Gut microbial metabolome: regulation of host metabolism by SCFAs

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Title: Gut microbial metabolome: regulation of host metabolism by SCFAs
Authors: Abdul Rahim, Mohd Badrin Hanizam Bin
Item Type: Thesis or dissertation
Abstract: There is increasing evidence demonstrating a determinant role of gut microbiota in host health, and one underlying mechanism is via gut-microbial metabolites-host interaction in modulating host’s cellular functions. SCFAs, main fermentation products of dietary fibres by gut microbiota in GI tract, are considered to be generally beneficial to the host. It has been shown that SCFAs act as substrates for energy metabolism, receptor agonists, and as histone deacetylase (HDAC) inhibitors. However, there are still gaps in the knowledge of their biological effects. It has been hypothesised that SCFAs may act as substrate for energy metabolism as well as ligand for several GPCRs, thus play roles in many cellular functions. Combining 1H nuclear magnetic resonance (NMR) spectroscopy with multivariate statistical analysis of the effect of SCFAs on the hepatic cancer metabolic network identified a metabolic signature associated dose- and time- related SCFA exposure. TCA cycle intermediate, α-keto-β-methylvalerate was strongly correlated with the treatment of SCFAs suggesting the preferential of the cells to SCFAs for energy production. This signature further confirms that SCFAs play direct role in host energy metabolism. Having implemented a harmonised pharmacological assessment of a comprehensive SCFA panel on FFAR2, FFAR3, and GPR109A, this study is the first to reveal that isobutyrate and isovalerate are novel partial agonists for GPR109A. Furthermore, niacin, a classical agonist for GPR109A also has been shown to activate FFAR2 and FFAR3 but with much lower affinity. In another study, the effect of SCFAs on 3T3-L1 adipogenesis and adipocytes lipolysis has been characterised. Dosing the 3T3-L1 cells with isobutyrate, valerate, and isovalerate significantly induce the adipogenesis of the cells. In contrast, other SCFAs have no effect of the 3T3-L1 cell differentiation. Subsequent study focused on the effect of SCFAs on basal adipocyte lipolysis. Mature adipocytes were treated with 100 µM of SCFAs for 3hr and glycerol release was measured. This study revealed the anti-lipolytic property of propionate, butyrate, and valerate by significantly inhibits lipolysis in mature 3T3-L1 adipocytes. Thus, the role of SCFAs in regulating adipocytes functions may be particular important and beneficial in regulating plasma lipid profile and possibly aspects of metabolic syndrome. Together, these data enhance our understanding on the role of SCFAs on important metabolic tissues, which are hepatocyte and adipocyte.
Content Version: Open Access
Issue Date: Jan-2016
Date Awarded: May-2016
Supervisor: Dumas, Marc
Sponsor/Funder: Universiti Teknologi MARA
Malaysia. Kementerian Pengajian Tinggi
Department: Department of Surgery & Cancer
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses

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