A Mechanism-Guided Delivery System for Long-Acting Postpartum Depression Therapy via Hydrogen-Facilitated Gut Microbiota Reprogramming

To address the limitations of current pharmacotherapies for postpartum depression (PPD), this study developed an innovative oral delivery system (EL@HRG) based on calcium-cross-linked alginate/WPI emulsion nanogel particles, leveraging the mechanism reported in Cell where in hydrogen (H 2 ) drives the gut commensal bacterium Eggerthella lenta to convert host corticosterone into the neuroactive steroid allopregnanolone. The core innovation of this work lies in the of a controlled hydrogen-release carrier with a probiotic delivery platform into a unified system. Using a scaffold of sodium alginate and whey protein integrated with corn oil to form an emulsion, we leveraged the higher solubility of H 2 in the oil phase to overcome the key bottleneck of maintaining effective intestinal hydrogen concentration after oral administration. Concurrently, l -arginine, an essential nutrient for E. lenta growth, was incorporated into the gel network, achieving an integrated “delivery-colonization-activation” function. In vitro experiments confirmed that EL@HRG provided sustained hydrogen release and efficiently encapsulated viable bacteria. In vivo studies demonstrated that EL@HRG significantly enhanced the intestinal colonization and retention of E. lenta, leading to sustained activation of the steroid conversion pathway and elevated levels of allopregnanolone in the brain. In a PPD mouse model, EL@HRG, acting via the gut-brain axis, inhibited hippocampal neuroinflammation, restored synaptic plasticity and GABAergic signaling, and consequently markedly improved depressive-like behaviors, anxiety, and maternal behavior deficits. Its therapeutic efficacy showed enhanced sustainability compared to the short-term effects of injected allopregnanolone, with no observed systemic toxicity. Metabolomic analysis further revealed a reshaping of the “steroid hormone biosynthesis” pathway, underpinning the therapeutic effect. In conclusion, this study provides a novel, nonpharmacological, long-acting, and safe interventional strategy for PPD. It also establishes a new paradigm of mechanism-guided delivery systems for precisely modulating the gut microenvironment to achieve specific physiological functions.