Velmurugesan Arulampalam Project
Dietary components and bacterial metabolites can influence physiological parameters
such as inflammation and metabolism, with important consequences for health
Environmental sensors in the service of immunity and energy metabolism
Receptors are essentially environmental sensors that drive physiological effects such as inflammation and metabolism, and the intestinal tract is an excellent milieu to study this dialogue. The ligand induced transcription factor Aryl-hydrocarbon Receptor (AhR) is a classical environmental sensor that can modulate innate immunity and metabolism. Compared to WT mice, AhR-deficient (AhRKO) mice weigh less and are more immunocompromised as adults. High-throughput analyses have revealed major metabolic imbalances in the AhRKO mice. These mice also show an altered glucose response when fed fatrich Western Diet.
We have set out to map AhR-microbiota crosstalk in the intestine and identify bacterial metabolites that govern AhR function. Short chain fatty acids (SCFAs) such as propionate and butyrate are bacterial fermentation products of dietary fibers. Butyrate administration or monocolonization of germfree mice with a known butyrate-producing bacterium, Clostridium tyrobutyricum, resulted in expression of genes involved in lipid metabolism in intestinal epithelial cells (Korecka et al 2013). C. tyrobutyricum was previously shown to ameliorate DSS-induced colitis in mice. SCFAs have also been shown to be useful in the prevention and treatment of metabolic syndrome in humans. We show that target genes of AhR are selectively induced by SCFAs.
This project now looks to develop new strategies to manage host metabolism by targeting the gut microbiota through diet and activation of key regulators of immunity and metabolism, such as AhR. We aim to identify additional bacterial strains and metabolites modulating AhR activity and propose a clear role for AhR in the regulation of energy metabolism. Our overarching aim is to translate this knowledge to treat or prevent metabolic diseases through the design of tailor made functional foods using components such as natural AhR ligands.
The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation.
J. Hepatol. 2017 02;66(2):382-389
Bidirectional communication between the Aryl hydrocarbon Receptor (AhR) and the microbiome tunes host metabolism
Agata Korecka, Anthony Dona, Shawon Lahiri, Adrian James Tett, Maha Al-Asmakh, Viorica Braniste, Rossana D’Arienzo, Afrouz Abbaspour, Nicole Reichardt, Yoshiaki Fujii-Kuriyama, Joseph Rafter, Arjan Narbad, Elaine Holmes, Jeremy Nicholson, Velmurugesan Arulampalam, Sven Pettersson
npj Biofilms and Microbiomes 2, Article number: 16014 (2016) doi:10.1038/npjbiofilms.2016.14
Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals.
Sci Rep 2016 Feb;6():20127
Absence of intestinal PPARγ aggravates acute infectious colitis in mice through a lipocalin-2-dependent pathway.
PLoS Pathog. 2014 Jan;10(1):e1003887
ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways.
Am. J. Physiol. Gastrointest. Liver Physiol. 2013 Jun;304(11):G1025-37
The gut microbiome: scourge, sentinel or spectator?
J Oral Microbiol 2012 ;4():