Making migraine easier to stomach: the role of the gut-brain-immune axis in headache disorders.

BACKGROUND AND PURPOSE: Headache disorders place a significant burden on the healthcare system, being the leading cause of disability in those under 50 years. Novel studies have interrogated the relationship between headache disorders and gastrointestinal dysfunction, suggesting a link between the gut-brain-immune (GBI) axis and headache pathogenesis. Although the exact mechanisms driving the complex relationship between the GBI axis and headache disorders remain unclear, there is a growing appreciation that a healthy and diverse microbiome is necessary for optimal brain health. METHODS: A literature search was performed through multiple reputable databases in search of Q1 journals within the field of headache disorders and gut microbiome research and were critically and appropriately evaluated to investigate and explore the following; the role of the GBI axis in dietary triggers of headache disorders and the evidence indicating that diet can be used to alleviate headache severity and frequency. The relationship between the GBI axis and post-traumatic headache is then synthesized. Finally, the scarcity of literature regarding paediatric headache disorders and the role that the GBI axis plays in mediating the relationship between sex hormones and headache disorders are highlighted. CONCLUSIONS: There is potential for novel therapeutic targets for headache disorders if understanding of the GBI axis in their aetiology, pathogenesis and recovery is increased.

The Development of Adolescent Chronic Pain following Traumatic Brain Injury and Surgery: The Role of Diet and Early Life Stress.

Pain is evolutionarily necessary for survival in that it reduces tissue damage by signaling the body to respond to a harmful stimulus. However, in many circumstances, acute pain becomes chronic, and this is often dysfunctional. Adolescent chronic pain is a growing epidemic with an unknown etiology and limited effective treatment options. Given that the relationship between acute pain and chronic pain is not straightforward, there is a need to better understand the factors that contribute to the chronification of pain. Since early life factors are critical to a variety of outcomes in the developmental and adolescent periods, they pose promise as potential mechanisms that may underlie the transition from acute to chronic pain. This review examines two early life factors: poor diet and adverse childhood experiences (ACEs); they may increase susceptibility to the development of chronic pain following surgical procedures or traumatic brain injury (TBI). Beyond their high prevalence, surgical procedures and TBI are ideal models to prospectively understand mechanisms underlying the transition from acute to chronic pain. Common themes that emerged from the examination of poor diet and ACEs as mechanisms underlying this transition included: prolonged inflammation and microglia activation leading to sensitization of the pain system, and stress-induced alterations to hypothalamic-pituitary-adrenal axis function, where cortisol is likely playing a role in the development of chronic pain. These areas provide promising targets for interventions, the development of diagnostic biomarkers, and suggest that biological treatment strategies should focus on regulating the neuroinflammatory and stress responses in an effort to modulate and prevent the development of chronic pain.

Microbiome depletion prior to repeat mild TBI differentially alters social deficits and prefrontal cortex plasticity in adolescent and adult rats.

Although aging, repeat mild traumatic brain injury (RmTBI), and microbiome modifications independently change social behavior, there has been no investigation into their cumulative effects on social behavior and neuroplasticity within the prefrontal cortex. Therefore, we examined how microbiome depletion prior to RmTBI affected social behavior and neuroplasticity in adolescent and adult rats. Play, temperament analysis, elevated plus maze, and the hot/cold plate assessed socio-emotional function. Analyses of perineuronal nets (PNNs) and parvalbumin (PV) interneurons was completed. Social-emotional deficits were more pronounced in adults, with microbiome depletion attenuating social behavior deficits associated with RmTBI in both age groups. Microbiome depletion increased branch length and PNN arborization within the PFC but decreased the overall number of PNNs. Adults and males were more vulnerable to RmTBI. Interestingly, microbiome depletion may have attenuated the changes to neuroplasticity and subsequent social deficits, suggesting that the microbiome is a viable, but age-specific, target for RmTBI therapeutics.

Repetitive mild traumatic brain injury alters central and peripheral clock gene expression in the adolescent rat.

