Serotonergic and immunomodulatory properties of the psychobiotic candidate Bacteroides finegoldii UO.H1052 and its extracellular vesicles.

Bacteroides finegoldii UO.H1052, a human gut commensal, was evaluated for its potential psychobiotic and immunomodulatory properties. Whole-genome analysis confirmed the absence of virulence factors, plasmids, and antibiotic-resistance genes. Metabolomic profiling of cell-free supernatants (CFSs) and extracellular vesicle (EV) postbiotics revealed a high- and medium-dependent production of neuroactive metabolites, including γ-aminobutyric acid, tryptophan, tyrosine, and tyramine, as well as physiologically relevant levels of short-chain fatty acids, such as acetate, propionate, and butyrate. Functionally, CFS enhanced epithelial barrier integrity by increasing transepithelial electrical resistance and mitigating LPS-induced disruption in Caco2/HT29 monolayers without cytotoxic effects. Both CFS and EVs exhibited immunomodulatory properties, characterized by elevated Il-10/Tnf-α ratios under basal conditions and significant suppression of Tnf-α expression in LPS-stimulated RAW 264.7 macrophages. Notably, CFS and EVs increased tryptophan hydroxylase 1 (Tph1) gene expression in enterochromaffin RIN14B cells by 6.6- and 3.2-fold, respectively, suggesting enhanced serotonergic activity. These findings highlight B. finegoldii UO.H1052 as a promising next-generation psychobiotic candidate with neuroactive, barrier-protective, and immunoregulatory properties, supporting its potential for gut-brain axis modulation.

Importance: Emerging evidence supports the critical role of the gut microbiota in modulating host neurophysiology and immune function via the gut-brain axis. Here, we present a comprehensive characterization of Bacteroides finegoldii UO.H1052, a human gut commensal that exhibits promising psychobiotic attributes, including the production of neuroactive compounds and extracellular vesicles (EVs) with immunoregulatory and serotonin-inducing properties. The strain exhibits a favorable safety profile, with no detected virulence factors or transmissible antibiotic resistance. Importantly, cell-free supernatants and EVs enhanced epithelial barrier integrity, modulated pro- and anti-inflammatory cytokine responses, and significantly upregulated the expression of Tph1, a key enzyme in serotonin biosynthesis. These findings underscore the potential of B. finegoldii UO.H1052 as a next-generation psychobiotic candidate and highlight EVs as effective postbiotic mediators of host-microbe communication. This study advances the understanding of Bacteroides-derived psychobiotics and provides a foundation for their development in modulating gut-brain and immune pathways relevant to neuroinflammatory and gastrointestinal disorders.