Involvement of the gut-brain axis in vascular depression via tryptophan metabolism: A benefit of short chain fatty acids

Cerebral hemodynamic dysfunction and hypoperfusion have been found to underlie vascular depression, but whether the gut-brain axis is involved remains unknown. In this study, a rat model of bilateral common carotid artery occlusion (BCCAO) was adopted to mimic chronic cerebral hypoperfusion. A reduced sucrose preference ratio, increased immobility time in the tail suspension test and forced swim test, and compromised gut homeostasis were found. A promoted conversion of tryptophan (Trp) into kynurenine (Kyn) instead of 5-hydroxytryptamine (5-HT) was observed in the hippocampus and gut of BCCAO rats. Meanwhile, 16S ribosomal RNA gene sequencing suggested a compromised profile of the gut SCFA-producing microbiome, with a decreased serum level of SCFAs revealed by targeted metabolomics analysis. With SCFA supplementation, BCCAO rats exhibited ameliorated depressive-like behaviors and improved gut dysbiosis, compared with the salt-matched BCCAO group. Enzyme-linked immunosorbent assays and quantitative RT-PCR suggested that SCFA supplementation suppressed the conversion of Trp to Kyn and rescued the reduction in 5-HT levels in the hippocampus and gut. In addition to inhibiting the upregulation of inflammatory cytokines, SCFA supplementation ameliorated the activated oxidative stress and reduced the number of microglia and the expression of its proinflammatory markers in the hippocampus post BCCAO. In conclusion, our data suggested the participation of the gut-brain axis in vascular depression, shedding light on the neuroprotective potential of treatment with gut-derived SCFAs.