[F31] Role of diet-associated metabolites in mediating colonization resistance against Salmonella
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2029-08-14
Importo max: 43.773 EUR
Paese: US
Descrizione
SUMMARY
The enteric pathogen Salmonella enterica serovar Typhimurium (STm) induces inflammation, disrupting the
microbiota and diminishing commensal competitors, thereby allowing STm to gain a fitness advantage. STm and
other non-typhoidal Salmonella are leading causes of inflammatory diarrhea in humans, with over 100 million
infections worldwide each year. The protection conferred by host immunity and microbiota-mediated colonization
resistance is critical to combat STm. Microbiota-derived metabolites, including short-chain fatty acids and
secondary bile acids, influence host immunity by modulating the activity of several immune cells, including
dendritic cells, regulatory T cells, and epithelial cells. Moreover, additional factors, including diet, influence the
gut microbiota and metabolite production, thereby affecting immune cell responses. The overall goal of this
project is to determine how diet alters the chemistry of the microbiome during STm infection and how these
metabolite changes influence STm pathogenesis and host immunity. To study the impact of diet during STm
infection, I compared the course of disease in mice fed different diets: regular chow, a highly processed control
low-fat diet (LFD), or a highly processed high-fat diet (HFD). Mice fed LFD or HFD exhibited higher STm
colonization in the gut and systemic sites than mice fed regular chow. Furthermore, examination of the
microbiome composition by quantitative shotgun metagenomics revealed that mice fed highly processed diets
had significantly lower absolute microbial abundances both pre- and post-infection. Similarly, preliminary
metabolomics analysis of fecal samples from mice fed regular chow, LFD, HFD, pre- and post-infection
demonstrated diet-dependent modifications to the microbial-derived metabolome, including N-acyl lipids and bile
acids. Based on these preliminary data, my central hypothesis is that diet alters gut microbial communities and
microbial metabolite production, which, in turn, modulates immune responses that influence STm pathogenesis.
In Aim 1, I will evaluate how diet-associated metabolites enhance macrophage responses during infection. I will
focus on the role of N-acyl lipids and microbial-derived bile acids in modulating macrophage responses and STm
intracellular replication. In Aim 2, I will assess the contribution of selected metabolites to colonization resistance
during STm infection. I will administer select metabolites to mice fed highly processed diets to elucidate whether
we can restore colonization resistance, and I will track the metabolites in vivo via stable isotope labeling. This
study will provide a comprehensive analysis of bacteria in the gut during homeostasis (regular chow diet) and
dysbiosis (highly processed diets), and reveal how modifications to the microbial-derived metabolome influence
immunity and STm pathogenesis, providing critical insights that can be leveraged for novel therapeutic strategies
against enteric pathogens.
Istituzione: UNIVERSITY OF CALIFORNIA, SAN DIEGO
PI: Vanessa Castillo
Progetto: 1F31AI203073-01
Settori: National Institute of Allergy and Infectious Diseases
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.