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

Area of Science:

• Microbiology
• Neuroscience
• Biomaterials Science

Background:

• Current postpartum depression (PPD) treatments have limitations.
• The gut microbiome influences brain function via the gut-brain axis.
• Allopregnanolone is a neuroactive steroid with therapeutic potential for PPD.

Purpose of the Study:

• To develop an oral delivery system (EL@HRG) for sustained allopregnanolone production.
• To leverage the mechanism of *Eggerthella lenta* converting corticosterone to allopregnanolone using hydrogen.
• To establish a novel therapeutic strategy for PPD targeting the gut-brain axis.

Main Methods:

• Developed EL@HRG using calcium-cross-linked alginate/WPI emulsion nanogel particles.
• Incorporated sodium alginate, whey protein, corn oil, and l-arginine for controlled hydrogen release and bacterial support.
• Conducted in vitro and in vivo studies in a PPD mouse model, including behavioral tests and metabolomic analysis.

Main Results:

• EL@HRG demonstrated sustained hydrogen release and efficient encapsulation of viable *E. lenta*.
• In vivo studies showed enhanced *E. lenta* colonization, increased brain allopregnanolone levels, and reduced neuroinflammation.
• EL@HRG significantly improved depressive-like behaviors, anxiety, and maternal deficits in a PPD mouse model with no systemic toxicity.

Conclusions:

• EL@HRG offers a novel, nonpharmacological, long-acting, and safe therapeutic strategy for PPD.
• This work establishes a new paradigm for mechanism-guided delivery systems modulating the gut microenvironment.
• The study highlights the potential of precisely targeting gut bacteria for neurosteroid production to treat mood disorders.