The article reviews the emerging evidence that microbial tryptophan catabolites, produced by gut microbes through proteolysis, play a crucial role in mediating diet-induced host-microbial cross-talk. These metabolites influence host health by activating the immune system through the aryl hydrocarbon receptor (AHR), enhancing the intestinal epithelial barrier, stimulating gastrointestinal motility, and modulating gut hormone secretion. They also exert anti-inflammatory, antioxidative, or toxic effects in systemic circulation and potentially modulate gut microbial composition. The review highlights the importance of tryptophan catabolites in various physiological processes and their potential contributions to intestinal and systemic homeostasis in health and disease. The authors suggest that further research is needed to identify the main producers of these metabolites in the human gut and to understand their specific roles in different physiological contexts.The article reviews the emerging evidence that microbial tryptophan catabolites, produced by gut microbes through proteolysis, play a crucial role in mediating diet-induced host-microbial cross-talk. These metabolites influence host health by activating the immune system through the aryl hydrocarbon receptor (AHR), enhancing the intestinal epithelial barrier, stimulating gastrointestinal motility, and modulating gut hormone secretion. They also exert anti-inflammatory, antioxidative, or toxic effects in systemic circulation and potentially modulate gut microbial composition. The review highlights the importance of tryptophan catabolites in various physiological processes and their potential contributions to intestinal and systemic homeostasis in health and disease. The authors suggest that further research is needed to identify the main producers of these metabolites in the human gut and to understand their specific roles in different physiological contexts.