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

Neural circuits driving mammalian behaviors are highly plastic and modulated by internal and external factors, including the gut microbiome. We identify imidazole propionate (ImP), a microbial metabolite linked to metabolic disorders, as a key modulator of brain activity and behavior. Bacterially derived ImP enters the systemic circulation and brain, where it alters neuronal gene expression and activity in the hypothalamus without inducing overt neuroinflammation. Elevating systemic ImP promotes stress-related pathways and disrupts GABAergic/glutamatergic signaling in the hypothalamus before peripheral glucose dysregulation occurs. Similarly, colonization with the ImP-producing bacterium Eggerthella lenta elevates behavioral and molecular features of stress. In a mouse model of type 2 diabetes, the gut microbiome exhibits an enhanced ability to produce ImP, leading to elevated systemic levels that are associated with heightened stress responses. In humans, higher ImP associates with reduced hypothalamic reactivity to food cues, impaired stress-coping, and increased emotional eating, mirroring the causal links between ImP, hypothalamic activity, and stress-related behaviors in mice. Overall, these findings establish ImP as a notable microbial metabolite that links gut dysbiosis to altered hypothalamic function and stress in metabolic disease.