Phocaeicola vulgatus improves anxiety-like behavior by ameliorating amygdala neuroinflammation and the neurite impairment in IBS

Anxiety is highly comorbid with disorders of gut-brain interaction, including irritable bowel syndrome (IBS). The gut microbiota is implicated in both conditions, yet the underlying mechanisms remain unclear. This study aimed to elucidate the neuropathological basis of anxiety in diarrhea-predominant IBS (IBS-D) and identify potential microbiota-based therapeutic targets. Here, Mendelian randomization analysis established a bidirectional causal relationship between IBS and anxiety. In our clinical cohort, 35.85% of IBS-D patients presented with comorbid anxiety, and GAD-7 anxiety scores correlated significantly with IBS symptom severity. Resting-state functional magnetic resonance imaging (rs-fMRI) revealed that IBS-D patients with comorbid anxiety exhibited significantly altered regional homogeneity (ReHo) in nine brain regions, with the most pronounced reductions observed in the bilateral amygdala. Moreover, bilateral amygdala ReHo could effectively differentiate these patients, with receiver operating characteristic (ROC) analysis yielding area under curve (AUC) of 0.746. To investigate the underlying pathology, we established a water avoidance stress (WAS) mouse model that successfully recapitulated the anxiety-like behaviors and visceral hypersensitivity observed clinically. Critically, these phenotypes were transmissible, as recipient mice colonized with microbiota from the WAS-induced IBS-D group also developed visceral hypersensitivity and anxiety-like behaviors. Phocaeicola vulgatus was determined as a key bacterial strain significantly depleted in both our IBS-D patient cohort and the WAS-induced IBS-D mice, with its abundance negatively correlating with anxiety levels. As anticipated, IBS-D patients with lower abundance of P. vulgatus exhibited reduced amygdala ReHo and Mendelian randomization analysis identified P. vulgatus as a protective factor against anxiety. Correspondingly, therapeutic supplementation with P. vulgatus ameliorated anxiety-like behaviors in WAS-induced IBS-D mice by attenuating neuroinflammation and restoring neuronal morphology in the amygdala. In conclusion, this study provides the first evidence that P. vulgatus can alleviate anxiety in IBS by targeting amygdala-centered neuropathology, presenting a novel psychobiotic strategy for treating emotional comorbidities in disorders of gut-brain interaction.