The microbial metabolite imidazole propionate modulates hypothalamic activity and stress-induced behaviors.

Metabolic disorders are associated with gut microbiome imbalance, which can have additional physiological effects. The microbial metabolite imidazole propionate (ImP) is elevated in type 2 diabetes and has been linked to exacerbated metabolic dysfunctions. Here, we show that bacteria-produced ImP can enter the bloodstream and modulate brain activity and behavior. Elevated circulating ImP reaches the brain, leading to altered neuronal gene expression in the hypothalamus, disrupted GABAergic/glutamatergic signaling, and stress-related behaviors. Similarly, colonization with ImP-producing Eggerthella lenta elevates behavioral and molecular stress features. In a mouse model of type 2 diabetes, the gut microbiome shows greater capacity to generate ImP, leading to elevated systemic levels associated with heightened stress responses. In humans, higher ImP levels are associated with reduced hypothalamic reactivity to food cues, impaired stress coping, and increased emotional eating. Overall, these findings establish ImP as a microbial metabolite that links gut dysbiosis to altered hypothalamic function and stress in metabolic disease.