Bidirectional communication between the gut microbiome and the Aryl-Hydrocarbon-Receptor (AhR) influences host energy homeostasis as well as microbiome composition in the small intestine

Pettersson S., Korecka A., Dona D., Lahiri S., Tett A., Al-Asmakh M., Braniste V., D'Arienzo R., Abbaspour A., Reichardt N., Fujii-Kuriyama Y., Rafter R., Narbad A., Holmes E., Nicholson J., Arulampalam V.. (2016)

npj Biofilms and Microbiomes, 27, 16014

AhR is a ligand-activated transcription factor known for its diverse functions including    immune regulation and involvement in xenobiotic metabolism. The increasing diverse collection of AhR ligands food derived ligands (broccoli) and those made by gut microbes (indoles, kynurenine and phenazines) imply suggest that the AhR -receptor may also exercise a metabolic regulatory role. Indeed, here we report a direct bidirectional communication between microbes and AhR function regulating host energy metabolism in intestine and liver. While the bacterial metabolite short chain fatty acid, butyrate, activates target genes in the liver and in intestine, a reciprocal AhR dependent regulation of the microbiota composition is specifically observed in the small intestine but not in colon and stool samples of microbiota.  Specifically we observed an amplification of Firmicutes and reduction of Bacteroides phyla in AhR KO mice compared to AhR WT mice. Applying 1H-NMR-based metabolomic studies on plasma, liver and muscle tissue of AhR -/- and AhR +/+ mice, revealed reduced ketone body production in liver and increased levels of lactate and alanine in blood in AhR -/- mice. Adding also an observation of increased gluconeogenesis and reduced expression of genes regulating uptake and β-oxidation of fatty acids in liver implied that AHR -/- mice are under metabolic stress. Further findings revealed a metabolic switch in energy utilization from lipids to glucose during fasting, increased levels of corticosterol in the plasma and a massive induction of the cell stress sensing protein p53. These findings demonstrate a bidirectional communication between the gut microbes in the small intestine and in the liver of the host via SCFA and AhR receptor expression.

npj Biofilms and Microbiomes, 27, 16014

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