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Determining how high-fat diet derived fatty acids and the gut microbiota interact to engage innate immunity via pattern recognition receptors

Grant number: 22/14545-8
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): July 30, 2023
Effective date (End): July 29, 2024
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Francemilson Goulart da Silva
Grantee:Paulo Henrique Evangelista Silva
Supervisor: Fernando Forato Anhe
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Université Laval, Canada  
Associated to the scholarship:20/12201-4 - Pro-inflammatory cytokines expression and their correlation to nutrient transporters and intestinal permeability in murine treated with fatty acids, BP.DR

Abstract

Ingestion of a high-fat diet (HFD) by mice can alter macronutrient transporters, intestinal permeability, and gut microbiota composition, which drive changes to nutrient absorption. The most abundant fatty acids (FA) in HFD are palmitic (PA), stearic (EA) and oleic (OA) acids, and the SFAs (PA and EA) are associated with the pro-inflammatory action via TLR/NF-º² in different tissues. Pattern recognition receptors (PRRs), such as TLR2, TLR4, NOD1 and NOD2, are known to be molecular targets connecting obesity to inflammation. Thus, innate immune PRR-mediated inflammatory process can link the effects of HFD to changes in nutrient transporter content and intestinal permeability. Preliminary data from our study (FAPESP grant #2020/12201-4) show that PA administration was able to increase both MD-2 and IFN-g mRNA expression in the small intestine (SI) of mice. Considering that IFN-g and MD-2 are implicated in TLR4 responsiveness, we hypothesized that TLR4 plays a role in mediating the pro-inflammatory effects of PA. While evidence suggests that FAs can help to activate PRRs such a nutrient-mediated activation seems to require synergy with microbial ligands to elicit robust inflammatory response. We hypothesized that the gut microbiota may participates in the activation of PRRs by FAs. FAs can easily access the intracellular compartment; we hypothesized that cytoplasmic NOD receptors might provide a key alternative route for FAs to synergize with microbial ligands to induce inflammation. We will test these hypotheses using HEK-Blue cells overexpressing TLR2, TLR4, NOD1 or NOD2 and that secreted embryonic alkaline phosphatase (SEAP) to report on PRR activation. This approach allows assessing the potential of constituents of biological fluids (eg, feces and serum) to activate PRRs. We will incubate these cells with the most abundant FAs from HFD (OA, PA, EA), and with the fecal microbiota and serum from mice treated or not with these FAs. These data will shed light onto the synergy between FAs and microbiota to drive inflammatory responses that can alter gut absorptive processes. (AU)

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