Evaluating the therapeutic potential of genetically engineered probiotic Zbiotics (ZB183) for non-alcoholic steatohepatitis (NASH) management via modulation of the cGAS-STING pathway†

Abstract

NAFLD/NASH has emerged as a global health concern with no FDA-approved treatment, necessitating the exploration of novel therapeutic elements for NASH. Probiotics are known as an important adjunct therapy in NASH. Zbiotics (ZB183) is the first commercially available genetically engineered probiotic. Herein, we aimed to evaluate the potential therapeutic effects of Zbiotics administration on NASH management by modulating the cGAS-STING-signaling pathway-related RNA network. In silico data analysis was performed and three DEGs (MAPK3/EDN1/TNF) were selected with their epigenetic modulators (miR-6888-5p miRNA, and lncRNA RABGAP1L-DT-206). The experimental design included NASH induction with an HSHF diet in Wistar rats and Zbiotics administration in NASH rats in comparison to statin treatment. Liver functions and lipid profile were assessed. Additionally, the expression levels of the constructed molecular network were assessed using RT-PCR. Moreover, the Zbiotics effects in NASH were further validated with histopathological examination of liver and colon samples. Also, immunohistochemistry staining of hepatic TNF-α and colonic occludin was assessed. Oral administration of Zbiotics for four weeks downregulated the expression of the cGAS-STING-related network (MAPK3/EDN1/TNF/miR-6888-5p miRNA/lncRNA RABGAP1L-DT-206) in NASH models. Zbiotics also ameliorated hepatic inflammation and steatosis, as evidenced by a notable improvement in NAS score and decreased hepatic TNF-α levels. Furthermore, Zbiotics exhibited favorable effects on colon health, including increased crypt length, reduced inflammatory cell infiltration, and restoration of colonic mucosa occludin expression. In conclusion, our findings suggest that Zbiotics has potential therapeutic effects on NASH via modulating the gut–liver axis and the cGAS-STING signaling pathway.