Nod-like receptors are critical for gut-brain axis signalling in mice.

KEY POINTS: •Nucleotide binding oligomerization domain (Nod)-like receptors regulate cognition, anxiety and hypothalamic-pituitary-adrenal axis activation. •Nod-like receptors regulate central and peripheral serotonergic biology. •Nod-like receptors are important for maintenance of gastrointestinal physiology. •Intestinal epithelial cell expression of Nod1 receptors regulate behaviour. ABSTRACT: Gut-brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre+ Nod1f/f ), but not Nod2, increased susceptibility to stress-induced anxiety-like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.

A Six Week Therapeutic Ballet Intervention Improved Gait and Inhibitory Control in Children With Cerebral Palsy-A Pilot Study.

Children with cerebral palsy (CP) have motor impairments that make it challenging for them to participate in standard physical activity (PA) interventions. There is a need to evaluate adapted PA interventions for this population. Dance can promote coordination, posture, muscle strength, motor learning, and executive functioning. This pilot study evaluated the feasibility and the effects of a new therapeutic ballet intervention specifically designed for children with CP. Methods: Eight children with CP (9-14 y/o; 75% female) participated in a 6-week therapeutic ballet intervention. Outcomes were measured in multiple domains, including body composition (DXA), muscle strength (hand-grip dynamometer), habitual physical activity, gait and selective motor control functions, and executive functioning. Follow-up assessments of habitual physical activity, gait, and executive functioning were completed 4 to 5 weeks post-intervention. Results: Five of the eight participants were overfat or obese based on DXA percentage of body fat. All participants were below the 50th percentile for their age and gender for bone density. Four participants showed a trend to improve hand-grip strength in one hand only, while one improved in both hands. There were significant improvements in gait across time points (pre, post, and follow-up), specifically in time of ambulation (X pre = 4.36, X post = 4.22, X follow-up = 3.72, d = 0.056, p = 0.02), and in step length (cm) on the right: X pre = 48.29, X post = 50.77, X follow-up = 52.11, d = 0.22, p = 0.027, and left stride: X pre = 96.29, X post = 102.20, X follow-up = 104.20, d = 0.30, p = 0.027, indicating gait changes in bilateral lower extremities. There was improvement in inhibitory control (d = 0.78; 95% Confidence Limit = ±0.71, p < 0.05) with large individual responses primarily among those above the mean at baseline. Conclusions: Therapeutic ballet may prove to be a useful intervention to promote physiological and cognitive functions in children with CP. Results demonstrated feasibility of the physical, physiological, and cognitive assessments and suggested improvements in participants' gait and inhibitory control with large individual responses. Modifications to personalize the intervention may be needed to optimize positive outcomes. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03681171.