Fetal alcohol spectrum disorders (FASD) are associated with social interaction behavior and gastrointestinal (GI) abnormalities. These abnormal behaviors and GI abnormalities overlap with autism spectrum disorder (ASD). We investigated the effect of fetal alcohol exposure (FAE) on social interaction deficits (hallmark of autism). Evidence indicates that exogenous lipopolysaccharide (LPS) administration during gestation induces autism-like behavior in the litters. LPS regulates the expression of genes underlying differentiation, immune function, myelination and synaptogenesis in fetal brain by the LPS receptor, TLR-4-dependent mechanism. In this study, we evaluated the role of TLR-4 in FAE-induced social behavior deficit. WT and TLR4−/− pregnant mice were fed Lieber-DeCarli liquid diet with or without EtOH. Control group was pair-fed with isocaloric diet. Social behavior was tested in the adult litters at postnatal day 60. Frontal cortex mRNA expression of autistic candidate genes (Ube3a, Gabrb3, Mecp2) and inflammatory cytokine genes (IL-1β, IL-6, TNF-α) were measured by RT-qPCR. Adult male litters of EtOH-fed WT dams showed low birth weight compared to litters of pair-fed WT dams. However, their body weights at adulthood were greater compared to the body weights of litters of pair-fed WT dams. There were no body weight differences in litters of TLR4−/− dams. Social interaction deficit was observed only in male litters of EtOH-fed WT dams, but it was not observed in both male and female litters of EtOH-fed TLR4−/− dams. Expressions of autism candidate genes, Gabrb3 and Ube3a were elevated, while that of Mecp2 gene was suppressed in the frontal cortex of male, but not female litters of EtOH-fed WT mice. The expressions of inflammatory cytokine genes, IL-1β, IL-6 and TNF-α were also significantly increased in the frontal cortex of male, but not female, litters of EtOH-fed dams. The changes in the expression of autistic and cytokine genes were unaffected in the litters of EtOH-fed TLR4−/− dams. These data also indicate that TLR4 mediates FAE-induced changes in social interactions and gene expression in brain, suggesting that EtOH-induced LPS absorption from the maternal gut may be involved in gene expression changes in the fetal brain.
IntroductionChronic stress is co-morbid with alcohol use disorder that feedback on one another, thus impeding recovery from both disorders. Stress and the stress hormone corticosterone aggravate alcohol-induced intestinal permeability and liver damage. However, the mechanisms involved in compounding tissue injury by stress/corticosterone and alcohol are poorly defined. Here we explored the involvement of the TRPV6 channel in stress (or corticosterone) 3and alcohol-induced intestinal epithelial permeability, microbiota dysbiosis, and systemic inflammation. MethodsChronic alcohol feeding was performed on adult wild-type and Trpv6-/- mice with or without corticosterone treatment or chronic restraint stress (CRS). The barrier function was determined by evaluating inulin permeability in vivo and assessing tight junction (TJ) and adherens junction (AJ) integrity by immunofluorescence microscopy. The gut microbiota composition was evaluated by 16S rRNA sequencing and metagenomic analyses. Systemic responses were assessed by evaluating endotoxemia, systemic inflammation, and liver damage.ResultsCorticosterone and CRS disrupted TJ and AJ, increased intestinal mucosal permeability, and caused endotoxemia, systemic inflammation, and liver damage in wild-type but not Trpv6-/- mice. Corticosterone and CRS synergistically potentiated the alcohol-induced breakdown of intestinal epithelial junctions, mucosal barrier impairment, endotoxemia, systemic inflammation, and liver damage in wild-type but not Trpv6-/- mice. TRPV6 deficiency also blocked the effects of CRS and CRS-mediated potentiation of alcohol-induced dysbiosis of gut microbiota. ConclusionsThese findings indicate an essential role of TRPV6 in stress, corticosterone, and alcohol-induced intestinal permeability, microbiota dysbiosis, endotoxemia, systemic inflammation, and liver injury. This study identifies TRPV6 as a potential therapeutic target for developing treatment strategies for stress and alcohol-associated comorbidity.
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