2025/01/01 by Basit Yousuf, Walid Mottawea, Galal Ali Esmail +7 · 1 voice
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Gut microbiota and health #Lipid Membrane Structure and Behavior #Neuroinflammation and Neurodegeneration Mechanisms
paper · doi:10.1016/j.crmicr.2025.100358
openalex publication_date 2025/01/01 · openalex created_date 2025/02/06 · openalex updated_date 2026/07/22
• Bacteroides species produce a myriad of neurotransmitter-related metabolites. • Bacteroides signaling via EVs may modulate the gut-brain axis and immune responses. • B. finegoldii shows anti-inflammatory characteristics via GABA and EV production. • Bacteroides and their EVs hold great promise as next-generation psychobiotics. 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 Δ gadB (GABA-) provided GABA-independent reinforcement of epithelial membrane integrity in LPS-treated Caco-2/HT29-MTX co-cultures. EVs from WT and Δ gadB 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.