Gut-to-brain Neuromodulation by Synthetic Butyrate-Producing Commensal Bacteria

Previous studies have revealed the existence of gut epithelial-neuronal synapses and an array of neuroactive bacterial metabolites, highlighting the potential of gut chemicals in stimulating gut-to-brain neurotransmission. However, bacterial metabolite-focused studies in murine models frequently apply systemic administration of the chemicals, and the illustrated gut-to-brain signals are generally through humoral pathways, probably distinct from the physiological working mechanism, since many bacterial metabolites could not cross the blood-brain barrier in primates. Limited by delivery approach, research on gut-to-brain neurotransmission pathway regulated by gut bacterial metabolites is sparse. To address this challenge, engineered commensal bacteria were harnessed for gut delivery of bacterial metabolites with physiological biogeography. In murine model of depression, the synthetic butyrate-overproducing Escherichia coli Nissle 1917 (EcN) significantly attenuates depressive-like syndromes. The aberrantly activated paraventricular thalamus (PVT) is modulated by gut butyrate via a gut-to-brain neurotransmission route, which is illuminated for the first time. We provide a paradigm for dissecting gut-to-brain neurotransmission pathways regulated by gut bacterial metabolites, and point out a new avenue for non-invasive gut-to-brain neuromodulation by oral administration of metabolically engineered commensal bacteria, without the dependence on external devices or surgery.