Multi-omics unveils strain-specific neuroactive metabolite production linked to inflammation modulation by Bacteroides and their extracellular vesicles

被引：0

作者：

Yousuf, Basit ^{[1
]}

Mottawea, Walid ^{[1
,2
]}

Esmail, Galal Ali ^{[1
]}

Nazemof, Nazila ^{[1
]}

Bouhlel, Nour Elhouda ^{[1
]}

Njoku, Emmanuel ^{[1
]}

Li, Yingxi ^{[3
]}

Zhang, Xu ^{[4
]}

Minic, Zoran ^{[3
]}

Hammami, Riadh ^{[1
,5
]}

机构：

[1] Univ Ottawa, Fac Hlth Sci, Sch Nutr Sci, NuGut Res Platform, Ottawa, ON K1N 6N5, Canada

[2] Mansoura Univ, Fac Pharm, Dept Microbiol & Immunol, Mansoura 35516, Egypt

[3] Univ Ottawa, Fac Sci, John L Holmes Mass Spectrometry Facil, Ottawa, ON, Canada

[4] Hlth Canada, Ctr Oncol Radiopharmaceut & Res, Biol & Radiopharmaceut Drugs Directorate, Regulatory Res Div,Hlth Prod & Food Branch, Ottawa, ON, Canada

[5] Univ Ottawa, Fac Med, Dept Biochem Microbiol & Immunol, Ottawa, ON K1H 8M5, Canada

来源：

CURRENT RESEARCH IN MICROBIAL SCIENCES | 2025年 / 8卷

基金：

加拿大自然科学与工程研究理事会;

关键词：

Bacteroides; Neuroactive metabolites; Extracellular vesicles; GABA; Immunomodulation; Gut microbiome; Multi-omics; GUT MICROBIOTA; TIME; GABA;

D O I：

10.1016/j.crmicr.2025.100358

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Bacteroides species are key members of the human gut microbiome and play crucial roles in gut ecology, metabolism, and host-microbe interactions. This study investigated the strain-specific production of neuroactive metabolites by 18 Bacteroidetes (12 Bacteroides, 4 Phocaeicola, and 2 Parabacteroides) using multi-omics approaches. Genomic analysis revealed a significant potential for producing GABA, tryptophan, tyrosine, and histidine metabolism-linked neuroactive compounds. Using untargeted and targeted metabolomics, we identified key neurotransmitter-related or precursor metabolites, including GABA, L-tryptophan, 5-HTP, normelatonin, kynurenic acid, L-tyrosine, and norepinephrine, in a strain- and media-specific manner, with GABA (1-2 mM) being the most abundant. Additionally, extracellular vesicles (EVs) produced by Bacteroides harbor multiple neuroactive metabolites, mainly GABA, and related key enzymes. We used CRISPR/Cas12a-based gene engineering to create a knockout mutant lacking the glutamate decarboxylase gene (gadB) to demonstrate the specific contribution of Bacteroides finegoldii-derived GABA in modulating intestinal homeostasis. Cell-free supernatants from wild-type (WT, GABA+) and Delta gadB (GABA-) provided GABA-independent reinforcement of epithelial membrane integrity in LPS-treated Caco-2/HT29-MTX co-cultures. EVs from WT and Delta gadB attenuated inflammatory immune response of LPS-treated RAW264.7 macrophages, with reduced pro-inflammatory cytokines (IL-1 beta and IL-6), downregulation of TNF-alpha, and upregulation of IL-10 and TGF-beta. GABA production by B. finegoldii had a limited impact on gut barrier integrity but a significant role in modulating inflammation. This study is the first to demonstrate the presence of a myriad of neuroactive metabolites produced by Bacteroides species in a strain- and media-specific manner in supernatant and EVs, with GABA being the most dominant metabolite and influencing immune responses.

引用

页数：11

共 2 条

[1] Multi-Omics Reveal Rhinovirus Strain-Specific Metabolic Signatures in Highly Differentiated Human Airway Epithelial Cells
Michi, A. N.
Yipp, B.
Dufour, A.
Lopes, F.
Proud, D.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2021, 203 (09)
[2] Multi-omics data indicate that primary and lymph node oral cancer cells-derived extracellular vesicles carry cargo molecules with a specific aggressive pattern
Busso-Lopes, Ariane F.
Carnielli, Carolina M.
Winck, Flavia
Riano-Pachon, Diego M.
Oliveira, Ana K.
Costa, Rute A.
Rivera, Cesar
Caldana, Camila
Fox, Jay W.
Paes Leme, Adriana F.
CANCER RESEARCH, 2018, 78 (13)

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