Mild traumatic brain injury (mTBI) or concussion is a common injury worldwide leading to substantial medical costs and a high burden on society. In adolescents, falls and sports related trauma are often the causes of mTBI. Importantly, critical brain growth and development occurs during this sensitive period making the prospect of a brain injury a worrying phenomenon. Upwards of 70% of patients report circadian disruption following these injuries and this has been shown to impede recovery. Therefore, we sought to determine if core circadian clock gene expression was disrupted in rat model of repetitive mTBI (RmTBI). Male and female adolescent rats (n = 129) received sham or RmTBI. The animals were then euthanized at different times throughout the day and night. Tissue from the hypothalamus, cerebellum, hippocampus, liver, and small intestine were evaluated for the expression of per1, per2, cry1, clock, bmal1 and rev-erb-α. We found most clock genes varied across the day/night indicating circadian expression patterns. In the hypothalamus we found RmTBI altered the expression of cry1 and bmal1 in addition to sex differences in per2, cry1, clock, bmal1 and rev-erb- α. In the cerebellum, per1, per2, cry1, clock, bmal1 and rev-erb-α rhythms were all knocked out by RmTBI in addition to sex differences in cry1, clock and bmal1 expression. We also detected a significant decrease in overall expression of all clock genes in males in the middle of the night. In the hippocampus we found that RmTBI changed the rhythm of rev-erb-α expression in addition to sex differences in bmal1 expression. In the liver we detected strong rhythms in all genes examined, however only per2 expression was knocked out by RmTBI, in addition we also detected sex differences in per2 and cry1. We also detected an overall decrease in female clock gene expression in the early night. In the small intestine, RmTBI altered cry1 expression and there were sex differences in rev-erb-α. These results indicate that RmTBI alters core circadian clock gene expression in the central and peripheral nervous system in a time, tissue and sex dependent manner. This may be disrupting important phase relationships between the brain and peripheral nervous system and contributing to post-injury symptomology and also highlights the importance for time and sex dependent assessment of injury outcomes.

Persistent Changes in Mechanical Nociception in Rats With Traumatic Brain Injury Involving Polytrauma.

Traumatic brain injury (TBI) survivors often experience debilitating consequences. Due to the high impact nature of TBI, patients often experience concomitant peripheral injuries (ie, polytrauma). A common, yet often overlooked, comorbidity of TBI is chronic pain. Therefore, this study investigated how common concomitant peripheral injuries (ie, femoral fracture and muscle crush) can affect long-term behavioral and structural TBI outcomes with a particular focus on nociception. Rats were randomly assigned to 1 of 4 groups: polytrauma (POLY; ie, fracture + muscle crush + TBI), peripheral injury (PERI; ie, fracture + muscle crush + sham TBI), TBI (ie, sham fracture + sham muscle crush + TBI), and sham-injured (SHAM; ie, sham fracture + sham muscle crush + sham TBI). Rats underwent behavioral testing at 3-, 6-, and 11-weeks postinjury, and were then euthanized for postmortem magnetic resonance imaging (MRI). POLY rats had a persisting increase in pain sensitivity compared to all groups on the von Frey test. MRI revealed that POLY rats also had abnormalities in the cortical and subcortical brain structures involved in nociceptive processing. These findings have important implications and provide a foundation for future studies to determine the underlying mechanisms and potential treatment strategies for chronic pain in TBI survivors. PERSPECTIVE: Rats with TBI and concomitant peripheral trauma displayed chronic nociceptive pain and MRI images also revealed damaged brain structures/pathways that are involved in chronic pain development. This study highlights the importance of polytrauma and the affected brain regions for developing chronic pain.

Synchronizing our clocks as we age: the influence of the brain-gut-immune axis on the sleep-wake cycle across the lifespan.

The microbes that colonize the small and large intestines, known as the gut microbiome, play an integral role in optimal brain development and function. The gut microbiome is a vital component of the bidirectional communication pathway between the brain, immune system, and gut, also known as the brain-gut-immune axis. To date, there has been minimal investigation into the implications of improper development of the gut microbiome and the brain-gut-immune axis on the sleep-wake cycle, particularly during sensitive periods of physical and neurological development, such as childhood, adolescence, and senescence. Therefore, this review will explore the current literature surrounding the overlapping developmental periods of the gut microbiome, brain, and immune system from birth through to senescence, while highlighting how the brain-gut-immune axis affects the maturation and organization of the sleep-wake cycle. We also examine how a dysfunction to either the microbiome or the sleep-wake cycle negatively affects the bidirectional relationship between the brain and gut, and subsequently the overall health and functionality of this complex system. Additionally, this review integrates therapeutic studies to demonstrate when dietary manipulations, such as supplementation with probiotics and prebiotics, can modulate the gut microbiome to enhance the health of the brain-gut-immune axis and optimize our sleep-wake cycle.

Age matters: Microbiome depletion prior to repeat mild traumatic brain injury differentially alters microbial composition and function in adolescent and adult rats.

