Abstract
BackgroundRetinoic acid-related orphan receptor alpha (RORA) has been reported to be suppressed in autistic patients and is associated with autism spectrum disorders (ASD), although the potential role and mechanism of RORA on gastrointestinal (GI) symptoms in ASD patients is still not reported. In this study, we aim to investigate the contribution of RORA to GI symptoms through a maternal diabetes-mediated autism-like mouse model.ResultsMale offspring of diabetic dams were treated with either superoxide dismutase (SOD) mimetic MnTBAP or RORA agonist SR1078, or were crossbred with intestine epithelial cells (IEC)-specific RORA knockout (RORA−/−) mouse. Gene expression, oxidative stress and inflammation were measured in brain tissues, peripheral blood mononuclear cells (PBMC) and IEC, and GI symptoms were evaluated. Our results showed that SOD mimetic MnTBAP completely, while RORA agonist SR1078 partly, reversed maternal diabetes-mediated oxidative stress and inflammation in the brain, PBMC and IEC, as well as GI symptoms, including intestine permeability and altered gut microbiota compositions. IEC-specific RORA deficiency either mimicked or worsened maternal diabetes-mediated GI symptoms as well as oxidative stress and inflammation in IEC, while there was little effect on maternal diabetes-mediated autism-like behaviors.ConclusionsWe conclude that RORA suppression contributes to maternal diabetes-mediated GI symptoms in autism-like mouse offspring, this study provides a potential therapeutical target for maternal diabetes-mediated GI symptoms in offspring through RORA activation.
Highlights
Retinoic acid-related orphan receptor alpha (RORA) has been reported to be suppressed in autistic patients and is associated with autism spectrum disorders (ASD), the potential role and mechanism of RORA on gastrointestinal (GI) symptoms in ASD patients is still not reported
The results showed that maternal diabetes (STZ/VEH) treatment significantly deceased the mRNA levels of RORA, CYP19A1 and superoxide dismutase 2 (SOD2) (P < 0.0001), respectively, compared to the CTL/ VEH group; superoxide dismutase (SOD) mimetic MnTBAP treatment (STZ/ MnTBAP) completely reversed this effect; while RORA agonist (STZ/SR1078) completely reversed the expression of CYP19A1, partly reversed on SOD2 (P < 0.01), but showed no effect on RORA
We evaluated SOD2 activity, and the results showed that maternal diabetes (STZ/VEH) significantly decreased SOD2 activity (P < 0.0001) compared to the CTL group mice receiving only vehicle treatment (CTL/VEH) group; treatments of either STZ/MnTBAP or STZ/SR1078 completely reversed this effect
Summary
Retinoic acid-related orphan receptor alpha (RORA) has been reported to be suppressed in autistic patients and is associated with autism spectrum disorders (ASD), the potential role and mechanism of RORA on gastrointestinal (GI) symptoms in ASD patients is still not reported. Retinoic acid-related orphan receptor alpha (RORA) is involved in many pathophysiological processes [21, 22] and has been shown to be associated with ASD development, with suppressed expression of RORA being identified in autistic patients [23]. We hypothesize that RORA may play a role in GI symptoms in maternal diabetes-mediated autism-like mouse offspring through pathways involving the suppression of RORA and its target genes CYP19A1 and SOD2 in the gut system [30, 31]
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