Speaker: Dr Elizabeth Mann, University of Manchester, will present a seminar entitled : The intestinal microbiota shapes the regulatory functions of intestinal macrophages via metabolic reprogramming

Host:     Lindsay Hall

Abstract:
The intestinal immune system has adapted to prevent harmful immune responses against the commensal microbiota. Macrophages in particular are highly specialised in the intestine, being hypo-responsive to bacterial stimulation. However, it is unclear how macrophages become conditioned to adopt these regulatory properties.

We provide evidence that disruption of the gut microbiota with antibiotic use primes intestinal macrophages to respond inappropriately to bacterial stimulation, producing excess amounts of inflammatory cytokines in response to LPS. Accordingly, re-exposure of antibiotic-treated macrophages to the gut microbiota (recolonisation) caused inflammatory changes in intestinal macrophages, driving a long-term, sustained inflammatory Th1 response in the colon and rendering mice more susceptible to Th17 and Th2-mediated infections.

Short-chain fatty acids (SCFAs) are generated from dietary fibre by the gut microbiota and have a range of immunomodulatory effects in the intestine. Strikingly, the SCFA butyrate was depleted during antibiotic administration, but supplementation with butyrate restored the hypo-responsiveness of macrophages to LPS following antibiotic administration, abolished the dysregulated T-cell response and prevented the enhanced susceptibility to infection. RNA-seq analysis of intestinal macrophages from mice administered butyrate revealed increased expression of genes involved in metabolic processes including oxidative phosphorylation and lipid metabolism. Moreover, butyrate acted directly on macrophages in vitro to enhance oxidative phosphorylation and lipid metabolism, skewing macrophages towards an anti-inflammatory, alternatively-activated phenotype.

In summary, the gut microbiota is critical for maintaining the regulatory properties of intestinal macrophages, at least in part driven by SCFAs which shape metabolic reprogramming of intestinal macrophages.

Biography:
I obtained a BSc in Genetics and an MSc in Molecular Medicine from University College London, finishing in 2006. I then undertook my PhD in the laboratory of Professor Stella Knight at Imperial College London, focusing on human dendritic cell (DC) immunobiology, including tissue-specific specialization of human DC. I later trained as a postdoc at Johns Hopkins University in Baltimore in the laboratory of Dr Xuhang Li where I developed my expertise in murine models of IBD and molecular techniques, before joining the laboratory of Professor Simon Milling at the University of Glasgow. In this position, I investigated microbial interactions with intestinal immune cells to determine mechanisms by which broad-spectrum antibiotic use impacts on the intestinal immune system. Mid 2017 I moved to the University of Manchester as Wellcome Trust Sir Henry Dale Fellow and established an independent research group.

All staff from organisations on the Research Park are welcome to attend.