Gut microbiome-derived indole-3-carboxaldehyde regulates stress vulnerability in chronic restraint stress by activating aryl hydrocarbon receptors

Chronic stress constitutes a major precipitating factor for Major Depressive Disorder (MDD), and comprehending individual differences in stress responses is crucial for the development of effective intervention strategies for MDD. Recent studies indicate that an individual's vulnerability to chronic stress is closely associated with gut microbiota composition, but the underlying mechanisms remain unclear. This study aims to investigate whether the gut microbiota and its metabolites can serve as gut-brain signaling molecules and explores how the gut microbiota affects stress sensitivity. Here, we showed that gut microbiome-derived indole-3-carboxaldehyde (I3C) can act as a gut-brain signaling molecule that links tryptophan metabolism by gut microbes to stress vulnerability in the host. First, we identified a specific reduction in gut microbiome-derived I3C levels in the hippocampus and colon through untargeted and targeted metabolomic analyses. Then, the study of gut microbiota suggested that the relative abundance of lactobacillus was reduced significantly in stress-susceptible rats, whereas fecal microbiota transplantation regulates stress vulnerability. Furthermore, supplementation with I3C and the representative I3C-producing strain, Lactobacillus reuteri, was shown to alleviate depression-like behaviors induced by chronic stress. Further research confirms that I3C can inhibit neuroinflammation and promote hippocampal neurogenesis through the aryl hydrocarbon receptors (AhR) signal pathway, thereby mitigating the host's susceptibility to stress. In conclusion, our findings elucidate that the gut microbiomederived-I3C can help buffer the host's stress through the AhR/SOCS2/NF-kappa B/NLRP3 pathway, providing a gut-brain signaling basis for emotional behavior.