnani, Goh, Van Bever, Teoh, Chan, Lay, Knol, Yap, Tan, Chong, Godfrey, Chan, Lee and Ta.)

Background: Epidemiological studies suggest a link between eczema and attention deficit hyperactivity disorder (ADHD), but underlying mechanisms have not been examined., Objective: We aim to investigate the association between eczema and subsequent ADHD symptoms in the Growing Up in Singapore Towards healthy Outcomes cohort and explore the role of pro-inflammatory cytokines and gut microbiome., Methods: The modified International Study of Asthma and Allergies in Childhood questionnaire and Computerized Diagnostic Interview Schedule for Children Version IV were administered to assess reported eczema within the first 18 months and presence of ADHD symptoms at 54 months, respectively. Skin prick testing at 18 months, cytokines in maternal blood during pregnancy and cord blood and the mediating role of the gut microbiome at 24 months were assessed., Results: After adjusting for confounders, eczema with or without a positive skin prick test was associated with doubling the risk of ADHD symptoms. No differences in maternal and cord blood cytokines were observed in children with and without eczema, or children with and without ADHD. Gut microbiome dysbiosis was observed in children with eczema and children with ADHD. Children with eczema also had lower gut bacterial Shannon diversity. However, the relationship between eczema and ADHD was not mediated by gut microbiome., Conclusion: Early life eczema diagnosis is associated with a higher risk of subsequent ADHD symptoms in children. We found no evidence for underlying inflammatory mechanism or mediation by gut microbiome dysbiosis. Further research should evaluate other mechanisms underlying the link between eczema and ADHD., Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT01174875], identifier [NCT01174875]., Competing Interests: YSC and NK are part of an academic consortium that has received research funding from Abbot Nutrition, Nestle and Danone. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Loo, Ooi, Ong, Ta, Lau, Tay, Yap, Chan, Tham, Goh, Van Bever, Teoh, Eriksson, Chong, Gluckman, Yap, Karnani, Xu, Tan, Tan, Lee, Kramer, Shek, Meaney and Broekman.)

Evidence is accumulating that the establishment of the gut microbiome in early life influences the development of atopic eczema. In this longitudinal study, we used integrated multi-omics analyses to infer functional mechanisms by which the microbiome modulates atopic eczema risk. We measured the functionality of the gut microbiome and metabolome of 63 infants between ages 3 weeks and 12 months with well-defined eczema cases and controls in a sub-cohort from the Growing Up in Singapore Toward healthy Outcomes (GUSTO) mother-offspring cohort. At 3 weeks, the microbiome and metabolome of allergen-sensitized atopic eczema infants were characterized by an enrichment of Escherichia coli and Klebsiella pneumoniae , associated with increased stool D-glucose concentration and increased gene expression of associated virulence factors. A delayed colonization by beneficial Bacteroides fragilis and subsequent delayed accumulation of butyrate and propionate producers after 3 months was also observed. Here, we describe an aberrant developmental trajectory of the gut microbiome and stool metabolome in allergen sensitized atopic eczema infants. The infographic describes an impaired developmental trajectory of the gut microbiome and metabolome in allergen-sensitized atopic eczema (AE) infants and infer its contribution in modulating allergy risk in the Singaporean mother-offspring GUSTO cohort. The key microbial signature of AE is characterized by (1) an enrichment of Escherichia coli and Klebsiella pneumoniae which are associated with accumulation of pre-glycolysis intermediates (D-glucose) via the trehalose metabolic pathway, increased gene expression of associated virulence factors (invasin, adhesin, flagellin and lipopolysaccharides) by utilizing ATP from oxidative phosphorylation and delayed production of butyrate and propionate, (2) depletion of Bacteroides fragilis which resulted in lower expression of immunostimulatory bacterial cell envelope structure and folate (vitamin B9) biosynthesis pathway, and (3) accompanied depletion of bacterial groups with the ability to derive butyrate and propionate through direct or indirect pathways which collectively resulted in reduced glycolysis, butyrate and propionate biosynthesis.

Background: The prevalence of allergic diseases, such as asthma, allergic rhinitis, eczema and food allergy, has been increasing worldwide, as shown in a large number of studies, including the International Study of Asthma and Allergies in Childhood (ISAAC). However, there is significant variation in the prevalence of these diseases in different regions, suggesting that there may be location-specific factors such as environment and microbial exposure affecting allergic disease prevalence. Hence, in this study we determine if there is a difference in microbiota composition and allergen concentration of household dust collected from the homes of non-allergic and allergic subjects from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort., Methods: From the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort, 25 allergic subjects and 25 non-allergic subjects were selected at the year 5.5 follow up. Definitions of allergic outcomes were standardized in the questionnaires administered at 3, 6, 9, 12, 15, 18, 24, 36, 48 and 60 months to ensure consistency during interviews and home visits. Allergen sensitization was determined by skin prick testing (SPT) at 18, 36 and 60 months. Dust samples were collected from the subject's bed, sofa, and play area. DNA extraction was carried out and V3-V4 hypervariable regions of bacterial 16S rRNA gene were sequenced. Protein extraction was performed and allergens assayed by using multiplex assay and ELISA., Results: The most abundant phyla in house dust were Actinobacteria (29.8%), Firmicutes (27.7%), and Proteobacteria (22.4%). Although there were no differences in bacteria abundance and diversity between house dust samples of allergic and non-allergic subjects, the relative abundance of Anaplasmataceae , Bacteroidaceae , and Leptospiraceae were significantly higher in dust samples of allergic subjects as compared to non-allergic subjects in 2 or more locations. The concentration of Der p 1 was significantly lower in bed dust samples of allergic subjects (Median [Interquartile range], 174 ng/g [115-299 ng/g]) as compared to non-allergic subjects (309 ng/g [201-400 ng/g]; P  < 0.05). The concentration of tropomyosin was significantly higher in sofa dust samples of allergic subjects (175 ng/g [145-284 ng/g] as compared to non-allergic subjects (116 ng/g [52.8-170 ng/g]; P  < 0.05)., Conclusion: In conclusion, we found a differential microbiota and allergen profile between homes of allergic and non-allergic subjects., Trial Registration: NCT01174875 Registered 1 July 2010, retrospectively registered., Competing Interests: Ethics approval was obtained from the Domain Specific Review Board of Singapore National Healthcare Group and the Centralised Institutional Review Board of SingHealth. Conduct of this study was based on the guidelines in the Declaration of Helsinki. Informed consent was obtained from all participants.Not applicable.Chong YS has received reimbursement for speaking at conferences sponsored by Abbott Nutrition, Nestle, and Danone. Shek LP has received reimbursement for speaking at conferences sponsored by Danone and Nestle and consulting for Mead Johnson and Nestle. Chong YS is part of an academic consortium that has received research funding from Abbot Nutrition, Nestle and Danone. Shek LP has received research funding from Danone.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.