A novel Mediterranean diet-inspired supplement ameliorates cognitive, microbial, and metabolic deficits in a mouse model of low-grade inflammation.

The Mediterranean diet (MD) and its bioactive constituents have been advocated for their neuroprotective properties along with their capacity to affect gut microbiota speciation and metabolism. Mediated through the gut brain axis, this modulation of the microbiota may partly contribute to the neuroprotective properties of the MD. To explore this potential interaction, we evaluated the neuroprotective properties of a novel bioactive blend (Neurosyn240) resembling the Mediterranean diet in a rodent model of chronic low-grade inflammation. Behavioral tests of cognition, brain proteomic analysis, 16S rRNA sequencing, and 1H NMR metabolomic analyses were employed to develop an understanding of the gut-brain axis interactions involved. Recognition memory, as assessed by the novel object recognition task (NOR), decreased in response to LPS insult and was restored with Neurosyn240 supplementation. Although the open field task performance did not reach significance, it correlated with NOR performance indicating an element of anxiety related to this cognitive change. Behavioral changes associated with Neurosyn240 were accompanied by a shift in the microbiota composition which included the restoration of the Firmicutes: Bacteroidota ratio and an increase in Muribaculum, Rikenellaceae Alloprevotella, and most notably Akkermansia which significantly correlated with NOR performance. Akkermansia also correlated with the metabolites 5-aminovalerate, threonine, valine, uridine monophosphate, and adenosine monophosphate, which in turn significantly correlated with NOR performance. The proteomic profile within the brain was dramatically influenced by both interventions, with KEGG analysis highlighting oxidative phosphorylation and neurodegenerative disease-related pathways to be modulated. Intriguingly, a subset of these proteomic changes simultaneously correlated with Akkermansia abundance and predominantly related to oxidative phosphorylation, perhaps alluding to a protective gut-brain axis interaction. Collectively, our results suggest that the bioactive blend Neurosyn240 conferred cognitive and microbiota resilience in response to the deleterious effects of low-grade inflammation.

Dietary fiber supplementation increases Drosophila melanogaster lifespan and gut microbiota diversity.

Dietary fiber has been shown to have multiple health benefits, including a positive effect on longevity and the gut microbiota. In the present study, Drosophila melanogaster has been chosen as an in vivo model organism to study the health effects of dietary fiber supplementation (DFS). DFS extended the mean half-life of male and female flies, but the absolute lifespan only increased in females. To reveal the underlying mechanisms, we examined the effect of DFS on gut microbiota diversity and abundance, local gut immunity, and the brain proteome. A significant difference in the gut microbial community was observed between groups with and without fiber supplementation, which reduced the gut pathogenic bacterial load. We also observed an upregulated expression of dual oxidase and a modulated expression of Attacin and Diptericin genes in the gut of older flies, possibly delaying the gut dysbiosis connected to the age-related gut immune dysfunction. Brain proteome analysis showed that DFS led to the modulation of metabolic processes connected to mitochondrial biogenesis, the RhoV-GTPase cycle, organelle biogenesis and maintenance, membrane trafficking and vesicle-mediated transport, possibly orchestrated through a gut-brain axis interaction. Taken together, our study shows that DFS can prolong the half-life and lifespan of flies, possibly by promoting a healthier gut environment and delaying the physiological dysbiosis that characterizes the ageing process. However, the RhoV-GTPase cycle at the brain level may deserve more attention in future studies.

Dietary (Poly)phenols and the Gut-Brain Axis in Ageing.

As the population ages, the incidence of age-related neurodegenerative diseases is rapidly increasing, and novel approaches to mitigate this soaring prevalence are sorely needed. Recent studies have highlighted the importance of gut microbial homeostasis and its impact on brain functions, commonly referred to as the gut-brain axis, in maintaining overall health and wellbeing. Nonetheless, the mechanisms by which this system acts remains poorly defined. In this review, we will explore how (poly)phenols, a class of natural compounds found in many plant-based foods and beverages, can modulate the gut-brain axis, and thereby promote neural health. While evidence indicates a beneficial role of (poly)phenol consumption as part of a balanced diet, human studies are scarce and mechanistic insight is still lacking. In this regard, we make the case that dietary (poly)phenols should be further explored to establish their therapeutic efficacy on brain health through modulation of the gut-brain axis, with much greater emphasis on carefully designed human interventions.

