Multi-omics unveils strain-specific neuroactive metabolite production linked to inflammation modulation by Bacteroides and their extracellular vesicles
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 Parabacteroide...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | Current Research in Microbial Sciences |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666517425000203 |
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| author | Basit Yousuf Walid Mottawea Galal Ali Esmail Nazila Nazemof Nour Elhouda Bouhlel Emmanuel Njoku Yingxi Li Xu Zhang Zoran Minic Riadh Hammami |
| author_facet | Basit Yousuf Walid Mottawea Galal Ali Esmail Nazila Nazemof Nour Elhouda Bouhlel Emmanuel Njoku Yingxi Li Xu Zhang Zoran Minic Riadh Hammami |
| author_sort | Basit Yousuf |
| collection | DOAJ |
| description | 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 ΔgadB (GABA-) provided GABA-independent reinforcement of epithelial membrane integrity in LPS-treated Caco-2/HT29-MTX co-cultures. EVs from WT and ΔgadB attenuated inflammatory immune response of LPS-treated RAW264.7 macrophages, with reduced pro-inflammatory cytokines (IL-1β and IL-6), downregulation of TNF-α, and upregulation of IL-10 and TGF-β. 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. |
| format | Article |
| id | doaj-art-a72074dcc8734e60affccf3717b593ed |
| institution | Kabale University |
| issn | 2666-5174 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Microbial Sciences |
| spelling | doaj-art-a72074dcc8734e60affccf3717b593ed2025-02-12T05:32:51ZengElsevierCurrent Research in Microbial Sciences2666-51742025-01-018100358Multi-omics unveils strain-specific neuroactive metabolite production linked to inflammation modulation by Bacteroides and their extracellular vesiclesBasit Yousuf0Walid Mottawea1Galal Ali Esmail2Nazila Nazemof3Nour Elhouda Bouhlel4Emmanuel Njoku5Yingxi Li6Xu Zhang7Zoran Minic8Riadh Hammami9NuGut Research Platform, School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, CanadaNuGut Research Platform, School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada; Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, EgyptNuGut Research Platform, School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, CanadaNuGut Research Platform, School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, CanadaNuGut Research Platform, School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, CanadaNuGut Research Platform, School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, CanadaJohn L. Holmes Mass Spectrometry Facility, Faculty of Science, University of Ottawa, Ottawa, CanadaRegulatory Research Division, Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, CanadaJohn L. Holmes Mass Spectrometry Facility, Faculty of Science, University of Ottawa, Ottawa, CanadaNuGut Research Platform, School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Corresponding author.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 ΔgadB (GABA-) provided GABA-independent reinforcement of epithelial membrane integrity in LPS-treated Caco-2/HT29-MTX co-cultures. EVs from WT and ΔgadB attenuated inflammatory immune response of LPS-treated RAW264.7 macrophages, with reduced pro-inflammatory cytokines (IL-1β and IL-6), downregulation of TNF-α, and upregulation of IL-10 and TGF-β. 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.http://www.sciencedirect.com/science/article/pii/S2666517425000203BacteroidesNeuroactive metabolitesExtracellular vesiclesGABAImmunomodulationGut microbiome |
| spellingShingle | Basit Yousuf Walid Mottawea Galal Ali Esmail Nazila Nazemof Nour Elhouda Bouhlel Emmanuel Njoku Yingxi Li Xu Zhang Zoran Minic Riadh Hammami Multi-omics unveils strain-specific neuroactive metabolite production linked to inflammation modulation by Bacteroides and their extracellular vesicles Current Research in Microbial Sciences Bacteroides Neuroactive metabolites Extracellular vesicles GABA Immunomodulation Gut microbiome |
| title | Multi-omics unveils strain-specific neuroactive metabolite production linked to inflammation modulation by Bacteroides and their extracellular vesicles |
| title_full | Multi-omics unveils strain-specific neuroactive metabolite production linked to inflammation modulation by Bacteroides and their extracellular vesicles |
| title_fullStr | Multi-omics unveils strain-specific neuroactive metabolite production linked to inflammation modulation by Bacteroides and their extracellular vesicles |
| title_full_unstemmed | Multi-omics unveils strain-specific neuroactive metabolite production linked to inflammation modulation by Bacteroides and their extracellular vesicles |
| title_short | Multi-omics unveils strain-specific neuroactive metabolite production linked to inflammation modulation by Bacteroides and their extracellular vesicles |
| title_sort | multi omics unveils strain specific neuroactive metabolite production linked to inflammation modulation by bacteroides and their extracellular vesicles |
| topic | Bacteroides Neuroactive metabolites Extracellular vesicles GABA Immunomodulation Gut microbiome |
| url | http://www.sciencedirect.com/science/article/pii/S2666517425000203 |
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