SummaryThe human gut microbiota contributes enzymatic functions that are unavailable to host cells and play crucial roles in host metabolism, nutrient processing and regulating immune functions. As dietary compounds that are only partially absorbed, flavonoids are available for metabolism by gut microbiota, leading to diverse bioactive products. Combining prediction of enzyme promiscuity, metabolomics, and in vitro model systems, we identified a bacterial enzyme that can catalyze heterocyclic C-ring cleavage of naringenin. Culture experiments using a wild-type and mutant strain of Bacillus subtilis confirmed that the enzyme is a chalcone synthase-like polyketide synthase. The prediction-validation methodology developed in this work could be used to systematically characterize the products of gut bacterial flavonoid metabolism and identify the responsible enzymes and species. Further, we demonstrated that naringenin and its ring cleavage metabolites differentially engage the AhR and NR4A in intestinal epithelial cells. Our results suggest that the abundance of selected gut bacterial species impacts the profile of bioactive flavonoids and flavonoid-derived metabolites and thereby influences inflammatory responses in the intestine. These results are significant for understanding the mechanisms of gut microbiota-dependent effects of dietary flavonoids.
Flavonoids are polyphenolic phytochemicals abundant in plant-based, health-promoting foods. They are only partially absorbed in the small intestine, and gut microbiota plays a significant role in their metabolism. As flavonoids are not natural substrates of gut bacterial enzymes, reactions of flavonoid metabolism have been attributed to the ability of general classes of enzymes to metabolize non-natural substrates. To systematically characterize this promiscuous enzyme activity, we developed a prediction tool that is based on chemical reaction similarity. The tool takes a list of enzymes or organisms to match microbial enzymes with their non-native flavonoid substrates and orphan reactions. We successfully predicted the promiscuous activity of known flavonoid-metabolizing bacterial and plant enzymes. Next, we used this tool to identify the multiple taxa required to catalyze an entire metabolic pathway of dietary flavonoids. Tilianin is a flavonoid-O-glycoside having biological and pharmacological activities, including neuroprotection. Using our prediction tool, we defined a novel bacterial pathway of tilianin metabolism that includes O-deglycosylation to acacetin, demethylation of acacetin to apigenin, and hydrogenation of apigenin to naringenin. We predicted and confirmed using in vitro experiments and LC-MS techniques that Bifidobacterium longum subsp. animalis, Blautia coccoides and Flavonifractor plautii can catalyze this pathway. Prospectively, the prediction-validation methodology developed in this work could be used to systematically characterize gut microbial metabolism of dietary flavonoids and other phytochemicals. The bioactivities of flavonoids and their metabolic products can vary widely. We used an in vitro rat neuronal model to show that tilianin metabolites exhibit protective effect against H2O2 through reactive oxygen species scavenging activity and thus, improve cell viability, while the parent compound, tilianin, was ineffective. These results are important to understand the gut microbiota-dependent physiological effects of dietary flavonoids.
Carbohydrates are significant components of both plant- and animal-based human diets. Depending on the type of diet, calories from carbohydrates can account for more than 70% of total daily energy intake of human adults. Bacteria residing in the colon have greater access to complex carbohydrates, as these molecules are only partially digested in the stomach and not fully absorbed in the small intestine. Microbial metabolism of these dietary microbiota-accessible carbohydrates (MACs) in the colon is important as organic acids such as short-chain fatty acids (SCFAs) produced upon fermentation of MACs are important mediators of host physiology, including promoting intestinal epithelial barrier integrity and development of the immune system. Here we review the microbial metabolism of three different MACs (dietary fiber, polyphenols, and amino sugars) and the enzymes involved in their metabolism. We also discuss advances in tools such as metabolomics and metabolic modeling that are needed for identifying and characterizing products of MAC metabolism by gut bacteria, and suggest future directions of research for elucidating the mechanisms whereby these products influence host physiological processes.
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