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Integrated metabolic and microbial analysis reveals host-microbial interactions in IgE-mediated childhood asthma.

ABSTRACT: A metabolomics-based approach to address the molecular mechanism of childhood asthma with immunoglobulin E (IgE) or allergen sensitization related to microbiome in the airways remains lacking. Fifty-three children with lowly sensitized non-atopic asthma (n = 15), highly sensitized atopic asthma (n = 13), and healthy controls (n = 25) were enrolled. Blood metabolomic analysis with ¹H-nuclear magnetic resonance (NMR) spectroscopy and airway microbiome composition analysis by bacterial 16S rRNA sequencing were performed. An integrative analysis of their associations with allergen-specific IgE levels for lowly and highly sensitized asthma was also assessed. Four metabolites including tyrosine, isovalerate, glycine, and histidine were uniquely associated with lowly sensitized asthma, whereas one metabolite, acetic acid, was strongly associated with highly sensitized asthma. Metabolites associated with highly sensitized asthma (valine, isobutyric acid, and acetic acid) and lowly sensitized asthma (isovalerate, tyrosine, and histidine) were strongly correlated each other (P < 0.01). Highly sensitized asthma associated metabolites were mainly enriched in pyruvate and acetyl-CoA metabolisms. Metabolites associated with highly sensitized atopic asthma were mostly correlated with microbiota in the airways. Acetic acid, a short-chain fatty acid (SCFA), was negatively correlated with the genus Atopobium (P < 0.01), but positively correlated with the genus Fusobacterium (P < 0.05). In conclusion, metabolomics reveals microbes-related metabolic pathways associated with IgE responses to house dust mite allergens in childhood asthma. A strong correlation of metabolites related to highly sensitized atopic asthma with airway microbiota provides linkages between the host-microbial interactions and asthma endotypes.

SUBMITTER: Chiu CY

PROVIDER: S-EPMC8642522 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:pH and fermentable substrates impose selective pressures on gut microbial communities and their metabolisms. We evaluated the relative contributions of pH, alkalinity, and substrate on microbial community structure, metabolism, and functional interactions using triplicate batch cultures started from fecal slurry and incubated with an initial pH of 6.0, 6.5, or 6.9 and 10 mM glucose, fructose, or cellobiose as the carbon substrate. We analyzed 16S rRNA gene sequences and fermentation products. Microbial diversity was driven by both pH and substrate type. Due to insufficient alkalinity, a drop in pH from 6.0 to ~4.5 clustered pH 6.0 cultures together and distant from pH 6.5 and 6.9 cultures, which experienced only small pH drops. Cellobiose yielded more acidity than alkalinity due to the amount of fermentable carbon, which moved cellobiose pH 6.5 cultures away from other pH 6.5 cultures. The impact of pH on microbial community structure was reflected by fermentative metabolism. Lactate accumulation occurred in pH 6.0 cultures, whereas propionate and acetate accumulations were observed in pH 6.5 and 6.9 cultures and independently from the type of substrate provided. Finally, pH had an impact on the interactions between lactate-producing and -consuming communities. Lactate-producing Streptococcus dominated pH 6.0 cultures, and acetate- and propionate-producing Veillonella, Bacteroides, and Escherichia dominated the cultures started at pH 6.5 and 6.9. Acid inhibition on lactate-consuming species led to lactate accumulation. Our results provide insights into pH-derived changes in fermenting microbiota and metabolisms in the human gut. IMPORTANCE The human gut is a dynamic environment in which microorganisms consistently interact with the host via their metabolic products. Some of the most important microbial metabolic products are fermentation products such as short-chain fatty acids. Production of these fermentation products and the prevalence of fermenting microbiota depend on pH, alkalinity, and available dietary sugars, but details about their metabolic interactions are unknown. Here, we show that, for in vitro conditions, pH was the strongest driver of microbial community structure and function and microbial and metabolic interactions among pH-sensitive fermentative species. The balance between bicarbonate alkalinity and formation of fatty acids by fermentation determined the pH, which controlled microbial community structure. Our results underscore the influence of pH balance on microbial function in diverse microbial ecosystems such as the human gut.

Project description:What is already known about this subjectOmalizumab is a humanized anti-IgE monoclonal antibody that binds and captures circulating IgE, preventing interaction with receptors on mast cells and basophils, thereby interrupting the allergic cascade. It has a well-characterized efficacy and safety profile in patients with asthma. While omalizumab is known to reduce serum free IgE concentrations, effects on total IgE and IgE production are less well characterized.What this study adds(i) Confirmation of prior hypotheses that IgE production can decrease with time when patients are given anti-IgE therapy; (ii) guidance on a biomarker, total IgE, which can be used to ascertain whether individual patients experience a change in their IgE production; and (iii) a way to assess whether patients' IgE production has been sufficiently down-regulated such that they may consider stopping anti-IgE therapy.AimTo determine whether excessive IgE production by patients with atopic allergic asthma decreases with omalizumab therapy.MethodsOmalizumab, free and total IgE data were obtained from an epidemiological study and six randomized, double-blind, placebo-controlled trials in patients with allergic asthma. The binding between omalizumab and IgE together with the production and elimination of IgE were modelled as previously, except that, in order to explain why total IgE was decreasing over a period of 5 years, the expression of IgE was allowed to change.ResultsThe prior constant IgE production model failed to converge on the data once long-term observations were included, whereas models allowing IgE production to decrease fitted. A feedback model indicated that, on average, IgE production decreased by 54% per year. This model was further developed with covariate searches indicating clinically small but statistically significant effects of age, gender, body mass index and race on some parameters. Model predictions were checked internally and externally against 3-5 year data from paediatric and adult atopic asthmatic patients and externally against extensive total IgE data from a long-duration (>1 year) phase 1 study which was not used in the model building.ConclusionsA pharmacokinetic-pharmacodynamic model incorporating omalizumab-IgE binding and feedback for control of IgE production indicates that omalizumab reduces production of IgE. This raises the possibility that indefinite treatment may not be required, only for perhaps a few years. After the initial accumulation, total IgE should provide a means to monitor IgE production and guide individual treatment decisions.

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Integrated metabolic and microbial analysis reveals host-microbial interactions in IgE-mediated childhood asthma.

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