Investigating the role of baseline gut Akkermansia muciniphila and its co-metabolite palmitoleic acid in BCG vaccine efficacy: a preclinical study.

Abstract

Bacillus Calmette-Guérin (BCG) is the only vaccine for tuberculosis (TB) and remains the most effective means of prevention; however, its effectiveness in humans is highly variable with unknown mechanism. Using microbiota transplantation and multi-omics strategies (16S rRNA sequencing, metabolomics, proteomics) in mouse models, we investigated the effect of pre-vaccination gut microbiota composition on BCG vaccine efficacy. Furthermore, key findings were validated in human datasets. Baseline abundance of gut microbiota, especially Akkermansia muciniphila, significantly affects BCG vaccine efficacy. Increasing the baseline levels of A. muciniphila in the gut before vaccination reduced the BCG vaccine responses, resulting in impaired protection against Mycobacterium tuberculosis (Mtb) infection in mice. A. muciniphila-contributed gut co-metabolite palmitoleic acid inhibits the vaccine responses of BCG. Palmitoleic acid acts on vaccine response through the mediation of effector protein MptpB of BCG and identified that MptpB-mediated inhibition of actin cytoskeleton remodelling to activate BCG vaccine responses is required for palmitoleic acid to regulate the efficacy of BCG vaccination. Inhibition of MptpB or actin cytoskeleton remodelling blocks the effects of higher baseline abundance of A. muciniphila on the efficacy of BCG vaccination. Analyses of human datasets provided hypothesis-generating support for these findings. Mechanistically, the higher baseline levels of gut A. muciniphila and its metabolite palmitoleic acid inhibit BCG vaccine efficacy by suppressing MptpB-mediated actin cytoskeleton remodelling. These results show that pre-vaccination differences in gut microbiota composition are a factor accounting for high variation in vaccine effectiveness. Stratifying by baseline gut microbiota profile and metabolism may represent a strategy to enhance future vaccine efficacy. Guang Dong Cheung Kong Philanthropy Foundation, Guangzhou key R & D project, National Natural Science Foundation of China, Key laboratory start-up project (Sixth Affiliated Hospital of Sun Yat-sen University), Guangdong Basic and Applied Basic Research Foundation, Guangzhou Basic and Applied Basic Research Foundation, Doctoral Initial Funding of Guangdong Medical University, Shenzhen Medical Research Fund, Discipline construction project of Guangdong Medical University, Project of Songshan Lake Innovation Center of Medicine & Engineering of Guangdong Medical University.