Chain, F. | bioRxiv Science

bioRxiv2024

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

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.

microbiology↗

bioRxiv2018

Highly accelerated rates of heritable large-scale mutations under prolonged exposure to a metal mixture of copper and nickel

Mutation rate variation has been under intense investigation for decades. Despite these efforts, little is known about the extent to which environmental stressors accelerate mutation rates and influence the genetic load of populations. Moreover, most studies have focused on point mutations rather than large-scale deletions and duplications (copy number variations or \"CNVs\"). We estimated mutation rates in Daphnia pulex exposed to low levels of environmental stressors as well as the effect of selection on de novo mutations. We conducted a mutation accumulation (MA) experiment in which selection was minimized, coupled with an experiment in which a population was propagated under competitive conditions in a benign environment. After an average of 103 generations of MA propagation, we sequenced 60 genomes and found significantly accelerated rates of deletions and duplications in MA lines exposed to ecologically relevant concentrations of metals. Whereas control lines had gene deletion and duplication rates comparable to other multicellular eukaryotes (1.8 x 10-6 per gene per generation), a mixture of nickel and copper increased rates fourfold. The realized mutation rate under selection was reduced to 0.4x that of control MA lines, providing evidence that CNVs contribute to mutational load. Our CNV breakpoint analysis revealed that nonhomologous recombination associated with regions of DNA fragility is the primary source of CNVs, plausibly linking metal-induced DNA strand breaks with higher CNV rates. Our findings suggest that environmental stress, in particular multiple stressors, can have profound effects on large-scale mutation rates and mutational load of populations.

genomics↗