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Melatonin system integrity shapes gut-brain interaction in schizophrenia-derived microbiota transplant phenotype in

Benedetta Barzon1, Atea Shkodra2, Michele D'Incalci2

  • 1Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.

Life Sciences
|August 11, 2026
PubMed
Abstract

Insights

The melatonin system influences how gut bacteria from schizophrenia patients affect brain and behavior. This highlights the tryptophan-kynurenine-melatonin axis as a target for schizophrenia treatment.

Area of Science:

  • Neuroscience
  • Microbiology
  • Psychiatry

Background:

  • Schizophrenia (SCZ) is linked to gut microbiota alterations.
  • The melatonin (MLT) system and tryptophan (Trp) metabolism pathways (kynurenine - Kyn) are implicated in SCZ.
  • The interaction between SCZ microbiota and the MLT system remains unclear.

Purpose of the Study:

  • To investigate if the MLT system modulates the effects of SCZ fecal microbiota transplantation (FMT) on behavior, neurophysiology, and neurochemistry.
  • To elucidate the role of the Trp-MLT and Trp-Kyn pathways in SCZ.

Main Methods:

  • Fecal microbiota transplantation (FMT) from SCZ patients (severe vs. mild) into MLT-deficient and MLT-proficient mice.
  • Assessed locomotor activity, working memory, dopamine neuron electrophysiology in the ventral tegmental area (VTA).
  • Quantified peripheral cytokines and central/peripheral Trp metabolites.

Main Results:

  • In MLT-deficient mice, SCZ FMT altered activity and peripheral inflammation.
  • In MLT-proficient mice, severe SCZ FMT caused memory deficits and reduced VTA dopamine neuron firing.
  • MLT-proficient mice with SCZ FMT showed increased brain Trp and a decreased Kyn/Trp ratio.

Conclusions:

  • The MLT system acts as a switch, determining the impact of SCZ microbiota on brain and behavior.
  • This study links circadian biology, microbiota, and SCZ pathophysiology via the Trp-Kyn-MLT axis.
  • Targeting circadian-microbiome interactions offers a novel therapeutic strategy for SCZ.
Keywords:
CytokinesDopamineFecal transplantKynurenineMelatoninSchizophreniaSerotonin

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