Gut-brain axis immune modulation triggered by fungi drives PVT activation and OCD-like behavior
Abstract
The gut–brain axis plays a critical role in regulating neurobehavioral processes, with growing evidence for the involvement of several bacterial metabolites and immune-mediated signals. The symbiotic co-existence with microbes has had a profound influence on the evolution of the mammalian immune system. Whether the lifelong interactions between host immunity and the cross-kingdom microbiota influence behavioral traits is currently unknown. Here, we identify a novel neuroimmune pathway in which innate immune hypofunction caused by caspase recruitment domain-containing protein 9 (CARD9) deficiency led to the emergence of obsessive-compulsive disorder (OCD)-like behavior triggered by intestinal mycobiota. In a model of fungal gastrointestinal colonization with Candida albicans , CARD9-deficient mice exhibited excessive self-grooming, a behavioral characteristic of OCD. Intestinal barrier integrity, disrupted by the fungal toxin candidalysin, was reinforced by CARD9 + CD11c + myeloid phagocytes. Fungal depletion reversed this overgrooming phenotype. In the central nervous system (CNS), the blood-brain barrier (BBB) was broadly compromised, with aberrant neuronal hyperactivation in the paraventricular thalamic nucleus (PVT), a brain region canonically associated with OCD as part of the cortico-striato-thalamo-cortical (CSTC) circuit. Chemogenetic inhibition of PVT neurons, as well as systemic ketamine administration, separately suppressed C. albicans- induced overgrooming behavior. This suggests a novel gut–immune–brain pathway (GIBP) that, during an immune deficiency, is induced by gut mycobiota, leading to disruptions in both intestinal and CNS barrier integrity, and driving acute onset of repetitive, compulsive behaviors. Notably, patients with CARD9 deficiency similarly exhibited OCD traits, suggestive of an analogous GIBP in humans. Our findings establish CARD9 as a neuroimmune modulator and reveal unexpected roles for the gut mycobiota in shaping brain function and behavior.
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