GUT MICROBIAL BILE ACID MODIFICATIONS MODULATE AGE-ASSOCIATED DYSMETABOLISM AND CIRCADIAN DYSSYNCHRONY

BACKGROUND: There are few interventions that, when introduced at an advanced age in mammals, are known to improve healthspan. Caloric restriction and time-restricted feeding (TRF) improve healthspan, with up to 35% extension in lifespan when used with circadian alignment. In young mice, TRF leads to improved adiposity, exercise tolerance, and metabolic function in the context of maintained luminal dynamics of microflora and metabolites such as bile acids. The relationship of aging with microbial and luminal dynamics is unknown.
METHODS: Aged (80 weeks old) and young (8 weeks old) male mice were fed a standard chow diet and subjected to metabolic and circadian characterization over the course of 16 weeks, after which mice were sacrificed and samples collected. We characterized liver transcriptomics, targeted bile acid metabolomics, cecal metatranscriptomics, and determined differences between aged and young mice. Publicly available human metabolomics data was also inspected to characterize the relevance of our findings to aging in humans. In another experiment, we gavaged 82-week-old mice with engineered native bacteria with the bile salt hydrolase gene (BSH+) or without it (BSH-), and assessed the impact on metabolic and circadian phenotypes. Mice were sacrificed 40 weeks post-gavage and samples were evaluated for metabolomics and transcriptomics.
RESULTS: Compared to young mice, aged mice display increased gonadal fat (p=0.0083), insulin resistance (p = 0.0097), disrupted circadian behavior (night sleep p = 0.007; night food consumption p = 0.0391), and altered hepatic gene expression. These changes occur in the context of altered bile acid physiology characterized by disruption in expression of bile acid-related genes and increased ratios of deconjugated to taurine-conjugated bile acids. Metatranscriptomic analysis demonstrates increased microbial function related to conjugated bile acid hydrolases. Publicly available metabolomics data from centenarians recapitulate our findings in taurine-conjugated bile acids, suggesting that BSH activity and bile acid regulation could also modulate the effects of aging in humans. Over-expression of BSH in aged mice using engineered native bacteria increased the ratios of unconjugated to taurine-conjugated bile acids and improved metabolic phenotype including circadian behavior and body adiposity.
CONCLUSIONS: Aging induces changes in microbial bile acid biotransformations in both mice and humans, suggesting an increase in BSH with aging. Over-expression of BSH improves metabolic and circadian phenotype in aged mice.