Environmental and genetic associations with aberrant early-life gut microbial maturation in childhood asthma

Chen, Yih‐Chieh; Chen, Yulu; Lasky‐Su, Jessica; Kelly, Rachel S.; Stokholm, Jakob; Bisgaard, Hans; Bønnelykke, Klaus; Pedersen, Casper-Emil Tingskov; Chawes, Bo; Laranjo, Nancy; Weiss, Scott T.; Litonjua, Augusto A.; Lee-Sarwar, Kathleen

doi:10.1016/j.jaci.2023.01.006

Cited by 11 publications

(6 citation statements)

References 53 publications

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“…The composition of the gut microbiome matures in the first few years of life and immature gut microbial composition in the first year of early life has been associated with an increased risk of asthma, 16 with evidence suggesting that this increased risk is cumulative with 17q21 risk alleles. 42 Similar to ORMDL3 risk variants, we found that the immature microbiome at age 1 year was associated with increases in ceramide(d18:1/26:1) and sphingosine(d16:1, d18:2) levels at age 6 years based on meta-analysis. Furthermore, we observed that ceramide(d18:1/26:1) had a strong negative average causal mediation effect between MMAT and lung function measures in VDAART with capturing a large portion of the effect, indicating that the link between MMAT and asthma may be partially due to changes in specific ceramide level.…”

Section: Metabolitesupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors

Chen,

Checa,

Zhang

et al. 2023

Allergy

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BackgroundWhile dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship.MethodsWe performed targeted LC–MS/MS‐based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta‐analyzed together.ResultsWe observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p‐value range: 1.863E‐04 to 2.24E‐3], increased ceramide levels were associated with asthma risk factors [meta p‐value range: 7.75E‐5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes.ConclusionThis study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.

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Section: Metabolitesupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors

Chen,

Checa,

Zhang

et al. 2023

Allergy

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“…These polymorphisms were found to be mbQTLs related to S treptococcus, Tannerella , and Campylobacter in the upper airway ( Perez-Garcia et al, 2020 ). Nevertheless, as proposed by Chen et al, it is suggested that risk variants on 17q12-21 and perturbations in the maturation of intestinal microbiota associate independently and exhibit additive effects on the risk of asthma development ( Chen et al, 2023 ). Therefore, more studies are needed to define the role of host genetics in microbial diversity and asthma.…”

Section: Microbiome and Asthma: The Importance Of The Beginningmentioning

confidence: 99%

Winds of change a tale of: asthma and microbiome

Galeana-Cadena,

Gómez-García,

Lopez-Salinas

et al. 2023

Front. Microbiol.

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The role of the microbiome in asthma is highlighted, considering its influence on immune responses and its connection to alterations in asthmatic patients. In this context, we review the variables influencing asthma phenotypes from a microbiome perspective and provide insights into the microbiome’s role in asthma pathogenesis. Previous cohort studies in patients with asthma have shown that the presence of genera such as Bifidobacterium, Lactobacillus, Faecalibacterium, and Bacteroides in the gut microbiome has been associated with protection against the disease. While, the presence of other genera such as Haemophilus, Streptococcus, Staphylococcus, and Moraxella in the respiratory microbiome has been implicated in asthma pathogenesis, indicating a potential link between microbial dysbiosis and the development of asthma. Furthermore, respiratory infections have been demonstrated to impact the composition of the upper respiratory tract microbiota, increasing susceptibility to bacterial diseases and potentially triggering asthma exacerbations. By understanding the interplay between the microbiome and asthma, valuable insights into disease mechanisms can be gained, potentially leading to the development of novel therapeutic approaches.

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“…The etiology of asthma is complex and likely involves a variety of genetic, environmental, infectious, and nutritional factors [ 5 ]. Some environmental factors that may contribute to the onset and exacerbation of asthma include allergens, viral infections, tobacco smoke exposure, and air pollution [ 6 ]. The development of asthma may also be related to individual susceptibility.…”

Section: Introductionmentioning

confidence: 99%

Causal associations between gut microbiota, metabolites and asthma: a two-sample Mendelian randomization study

Li,

Zhang,

Tang

et al. 2024

BMC Pulm Med

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Background While several traditional observational studies have suggested associations between gut microbiota and asthma, these studies are limited by factors such as participant selection bias, confounders, and reverse causality. Therefore, the causal relationship between gut microbiota and asthma remains uncertain. Methods We performed two-sample bi-directional Mendelian randomization (MR) analysis to investigate the potential causal relationships between gut microbiota and asthma as well as its phenotypes. We also conducted MR analysis to evaluate the causal effect of gut metabolites on asthma. Genetic variants for gut microbiota were obtained from the MiBioGen consortium, GWAS summary statistics for metabolites from the TwinsUK study and KORA study, and GWAS summary statistics for asthma from the FinnGen consortium. The causal associations between gut microbiota, gut metabolites and asthma were examined using inverse variance weighted, maximum likelihood, MR-Egger, weighted median, and weighted model and further validated by MR-Egger intercept test, Cochran’s Q test, and “leave-one-out” sensitivity analysis. Results We identified nine gut microbes whose genetically predicted relative abundance causally impacted asthma risk. After FDR correction, significant causal relationships were observed for two of these microbes, namely the class Bacilli (OR = 0.84, 95%CI = 0.76–0.94, p = 1.98 × 10−3) and the order Lactobacillales (OR = 0.83, 95%CI = 0.74–0.94, p = 1.92 × 10−3). Additionally, in a reverse MR analysis, we observed a causal effect of genetically predicted asthma risk on the abundance of nine gut microbes, but these associations were no longer significant after FDR correction. No significant causal effect of gut metabolites was found on asthma. Conclusions Our study provides insights into the development mechanism of microbiota-mediated asthma, as well as into the prevention and treatment of asthma through targeting specific gut microbiota.

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Environmental and genetic associations with aberrant early-life gut microbial maturation in childhood asthma

Cited by 11 publications

References 53 publications

Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors

Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors

Winds of change a tale of: asthma and microbiome

Causal associations between gut microbiota, metabolites and asthma: a two-sample Mendelian randomization study

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