[R01] Genetic and Gut Microbial Regulation of Indole-3 Propionate in Metabolic Disease
Ente: National Institute of Diabetes and Digestive and Kidney Diseases
Scadenza: 2030-01-31
Importo max: 778.662 EUR
Paese: US
Descrizione
PROJECT SUMMARY
Metabolic diseases, such as obesity and type 2 diabetes (T2D), are characterized by perturbations of glucose
tolerance, pancreatic beta cell function, energy imbalance, appetite regulation, and other unknown pathways.
Clinical and genetic studies in humans and animal experiments have also implicated gut microbiota and products
derived from their metabolism of dietary nutrients as important mediators of metabolic risk. In this regard, we
have observed protective associations between plasma levels of indole-3-propionic acid (IPA) – a metabolite
generated entirely by gut bacteria from dietary tryptophan – and insulin resistance traits in humans and mice.
We have also identified 2 loci for IPA levels on chromosomes 2 and 16 in humans, which harbor genes encoding
lactase (LCT) and members of the medium-chain fatty acid acyl-CoA synthetases (ACSM1-5), respectively.
These observations point to host genetic factors that modulate IPA levels through both its production by gut
bacteria (LCT) and endogenous metabolism (ACSMs). This notion is consistent with our gnotobiotic studies in
germ-free mice that increasing Bifidobacterium abundance, which is reproducibly associated with the LCT locus
in humans, elevated plasma levels of IPA and attenuated high fat diet-induced (HFD) insulin resistance. In
parallel studies, IPA supplementation studies in mice also protected against metabolic disturbances, at least in
part, through maintenance of intestinal barrier function, activation of arylhydrocarbon receptor (Ahr), suppression
of nicotinamide N-methyl transferase (Nnmt), and elevation of tissue nicotinamide adenine dinucleotide (NAD+)
levels. Despite these observations, we still only have a poor understanding of the genetic architecture of IPA
metabolism in the host, through either main effects or interactions with diet/gut microbes; the interplay between
gut bacterial species that metabolize tryptophan to IPA and its precursors; and the mechanisms underlying the
tissue-specific protective effects of IPA on T2D-related traits. The goals of this project are use integrative
systems genetics, gut bacterial engineering and functional validation studies in humans and mice to address
these fundamental gaps in knowledge. In Aim 1, we will validate ACSM2 as one host genetic determinant of
IPA levels and further define the interrelationships between IPA levels, gut bacteria, host genetic factors, and
metabolic outcomes in humans. In Aim 2, we will use colonize gnotobiotic mice with synthetic bacterial
communities to elucidate the interactions between gut bacteria and dietary factors that promote IPA production
and beneficial metabolic improvements in the host. Finally, Aim 3 will determine the basis for the protective
association of IPA levels with metabolic phenotypes using genetically modified mouse models for genes involved
in IPA signaling. Taken together, these complementary approaches will provide important genetic and biological
insight into the cau
Istituzione: UNIVERSITY OF CALIFORNIA LOS ANGELES
PI: Hooman Allayee, Aldons Jake Lusis, Federico E Rey
Progetto: 1R01DK143650-01A1
Settori: National Institute of Diabetes and Digestive and Kidney Diseases
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