Alternating magnetic field-responsive engineered probiotics for anxiety therapy via gut-brain axis modulation

The discovery of the gut-brain axis demonstrated bidirectional regulation between the gut and the brain. The gastrointestinal branches of the vagal nerve have been proven to directly modulate multiple functions of the central nervous system (CNS), providing great opportunities to develop novel tools to remotely regulate CNS function from the gut. Engineered bacteria, acting as oral live biotherapeutics, offer a durable and controllable way of modulating neuronal function non-invasively and with low side effects. Here, we constructed an engineered bacterium by genetically modifying Escherichia coli Nissle 1917 (EcN) with Fe₃O₄ nanoparticles to release gamma-aminobutyric acid (GABA) under the control of the alternating magnetic fields (AMF). Bioavailability, assessed by survival rate in artificial gastric fluid, was further enhanced by encapsulating EcN with a poly-norepinephrine (NE) layer, which protected the probiotics from environmental stress and improved their viability during oral delivery. The oral administration of the EcN-GadABC@Fe-NE/AMF in restraint mice exhibited significant anxiolytic efficacy, which was attenuated by the chemogenetic counteraction of vagal sensory inhibition. Immunohistochemistry staining against c-fos showed reduced neuronal activation in both the nucleus of the solitary tract (NTS) and locus coeruleus (LC) area in the restraint mice treated by the EcN-GadABC@Fe-NE/AMF. Furthermore, acting as a probiotic, the EcN-GadABC@Fe-NE modulated gut microbiota homeostasis, additionally contributing to the alleviation of anxiety-like behaviors. This approach opens up a novel revenue for developing remote and non-invasive methods to modulate CNS function from the gut, and enhancing bacteriotherapy for mental disorders.