The Multiomics Analyses of Gut Microbiota, Urine Metabolome and Plasma Proteome Revealed Significant Changes in Allergy Featured with Indole Derivatives of Tryptophan

Abstract

Objective To explore changes in the gut microbiota (GM), urine metabolome and plasma proteome in individuals with allergies using multiomics analyses, and identify the key components and mechanism. Methods This was a cross-sectional study. All subjects were recruited to collect fecal, urine and blood samples. 16S rDNA sequencing was used to analyze the structure and function of the GM, liquid chromatography mass spectrometry was used to quantify metabolites in the urine, and data-independent acquisition quantitative proteome analysis was used to detect proteins in the plasma. Differences in GM, urine metabolites and plasma proteins between allergic and healthy individuals were displayed using principal component analysis (PCoA) and heatmap, and the co-occurrence network was visualized in Cytoscape using Spearman correlation among differential predominant genera, metabolites and proteins. The functional analysis was performed according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) dataset. The allergy-related cytokines, IL-4, IL-6 and IL-13, were measured to evaluate the effect of indole derivatives on LPS-induced macrophage activation. Results GM α indexes, β distances and the relative abundance of the core differential genera in the allergic group were different from those of healthy individuals, which resulted in a separate distribution in the PCoA and enterotypes. Similarly, the concentrations of 393 metabolites and 144 proteins were different between allergic and healthy individuals. Then, 634 significant correlations were identified among 6 predominant differential genera, 24 differential metabolites and 104 differential proteins, 301 of which were negative and 333 of which were positive. Notably, a core network centered on tryptophan metabolites, indole-3-butyric acid (IBA) and indole-3-lactic acid (ILA), displayed high consistency with the results of KEGG pathway analysis. In the LPS-stimulated macrophages, IBA reduced the expression of IL-4 and IL-6, and ILA inhibited the upregulation of IL-6. Conclusion The GM, urine metabolome and plasma proteome underwent systematic change in allergic individuals compared to healthy individuals, among which indole derivatives from tryptophan metabolism might play key roles in the progression of allergies and could serve as therapeutic targets of allergy.

Effects of Indole-3-Lactic Acid, a Metabolite of Tryptophan, on IL-4 and IL-13-Induced Human Skin-Equivalent Atopic Dermatitis Models

“…Our results of the reduced TSLP expression and the alleviation of AD after 7 days of the treatment are consistent with the previous reports of locally applied inole-derivatives which partially alleviated the skin inflammation and inhibited the TSLP formation in keratinocytes [ 29 ]. In previous reports, when macrophages that are differentiated from THP-1 cell lines were stimulated with LPS, IBA significantly inhibited the LPS-induced upregulation of IL-4 and IL-6 mRNA, and I3LA inhibited the expression of IL-6 mRNA [ 26 ]. Our results also showed that I3LA suppresses the IL-6 mRNA expression.…”

“…I3LA was effective in regulating the STAT1 signaling pathway [ 31 ]. In a previous study, the macrophages that were differentiated from THP-1 cell lines were stimulated with lipopolysaccharide (LPS) to confirm the effect of an indole derivative on the expression of IL-4, IL-6, and IL-13, which validated that indole-3-butyric acid (IBA) and I3LA play a role in allergic pathogenesis [ 26 ].…”

“…Indole and indole derivatives are essential amino acid Trp metabolites that influence the host’s physiology via several molecular mechanisms [ 24 , 25 ]. Indole-3-lactic acid (I3LA) is a metabolite of Trp, and indole derivatives participate in the differentiation of immune cells and the synthesis of cytokines via the aryl hydrocarbon receptors (AhR) to regulate the immune responses and participate in anti-inflammatory and allergic reactions [ 26 , 27 ]. AhR is involved in skin homeostasis in both physiological and pathological conditions [ 28 ].…”

Bacterial Metabolites: A Link between Gut Microbiota and Dermatological Diseases

“…Additionally, hypersensitivity reactions are associated with specific Trp metabolite alteration. Allergic subjects have decreased levels of indole-3-butyric and indole-3-lactic acids [ 103 ]. Additionally, new reports show that direct administration of some Trp metabolites can be useful in the management of delayed-type hypersensitivity [ 104 ].…”

Identification of thrombotic biomarkers in orthopedic surgery patients by plasma proteomics

“…Proteomic technology is an efficient tool for identifying potential biomarkers associated with pathological states [ 19 , 20 ]. With the rapid development of mass spectrometry (MS), proteomics can be used to accurately profile global proteomic alterations in various cells, tissues and body fluids.…”