Benedetta Barzon, Atea Shkodra, Michele D'Incalci, Jacopo Sapienza, Pasquale Paribello, Sofia Nasini, Stefano Dall'Acqua, Antonella Bertazzo, Nikolaos Pitsikas, Danilo De Gregorio, Flavia Valtorta, Mirko Manchia, Alessio Squassina, Paola Fadda, Roberto Cavallaro, Claudia Pisanu, Marta Bosia, Stefano Comai
Our findings identify the MLT system as a key biological switch that gates the impact of SCZ-associated microbiota on brain and behavior, dissociating behavioral from cognitive, neurophysiological and neurochemical outcomes. This work links circadian biology to microbiota-driven effects and points to the Trp-Kyn-MLT axis as a critical interface. This work provides a conceptual framework for targeting circadian-microbiome interactions, as a novel strategy to modulate disease-relevant phenotypes in SCZ.
AIMS: This study investigates whether the melatonin (MLT) system modulates the behavioral, neurophysiological and neurochemical effects of fecal microbiota transplantation (FMT) from individuals with schizophrenia (SCZ), highlighting the role of the tryptophan (Trp) to MLT and kynurenine (Kyn) pathways.
MATERIALS AND METHODS: FMT was performed using fecal samples from individuals with SCZ, characterized by distinct clinical, cognitive and metabolic profiles (severe vs mild SCZ), into antibiotic-treated MLT-deficient (C57BL/6) and MLT-proficient (C3H/HeJ) mice. Post-FMT evaluations included locomotor activity assessment (open field test), working memory testing (T-maze), in-vivo electrophysiological recordings from ventral tegmental area (VTA) dopamine (DA) neurons, and quantification of peripheral cytokines and central and peripheral Trp metabolites.
KEY FINDINGS: In MLT-deficient mice, FMT from severe SCZ induced hyperlocomotion and altered peripheral inflammatory markers (decreased IL-1β, increased keratinocyte-derived cytokine) compared to FMT from mild SCZ. Conversely, in MLT-proficient mice, severe SCZ FMT induced persistent spatial working memory deficits and a significant reduction in overall VTA DA neuronal firing, specifically driven by the high-firing subpopulation. Furthermore, MLT-proficient mice receiving severe SCZ FMT selectively exhibited increased brain Trp levels alongside a decreased Kyn/Trp ratio.
SIGNIFICANCE: Our findings identify the MLT system as a key biological switch that gates the impact of SCZ-associated microbiota on brain and behavior, dissociating behavioral from cognitive, neurophysiological and neurochemical outcomes. This work links circadian biology to microbiota-driven effects and points to the Trp-Kyn-MLT axis as a critical interface. This work provides a conceptual framework for targeting circadian-microbiome interactions, as a novel strategy to modulate disease-relevant phenotypes in SCZ.