Immune mechanisms of fungal influence on the gut-brain axis.

About This Grant

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. Recent experimental studies demonstrate that commensal fungi modulate a wide range of neuroimmunity ranging from cutaneous sensation to social behavior. A deeper assessment of how gut mucosa-associated fungi influence sociability has revealed a direct immune signaling on neurons via IL-17R, linking this phenomenon to mycobiota-triggered type-17 immunity. It remains unknown which specific immune mediators and fungal components drive this response, and to what extent these processes contribute to changes relevant to clinical conditions. Our preliminary data indicate that long-term intestinal fungal colonization under immune hypofunction of fungal surveillance can lead to spontaneous compulsion in mice. Notably, patients with analogous deficiency exhibit altered behavioral traits suggesting the existence of a conserved gut–immune–brain axis in humans. Despite these insights, the mechanism of gut fungi in shaping the gut-distal pathologies remains largely unexplored. This proposal addresses a critical gap in our understanding of fungal contributions to neuroimmune regulation. We propose to investigate a novel neuroimmune pathway in which innate immune deficiency promotes compulsive overgrooming in mice, triggered by gut fungal colonization. In three specific aims, we will define the cellular, molecular (aim 1), and microbial (aim 2) mechanisms by which intestinal fungi modulate the gut-brain axis. We will further apply a translational approach (aim 3) linking our findings to patients suffering from a genetic condition aggravated by Candida. We expect that the results will provide a foundation for novel approaches to the diagnosis and treatment of neurological conditions in patients with immune deficiencies.