Impact of Metabolites on the Intestinal Mucosa and Development of Inflammation

Abstract

The intestinal epithelial mucosal barrier plays a pivotal role in the maintenance of intestinal homeostasis, acting as an important barrier between microbes and the host s innate immune system. The metabolite-rich environment that is the intestinal lumen contains metabolic by-products deriving from microbial fermentation, host cell metabolism and ingested foods. Indeed, the intestinal mucosal epithelium and resident intestinal immune cells are constantly exposed to this metabolic flux. Epithelial barrier dysfunction allows passage of gut luminal contents across the intestinal epithelial monolayer into the lamina propria. Here, primed resident immune cells, in particular macrophages, respond by secreting inflammatory mediators and of recent, have shown to exhibit enhanced production of metabolic intermediates. These include succinate, lactate and the newly established itaconate, which has recently emerged as an important inflammatory regulator. The impact of these metabolites on intestinal mucosal barrier was investigated included their impact on macrophage responses to intestinal infection. This thesis reveals a novel role for succinate and itaconate in modulating the macrophage, specifically regulating phagocytosis, intracellular killing and bactericidal mechanisms of macrophages. These metabolites can drive distinct macrophage functional phenotypes in response to infection, limiting the intracellular bacterial niche and impeding the pathogenesis of infection. Importantly, these novel findings demonstrate how a distinct host-derived intestinal metabolite may be utilised as a therapeutic strategy for intestinal infection and inflammation.