Engineered probiotic co‑expressing IL‑10 and Amuc_1100 modulates the gut‑brain axis to improve ASD‑like behaviors in BTBR mice
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In BTBR mice, four weeks of oral engineered E. coli Nissle expressing IL-10 and Amuc_1100 rescued sociability deficits and reduced repetitive grooming. Treatment also reduced intestinal inflammation, shifted gut microbiota and moved cortical microglia toward a homeostatic state.
Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by social deficits and repetitive behaviors, yet no pharmacotherapy targeting its core symptoms currently exists. Immune dysregulation and neuroinflammation are increasingly recognized as key contributors to ASD pathogenesis, with deficient anti-inflammatory cytokine interleukin-10 (IL-10) representing a potential therapeutic target. However, systemic IL-10 delivery is limited by short half-life, poor bioavailability, and off-target toxicity. Here, we developed an engineered Escherichia coli Nissle 1917 strain that constitutively co-expresses murine IL-10 and the Akkermansia muciniphila outer membrane protein Amuc_1100 for oral delivery, and evaluated its therapeutic efficacy in the BTBR mouse model of ASD. Daily oral administration of IL-10/Amuc_1100-engineered bacteria to BTBR mice for four weeks significantly rescued sociability deficits in the three-chamber test and attenuated repetitive grooming behaviors. Mechanistically, the treatment alleviated intestinal inflammation, as evidenced by improved villus architecture and reduced lipocalin-2 levels, and remodeled the gut microbiota by increasing beneficial genera such as Muribaculum and Prevotella while suppressing pro-inflammatory taxa. In the medial prefrontal cortex (mPFC), treatment downregulated the IL-17 signaling pathway and reduced expression of pro-inflammatory genes including Tnf and Il17e . Single-cell RNA sequencing of mPFC microglia revealed a shift from a disease-associated inflammatory state toward a homeostatic, neuroprotective phenotype, accompanied by reduced pathological synaptic pruning. Collectively, these findings provide proof-of-concept evidence that oral delivery of IL-10/Amuc_1100 via an engineered probiotic is sufficient to induce concurrent changes in peripheral inflammation, central IL-17 signaling, and microglial state, together with behavioral improvements in BTBR mice. While further studies are required to establish causal relationships and long-term safety, this approach warrants consideration as a potential oral therapeutic strategy for ASD.
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