Intestinal epithelium aryl hydrocarbon receptor is involved in stress sensitivity and maintaining depressive symptoms

The aryl hydrocarbon receptor (AhR) is a key regulator in the microbiome-gut-brain axis, and AhR-active mi-crobial metabolites modulate multiple neuronal responses. We recently demonstrated that 3,3'-diindolylmethane (DIM) and 1,4-dihydroxy-2-naphthoic acid (DHNA), two selective AhR modulators (SAhRMs), act as antide-pressants in female mice. Thus, to examine the role of intestinal AhR in depression, anxiety, and spatial learning, this study employed transgenic mice in which the AhR was knockout only in the intestinal epithelium (AhR Delta IEC). Additionally, this study examined whether the antidepressant effects of dietary DIM and DHNA is mediated by intestinal AhR. AhR Delta IEC and WT female mice were fed daily with vehicle, 20 mg/kg DIM or DHNA for three weeks prior to four weeks of unpredictable chronic mild stress (UCMS). Mice were examined for weight gain, anhedonia-like behavior (sucrose preference test), anxiety levels (open field, light/dark, elevated plus maze, novelty-induced hypophagia, and marble burying tests), and spatial learning (Morris water maze). UCMS reduced weight gain in AhR Delta IECs, but not WTs. Moreover, UCMS initially reduced sucrose preference in both AhR Delta IECs and WTs, but over 4 weeks of UCMS, AhR Delta IECs develop resilience to UCMS-induced anhedonia. Additionally, AhR Delta IECs exhibit slightly reduced anxiety in certain tests and faster spatial learning. DIM and DHNA acted as antidepressants in both AhR Delta IECs and WTs. Thus, this study suggests that intestinal AhR plays differential roles, mitigating stress effects on weight gain, and increasing stress effects on mood. However, the site of antidepressant action of SAhRMs, such as DIM and DHNA, is not dependent on the expression of intestinal AhR.