Gut microbiota dysbiosis-induced neuroinflammation and IL-22/STAT3 activation in emotional disorders

Although gut microbiota dysbiosis is associated with emotional disorders, the signaling pathways that mediate gut-to-brain neuroinflammation remain unclear. This study employed a human microbiota-associated (HMA) mouse model colonized with microbiota from individuals with emotional abnormalities (HMA-EA), combined with functional oligosaccharides intervention experiments and a human intervention trial, to elucidate the mechanisms by which gut microbiota drives neuroinflammation. HMA-EA mice exhibited anxiety- and depression-like behaviors and a gut microbiota dysbiosis characterized by reduced abundance of immune and barrier-protective bacteria (including Turicibacter, Ligilactobacillus, and Lachnoclostridium), which compromised intestinal barrier integrity, compromised blood-brain barrier (BBB) integrity and induced neuroinflammation. Transcriptomic analysis combined with mechanistic validation suggested the IL-22/STAT3 pathway as a potential linkbetween gut microbiota and neuroinflammation. Functional oligosaccharides (chitooligosaccharides, mannan oligosaccharides, and fructo-oligosaccharides) ameliorated behavioral abnormalities, modulated immune and barrier-protective microbes, repaired intestinal barrier damage, and attenuated excessive activation of IL-22/STAT3 pathway, concurrently with attenuated neuroinflammation and preserved BBB integrity. A 12-week human intervention in a stress-exposed population provided preliminary evidence that functional oligosaccharides supplementation was associated withenrichment of microbeslinked to immune and barrier protection and attenuate activity of this pathway. Collectively, these findings reveal an association between gut microbiota, activation of the IL-22/STAT3 pathway, neuroinflammation, providing evidence to support microbiota-targeted interventions for mood disorders.