Friday, May 23, 2025
5/23/2025
Beneficial microbe driven rewiring of metabolic pathways in the gut and liver - SUMMARY Gut microbes generate a wealth of bioactive small molecules that are absorbed by the body and impact a plethora of physiological processes. Indeed, it is estimated that about 10% of all metabolites in circulation are derived from gut microbes. Despite the clear significance of gut microbe generated metabolites towards health, relatively little is known about how these metabolites mechanistically influence aspects of host biology. This is important because quantitative and qualitative abnormalities of the microbiota, and microbiota generated metabolites have been associated with metabolic conditions such as adult-onset diabetes, metabolic syndrome, nonalcoholic steatohepatitis, and obesity. With the goal of developing novel live biotherapeutics (beneficial microbes) to treat these metabolic conditions, our research group published that supplementation of mice fed a high fat and high sugar diet (western-style diet) with a novel beneficial microbe, namely Lactococcus lactis subsp. cremoris (LLC) lowers total cholesterol, decreases hepatic adiposity, and lowers the levels of pro-inflammatory cytokines in the liver. The goal of my graduate school studies, and the focus of this F30 proposal is to characterize the metabolome of western-style diet fed and LLC supplemented mice in an attempt to identify LLC-generated small molecules that confer its beneficial effects on the host. To this end, employing mass spectrometry-based metabolomics for analysis of small molecules, I generated preliminary data that demonstrate salient differences in the metabolite composition of western style diet fed mice supplemented with LLC compared to saline control. Computational analysis of the metabolomics dataset for pathway enrichment associated with the metabolomic profile using Mummichog v2.0 software revealed that LLC supplemented mice had metabolomic features associated with increased lipid and fatty acid metabolism, with Cytochrome P450 (CYP450) activity that functions in xenobiotic elimination in the liver, and with the activation of the Nrf2 cytoprotective signaling pathway. Based on my preliminary data, I hypothesize that metabolites generated by LLC act as regulatory integrators of host metabolism, especially in the context of a western style diet. Furthermore, I hypothesize that metabolites generated by LLC confer cytoprotective influences in the liver of mice by enhancing CYP450 activity, and by activating cytoprotective Nrf2 signaling pathway. I will test the hypothesis by 1) identifying LLC-induced shifts in the metabolome of mice fed a western style diet in the gut, liver, and hepatic portal vein of gnotobiotic and specific pathogen free mice and by 2) identifying the therapeutic target of LLC-mediated cytoprotection in the liver using clinically relevant mouse hepatic injury models. Our findings may uncover novel bacterial-generated bioactive metabolites that may be used as the next-generation therapies for disease of the liver. Through this research plan, I will be trained in gnotobiotic mouse husbandry, metabolomics analysis, mouse liver injury models, and histological analysis of liver tissue, all of which will form a basis to my career goal of becoming a gastroenterologist and physician scientist focusing on diseases of the liver.
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