Engineered P. distasonis-Derived Membrane Vesicles Ameliorate Gut-Liver Axis Disorders by Remodeling Intestinal Immunity and Bile Acid Homeostasis.

Abstract

The gut-liver axis is a central conduit through which intestinal immunity and metabolism regulate liver health. Although gut probiotics such as Parabacteroides distasonis (P. distasonis) and their postbiotics show promise for treating related disorders, safety and stability concerns and inconsistent efficacy limit their further application. Here, outer membrane vesicles (OMVs) derived from P. distasonis are engineered (termed POTA) for enhanced oral delivery. Specifically, biomineralization with tannic acid and encapsulation within calcium alginate microbeads boost their anti-inflammatory properties and enable targeted intestinal release. In mouse models of inflammatory bowel disease, POTA restores intestinal barrier integrity and suppresses inflammation by driving macrophage polarization from an M1 to M2 phenotype via fine-tuned STING signaling. Furthermore, POTA reprograms intestinal immune homeostasis, particularly by rebalancing regulatory T (Treg) and T helper 17 (Th17) cell populations. These changes are supported by a restored microbiota and elevated levels of immunomodulatory bile acids, including isoallolithocholic acid (isoalloLCA). Notably, this localized gut intervention elicits systemic benefits, alleviating hepatic steatosis, inflammation, and insulin resistance in metabolic liver disease. Collectively, engineered bacterial OMVs represent a safe and effective oral platform for ameliorating gut-liver axis disorders.