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| Item Type: | Article |
|---|---|
| Title: | Disrupting peripheral serotonin synthesis drives sex-specific alterations in sociability and cognition, and reshapes the gut-immune-brain axis |
| Creators: |
Castro, Rogério C.R., Alenina, Natalia  ORCID: https://orcid.org/0000-0002-6071-5433, Natasha, Eugenia E., Lodder, Thijs, Nair, Aiswarya R., Gonçalves, Susanne C., Mai, Lingling, Mulder, Danique, Woestenenk, Rob, Hesen, Rick, Samina, Marta C.F., Wang, Tianhua, Wöhr, Markus, Kolk, Sharon M., Bader, Michael ORCID: https://orcid.org/0000-0003-4780-4164, Vasquez, Alejandro A., Buitelaar, Jan K., Verheij, Michel M.M. and Homberg, Judith R.
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| Abstract: | Serotonin (5-HT) regulates neurodevelopment and behavior. Whereas central 5-HT is synthesized by tryptophan hydroxylase (TPH)-2, the TPH1 isoform produces 5-HT peripherally. Although these systems are anatomically segregated, TPH1 gene polymorphisms have been linked to neuropsychiatric vulnerability, suggesting that peripheral 5-HT may influence behavior through indirect pathways, potentially involving the gut-immune-brain axis. Here, we examined how lifelong peripheral 5-HT deficiency shapes behavior and cross-system communication in a sex-specific manner using adult TPH1 knockout (TPH1(-/-)) rats. Animals underwent behavioral testing combined with neurochemical and gene expression profiling, gut microbiome sequencing, and peripheral leukocyte phenotyping. TPH1(-/-) males and females displayed reduced anxiety-like behavior and enhanced attentional performance. TPH1(-/-) males also showed improved sociability and cognitive flexibility. These behavioral alterations were accompanied by attenuation of monoaminergic and GABA/glutamatergic signaling, alongside changes in HPA-axis and neuroplasticity-related pathways across cortico-limbic regions. Peripheral 5-HT deficiency further reshaped gut microbiome ecology, selectively reducing α-diversity in males and altering microbial community composition in both sexes. In the colon, TPH1 deficiency downregulated pro-inflammatory cytokines while upregulating adhesion marker expression. Circulating leukocyte populations were also altered, with reductions in γδ T cells, CD127(+) CD8(+) T cells, and B cells, and an increase in eosinophils. Integrative analyses showed that individual differences in anxiety-like behavior and cognition were associated with variation spanning neurochemical, microbial, and immune domains. Together, these findings support a role for peripheral 5-HT in behavioral regulation and reveal cross-system associations consistent with sex-specific modulation along the gut-immune-brain axis, while identifying TPH1-dependent signaling as a potential contributor to neuropsychiatric disorders’ pathophysiology. |
| Keywords: | Peripheral Serotonin, Tryptophan Hydroxylase-1 (TPH1), Sex Differences, Gut-Immunebrain Axis, Anxiety-Like Behavior, Sociability, Cognitive Flexibility, Attentional Performance, Gut Microbiome, Leukocyte Phenotyping |
| Source: | Brain Behavior and Immunity |
| ISSN: | 0889-1591 |
| Publisher: | Elsevier |
| Page Range: | 107006 |
| Date: | 8 September 2026 |
| Official Publication: | https://doi.org/10.1016/j.bbi.2026.107006 |
| PubMed: | View item in PubMed |
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