[R01] Identification of human gut microbe-derived xenolipids: impact of fibers and host metabolic health
Ente: National Institute of Diabetes and Digestive and Kidney Diseases
Scadenza: 2029-04-30
Importo max: 687.624 EUR
Paese: US
Descrizione
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.
Istituzione: UNIVERSITY OF CALIFORNIA AT DAVIS
PI: Sean Harrison Adams
Progetto: 5R01DK137173-03
Settori: National Institute of Diabetes and Digestive and Kidney Diseases
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