A Microbial Metabolite That Promotes Stress/Anxiety (UCLA Case No. 2026-007)

UCLA researchers in the Department of Integrative Biology and Physiology have identified microbiota-derived imidazole propionate (ImP) as a key neuromodulatory signal that can be targeted to treat stress-related behaviors and metabolic dysfunction.

BACKGROUND: The microbiota-gut-brain axis is a complex network that coordinates metabolic homeostasis. Ensuring balanced signaling between the gut microbiome and the hypothalamus, a major regulator of stress and metabolism, is important to preventing cardiometabolic disorders (CMDs).

Imidazole propionate (ImP) is a microbial metabolite generated from histidine, primarily by UrdA-expressing bacteria. Chronic exposure to ImP has been linked to inflammatory responses and insulin resistance via activation of the mTORC1 pathway. In humans, elevated levels of ImP are associated with CMDs like type 2 diabetes. While ImP influences the function of several cell types across tissue, implicating systemic physiological effects, little is known of its impact on host neural activity.

INNOVATION: Researchers at UCLA led by Dr. Elaine Hsiao have shown that microbiota-derived ImP acts as a gut-derived neuromodulatory signal that crosses the blood-brain barrier, accumulates in stress-associated brain regains, including the hypothalamus and amygdala, selectively disrupts excitatory signaling and promote stress-related behaviors. Using metabolite tracing, electrophysiology, neural activity mapping, and behavioral studies, researchers showed that ImP alters neuronal function and induces anxiety-like and stress-associated behavioral phenotypes. Furthermore, chronic exposure had a more pronounced effect than acute exposure, emphasizing the impact of prolonged activation of stress and inflammatory responses in the development of CMDs. These findings establish ImP as a metabolite that connects the gut microbiome to altered hypothalamic function and dysregulated stress responses in CMDs.

POTENTIAL APPLICATIONS:

• Biomarker for activation or dysregulation of stress response pathways
• Targeted preventative treatment for CMDs
• Microbiome-targeted strategies to decrease ImP production/signaling
• Therapeutic modulation of gut-brain signaling in stress/anxiety disorders/stress-induced eating

ADVANTAGES:

• Minimally invasive biomarker (blood-based measurement)
• Supports diagnostic and therapeutic development
• Microbially produced, and not correlated directly with dietary histidine intake
• Enables interventions at multiple levels (microbial production, metabolite signaling, neural pathways)

DEVELOPMENT-TO-DATE: ImP has been evaluated as a potential target for intervention for stress responses in animal studies wherein elevated levels induced anxiety-like and emotional eating-like behavior in mice.

Related Papers (from the inventors only):

Agirman G, Quicho MNB, Connelley KK, Zhang X, Lynch JB, Ha SM, Schmidt HM, Özcan E, Liang AX, Yu KB, Ahn IS, Qian C, Paramo J, Zhang S, Espinoza A, Turnbaugh PJ, de Aguiar Vallim TQ, Yang X, Church A, Hsiao EY. The microbial metabolite imidazole propionate modulates hypothalamic activity and stress-induced behaviors. Cell Host Microbe. 2025 Dec 10;33(12):2030-2042.e9. doi: 10.1016/j.chom.2025.10.019. Epub 2025 Nov 25. PMID: 41297540; PMCID: PMC12811846.

KEYWORDS: Metabolite, microbiome, hypothalamus, microbiota-gut-brain axis, gut-brain axis, stress response, cardiometabolic disorders (CMDs), type 2 diabetes (T2D), imidazole propionate, ImP, anxiety, neuro-metabolism, diagnostics