The food grade bacterium Lactobacillus helveticus VEL12193 promotes autophagy by releasing membrane vesicles

Abstract

Autophagy-related processes, including canonical macroautophagy, are crucial for maintaining cellular homeostasis in eukaryotic organisms. Alterations or reduced activity of these processes have been strongly linked to a broad range of human diseases including inflammatory bowel disease (IBD) and age-related diseases such as age-related macular degeneration - a disease that affect the central area of the retina. In contrast, long-term autophagy stimulation appears to be safe and to extend lifespan in model organisms such as mice. Thus, enhancing autophagy represents a promising strategy for promoting healthy aging. Several studies indicate that the gut microbiota can influence host autophagy at the gut mucosa but also in peripheral organs, and some microbial metabolites have been identified as autophagy modulators. In this study, we studied the capacity of bacterial species commonly used in food fermentation (ferments) or health (probiotics) to modulate host autophagy by in vitro and in vivo approaches. In vitro screening of a library of 11 bacterial strains revealed a strain-dependent ability of lactobacilli and bifidobacteria to stimulate autophagy in human epithelial cells. The Lactobacillus helveticus strain VEL12193, isolated from cheese, emerged as the most effective inducer of autophagy. In vivo experiment using mice showed that long-term dietary supplementation with L. helveticus VEL12193 was associated with stimulation of autophagy in the gut mucosa and retina. We identified L. helveticus-derived membrane vesicles (MVs) as a bacterial component involved in bacterial-induced autophagy in epithelial and immune cells. Moreover, in vitro, we demonstrated that L. helveticus VEL12193 possesses immunomodulatory properties in macrophages, as well as in the gut mucosa of a preclinical mouse model of IBD. With this study we provide robust proof of concept that ferments/probiotics can stimulate autophagy at the organism scale and that this phenotype involved MVs. In addition, we identify L. helveticus VEL12193 as a candidate strain of interest for the design of healthy-aging strategies.