Identification of human gut microbe-derived xenolipids: impact of fibers and host metabolic health

Project Summary: The nexus between diet, microbiome, and host involves molecular signals and xenometabolites (“non- self” molecules derived from microbial metabolism) that remain largely unmapped. DNA and RNA sequencing technologies have led to major advancements in understanding how abundances of specific gut microbes correlate to health, diet, and disease; however, the most important information about microbe-host and microbe-microbe communication will emerge from greater understanding of functional outcomes including microbial xenometabolism. To address this knowledge gap, the current proposal will leverage the diversity of innovative human gut bacterial cultures to expand the catalog of microbial metabolites, which can be screened to characterize binding and bioactivity characteristics relevant to physiology and health. This approach is a direct response to guidance from PAR-21-253, Identification and Characterization of Bioactive Microbial Metabolites for Advancing Research on Microbe-Diet-Host Interactions. Considering the paucity of information related to microbial fat metabolites in particular, our primary focus will be on xenolipid discovery, including (but not limited to) characterization of cyclopropane fatty acids (CpFAs) as an illustrative example of discovery-to-bioactivity proof-of-principle. For instance, the extant literature and our preliminary results indicate that novel odd-chain CpFAs are generated by bacteria harboring CpFA synthase (cfa), with CpFA catabolized by hepato-splanchnic tissues, stored, and released by white adipose tissue. Our data support anti-inflammatory effects of some CpFAs, as well as binding of peroxisome proliferator activated receptors (PPARs). The team will leverage human gut microbes cultured with combinations of fiber/complex carbohydrate substrates with or without diet-relevant fats, to drive substrate-specific bacterial communities and associated xenometabolomes. We will—for the first time—comprehensively identify xenolipids and non-lipid metabolite patterns that track the fiber and fatty acid milieu, and that correlate with specific bacterial communities varying in phylogeny. This will expand the library of microbe metabolites and shed light on how dietary components such as fibers and lipids interact to alter the xenometabolome. A complementary aim to interrogate the effects of xenolipids on nuclear receptors, inflammation and GPCR read-outs, and broader effects in gut organoids will link our findings to potential bioactivities, one of the remits of PAR-21-253.