The interaction between intestinal bacterial metabolites and phosphatase and tensin homolog in autism spectrum disorder

• Published in: Molecular and cellular neuroscience Vol. 124; p. 103805
• Main Authors: Zheng, Yuanpeng, Prince, Naika, van Hattem, Christine, Garssen, Johan, Pardo, Paula Perez, Kraneveld, Aletta D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2023
• Subjects: 4EPS; Animals; ASD; Autism Spectrum Disorder - genetics; Disease Models, Animal; Inflammation; LPS; Mice; Neuroimmune response; pCS; PTEN; PTEN Phosphohydrolase - metabolism; Valproic Acid; VPA; Neuroimmune response; pCS; ASD; VPA; PTEN; 4EPS; LPS
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2022.103805

Intestinal bacteria-associated para-cresyl sulfate (pCS) and 4-ethylphenyl sulfate (4EPS) are elevated in autism spectrum disorder (ASD). Both metabolites can induce ASD-like behaviors in mice, but the molecular mechanisms are not known. Phosphatase and tensin homolog (PTEN) is a susceptibility gene for ASD. The present study investigated the relation between pCS and 4EPS and PTEN in ASD in a valproic acid (VPA)-induced murine ASD model and an in vitro LPS-activated microglial model. The VPA-induced intestinal inflammation and compromised permeability in the distal ileum was not associated with changes of PTEN expression and phosphorylation. In contrast, VPA reduced PTEN expression in the hippocampus of mice. In vitro results show that pCS and 4EPS reduced PTEN expression and derailed innate immune response of BV2 microglial cells. The PTEN inhibitor VO-OHpic did not affect innate immune response of microglial cells. In conclusion, PTEN does not play a role in intestinal inflammation and compromised permeability in VPA-induced murine model for ASD. Although pCS and 4EPS reduced PTEN expression in microglial cells, PTEN is not involved in the pCS and 4EPS-induced derailed innate immune response of microglial cells. Further studies are needed to investigate the possible involvement of reduced PTEN expression in the ASD brain regarding synapse function and neuronal connectivity. •The expression of susceptibility gene for ASD, PTEN, is decreased in the hippocampus of VPA-exposed mice•Bacterial metabolites pCS and 4EPS decrease PTEN expression of BV2 microglial cells•pCS and 4EPS attenuates TNF-α and IL-6 release by BV2 microglial cells•pCS- or 4EPS-induced decreased PTEN expression is not involved in their inhibitory effects on cytokine release by BV2 microglial cells.