The Microbiome, PPARγ and AhR in the inflammation-metabolism interface within the gastrointestinal tract

Abstract: The mammalian body is a mosaic of different organisms - a holobiont, which contains all the biomolecules and their metabolites encoded in our eukaryotic genome and supplemented by an even larger pool of prokaryotic genes and products. This symbiotic coexistence is presumed to have evolved to necessitate the sharing of biological and biochemical needs important for growth, body physiology, survival and reproduction. In this thesis, the communication between the microbiome and its host has been studied using state-of-the-art high-throughput methodologies, modelled on two known ligand-activated transcription factors, AhR and PPARγ. We show that commensal bacteria and their metabolites, short chain fatty acids (SCFA) can induce the expression of ANGPTL4 and CYP1A1 in gut epithelial cells. These genes are regulated by PPARγ and AhR respectively. ANGPTL4 is known to regulate metabolic processes connected to energy storage and utilisation, whilst CYP1A1 is involved metabolism of toxins and pollutants. These results illustrate how innate and metabolic properties of intestinal cells can be modulated by gut microbial products. This model is further evaluated using the pathogen Salmonella enterica serovar Typhimurium. Infection studies in mice show that Salmonella inactivates PPARγ and elicits acute colitis and activation of the protein lipocalin 2 (LCN2). LCN2 stabilises the metalloproteinase protein MMP9 which, in turn, further fuels highlights PPARγ/LCN2/MMP9 as a set of metabolic and immune regulators of the host that Salmonella needs to “hijack” in order to pave its way for intestinal colonisation. As PPARγ is a regulator of energy balance and LCN2 is an important metabolic regulatory protein, these studies establish a functional link between pathophysiology, metabolism, immune responses and gut microbes. In the final study, the bidirectional communication between the AhR signalling pathway and gut microbiome is explored. While the bacterial metabolite SCFA can regulate AhR function and expression of its target genes in intestine and liver, the composition of the gut microbiota is altered in AhR KO mice. Furthermore, metabolomic studies of AhR KO mice show that these mice, when under metabolic stress are compromised in their ability to produce ketone bodies. The evidence of metabolic stress is further supported by the observation that young AhR KO mice show growth retardation at a developmental stage that is prone to dynamic fluctuations in microbiota composition. These findings illustrate the link between immunity and metabolic functions through the sharing of biological and biochemical modulators within the holobiont. The re-discovery of the gut microbiome and its apparent influence on body functions represent a paradigm shift. We are just beginning to appreciate the importance of the microbiome as a mediator of health and are starting to understand how microbes contribute to who we are and how we function as one organism.