A light-responsive engineered probiotic system to alleviate anxiety via gut-brain axis.

Abstract

Anxiety disorders are highly prevalent worldwide, yet effective treatment strategies remain limited. Overactive gut-brain communication has been linked to anxiety-like behaviors, and modulation of this signaling offers a promising approach for anxiety reduction. Leveraging the controllable release and biocompatibility of engineered bacteria, we developed a near-infrared (NIR)-responsive probiotic system that releases gamma-aminobutyric acid (GABA) to directly modulate gut vagal sensory input, thereby alleviating anxiety-like behavior. The system was constructed using Escherichia coli Nissle 1917 (EcN) carrying a thermosensitive GABA synthesis plasmid (EcN-Gadabc), coated with polydopamine (pDA), and further conjugated with a pepT1 targeting peptide for small-intestinal targeting. This design enabled precise NIR-triggered GABA release in the gut, improved bacterial survival under simulated gastrointestinal conditions, and enhanced intestinal retention following oral administration. In mice subjected to repeated restraint stress, treatment with the engineered bacteria under NIR irradiation alleviated anxiety-like behaviors, remodeled the gut microbiota, reduced the relative abundance of Clostridium, decreased serum IL-1β, IL-6 and TNF-α, increased IL-10, and reduced c-fos-positive neurons in the amygdala, nucleus tractus solitarius, and locus coeruleus. Transcriptomic analysis further indicated alterations in pathways associated with neuronal excitability, ion channel activity and calcium signaling. These findings support a non-invasive and remotely controllable strategy for gut-brain axis modulation using engineered probiotics and highlight its potential for precision bacteriotherapy in anxiety-related disorders.