Dysregulation of the gut microbiome has been shown to perpetuate neuroinflammation, alter intestinal permeability, and modify repetitive mild traumatic brain injury (RmTBI)-induced deficits. However, there have been no investigations regarding the comparative effects that the microbiome may have on RmTBI in adolescents and adults. Therefore, we examined the influence of microbiome depletion prior to RmTBI on microbial composition and metabolome, in adolescent and adult Sprague Dawley rats. Rats were randomly assigned to standard or antibiotic drinking water for 14 days, and to subsequent sham or RmTBIs. The gut microbiome composition and metabolome were analysed at baseline, 1 day after the first mTBI, and at euthanasia (11 days following the third mTBI). At euthanasia, intestinal samples were also collected to quantify tight junction protein (TJP1 and occludin) expression. Adolescents were significantly more susceptible to microbiome depletion via antibiotic administration which increased pro-inflammatory composition and metabolites. Furthermore, RmTBI induced a transient increase in 'beneficial bacteria' (Lachnospiraceae and Faecalibaculum) in only adolescents that may indicate compensatory action in response to the injury. Finally, microbiome depletion prior to RmTBI generated a microbiome composition and metabolome that exemplified a potentially chronic pathogenic and inflammatory state as demonstrated by increased Clostridium innocuum and Erysipelatoclostridium and reductions in Bacteroides and Clostridium Sensu Stricto. Results highlight that adolescents are more vulnerable to RmTBI compared to adults and dysbiosis prior to injury may exacerbate secondary inflammatory cascades.

Gut microbiome depletion and repetitive mild traumatic brain injury differentially modify bone development in male and female adolescent rats.

Dysregulation of the gut microbiome has been shown to disrupt both bone formation and bone resorption in several preclinical and clinical models. However, the role of microbiome in adolescent bone development remains poorly understood. This effect of disrupted bone development may be more pronounced during adolescence, when bone development is vulnerable to environmental stimuli and external insults (e.g., antibiotic treatment and traumatic brain injury), as this is a critical window of development. Therefore, in this study, we sought to investigate the effect of repetitive mild traumatic brain injury (RmTBI) and gut microbiome depletion by antibiotic treatment on femur length and bone density in male and female adolescent Sprague Dawley rats. Rats were randomly assigned to receive standard or antibiotic autoclaved drinking water and to receive sham or RmTBIs injuries. Using micro-computed tomography (µCT), we found sexually dimorphic changes in adolescent bone development in response to microbiome depletion and RmTBI. Specifically, gut microbiome depletion stunted femur growth in males and altered cross sectional bone area (CSA), bone area fraction, and the bone volume of low and mid density bone in the distal metaphyseal region of the femur. Conversely, RmTBI and antibiotic treatment individually disrupted bone growth, bone area fraction, and bone volume of high-density bone within the distal metaphyseal region of the femur in females, but not when combined. Therefore, findings from this study indicate that gut microbiome and RmTBI may alter bone development in a sex-dependent manner during adolescence.

Investigating the cumulative effects of Δ9-tetrahydrocannabinol and repetitive mild traumatic brain injury on adolescent rats.

The prevalence of mild traumatic brain injury is highest amongst the adolescent population and can lead to complications including neuroinflammation and excitotoxicity. Also pervasive in adolescents is recreational cannabis use. Δ9-Tetrahydrocannabinol, the main psychoactive component of cannabis, is known to have anti-inflammatory properties and serves as a neuroprotective agent against excitotoxicity. Thus, we investigated the effects of Δ9-tetrahydrocannabinol on recovery when administered either prior to or following repeated mild brain injuries. Male and female Sprague-Dawley rats were randomly assigned to receive Δ9-tetrahydrocannabinol or vehicle either prior to or following the repeated injuries. Rats were then tested on a behavioural test battery designed to measure post-concussive symptomology. The hippocampus, nucleus accumbens and prefrontal cortex were extracted from all animals to examine mRNA expression changes (Bdnf, Cnr1, Comt, GR, Iba-1 and Vegf-2R). We hypothesized that, in both experiments, Δ9-tetrahydrocannabinol administration would provide neuroprotection against mild injury outcomes and confer therapeutic benefit. Δ9-Tetrahydrocannabinol administration following repeated mild traumatic brain injury was beneficial to three of the six behavioural outcomes affected by injury (reducing anxiety and depressive-like behaviours while also mitigating injury-induced deficits in short-term working memory). Δ9-Tetrahydrocannabinol administration following injury also showed beneficial effects on the expression of Cnr1, Comt and Vegf-2R in the hippocampus, nucleus accumbens and prefrontal cortex. There were no notable benefits of Δ9-tetrahydrocannabinol when administered prior to injury, suggesting that Δ9-tetrahydrocannabinol may have potential therapeutic benefit on post-concussive symptomology when administered post-injury, but not pre-injury.