The Role of the Serotonin Transporter-Aryl Hydrocarbon Receptor Axis in Intestinal Inflammation

Inflammatory Bowel Diseases (IBD) are characterized by the chronic inflammation of the gastrointestinal (GI) tract resulting in debilitating symptoms, such as GI pain, diarrhea, and malnutrition. Recently, the Aryl Hydrocarbon Receptor (AhR), a ubiquitous environmental sensor tasked with xenobiotic detoxification and immune regulation, and its target genes, IL-10 and IL-22, were identified as IBD susceptibility genes. Notably, recent studies showed that AhR is regulated by the Serotonin Transporter (SLC6A4, SERT), which is responsible for the sodium-chloride dependent uptake of 5-hydroxytryptamine (5-HT, serotonin), and is also consistently decreased in IBD patients and in models of intestinal inflammation. Indeed, SERT KO and AhR KO mice exhibit an exacerbated response to intestinal injury via mechanisms that are not fully understood. Thus, the purpose of this thesis project was to investigate the role of the SERT-AhR axis in the pathogenesis of intestinal inflammation. AhR ligands can be derived from the diet or amino acids, such as tryptophan, through host- or microbial-metabolism. However, the impact of dietary AhR ligands on chronic intestinal inflammation resembling human IBD is unknown. Moreover, whether SERT deficiency causes altered availability of the amino acid profile and/or AhR ligands under basal condition or in intestinal inflammation is not known. To assess the impact of the SERT-AhR axis on intestinal inflammation, we hypothesized that i) consumption of dietary AhR ligand, indole-3-carbinole (I3C) found in broccoli, can attenuate chronic DSS-induced colitis, and ii) that deletion of SERT alters the levels of amino acids, including tryptophan, phenylalanine, and their metabolites, which may underlie the increased susceptibility to intestinal inflammation. The results demonstrated that AhR activation through the dietary supplementation of I3C attenuated intestinal inflammation and restored gut microbial diversity in mice induced with chronic DSS-colitis. Additionally, we observed reduced levels of tryptophan, phenylalanine, and their metabolites in the plasma, as well as an increase in these amino acids in the feces in SERT KO mice, similar to WT mice treated chronically with DSS. In line with this, the basolateral amino acid transporter, MCT10, was downregulated in models of intestinal inflammation and in SERT KO mice. Altogether, these data demonstrate the critical role of the AhR activation through dietary ligands in mitigating intestinal inflammation, as well as the necessity of SERT in maintaining amino acid levels. These studies highlight intestinal SERT as a novel therapeutic target for improving inflammation in IBD patients and warrant future investigations linking SERT-AhR and amino acid pathways in IBD patients.