Aspects of Physical Activity and Quality of Life in Adults with Cerebral Palsy.

Background: Physical activity and sedentary behavior may differentially impact health-related quality of life in adults with cerebral palsy. Objective: The present investigation assessed the independent relationships between aspects of physical activity and sedentary behavior related to health related quality of life in adults with cerebral palsy. Methods: Through a cross-sectional online survey of 118 adults with cerebral palsy, participants self-reported the extent of their functional impairments using the Gross Motor Function Classification System, Manual Ability Classification System, and Communication Function Classification System; while mental and physical health-related quality of life were assessed using the RAND-36. Physical activity and sedentary behavior were quantified using the Physical Activity and Disability Survey-Revised and Sedentary Behavior Questionnaire, respectively. Results: Accounting for potential confounding influences of impairments, neither exercise-related physical activity, leisure time- related physical activity, occupational physical activity, nor sedentary behavior was associated with any characterization of health-related quality of life. However, greater engagement in general lifestyle physical activity was related to superior mental health-related quality of life. Conclusion: These findings provide initial evidence to suggest that focusing public health and therapeutic recommendations for individuals with cerebral palsy on general physical activity engagement throughout the day might incur potential benefits for enhancing mental health- related quality of life in this population.

Refined diet consumption increases neuroinflammatory signalling through bile acid dysmetabolism.

Over recent decades, dietary patterns have changed significantly due to the increasing availability of convenient, ultra-processed refined foods. Refined foods are commonly depleted of key bioactive compounds, which have been associated with several deleterious health conditions. As the gut microbiome can influence the brain through a bidirectional communication system known as the 'microbiota-gut-brain axis', the consumption of refined foods has the potential to affect cognitive health. In this study, multi-omics approaches were employed to assess the effect of a refined diet on the microbiota-gut-brain axis, with a particular focus on bile acid metabolism. Mice maintained on a refined low-fat diet (rLFD), consisting of high sucrose, processed carbohydrates and low fibre content, for eight weeks displayed significant gut microbial dysbiosis, as indicated by diminished alpha diversity metrics (p < 0.05) and altered beta diversity (p < 0.05) when compared to mice receiving a chow diet. Changes in gut microbiota composition paralleled modulation of the metabolome, including a significant reduction in short-chain fatty acids (acetate, propionate and n-butyrate; p < 0.001) and alterations in bile acid concentrations. Interestingly, the rLFD led to dysregulated bile acid concentrations across both the colon (p < 0.05) and the brain (p < 0.05) which coincided with altered neuroinflammatory gene expression. In particular, the concentration of TCA, TDCA and T-α-MCA was inversely correlated with the expression of NF-κB1, a key transcription factor in neuroinflammation. Overall, our results suggest a novel link between a refined low-fat diet and detrimental neuronal processes, likely in part through modulation of the microbiota-gut-brain axis and bile acid dysmetabolism.

Concussion Risk and Recovery in Athletes With Psychostimulant-Treated Attention-Deficit/Hyperactivity Disorder: Findings From the NCAA-DOD CARE Consortium.

The aim of the present study was to examine the effects of attention-deficit/hyperactivity disorder (ADHD) -related psychostimulant use in the context of concussion risk and symptom recovery. Data were obtained from the National Collegiate Athletic Association Department of Defense Grand Alliance Concussion Assessment, Research, and Education (NCAA-DOD CARE) Consortium from 2014 to 2017. Relative to individuals without diagnosed ADHD (i.e., control), both ADHD diagnosis and the combination of ADHD diagnosis and psychostimulant use were associated with a greater risk of incurring a concussive injury. Following a concussive injury, ADHD diagnosis was associated with longer symptom recovery time relative to the control group. However, individuals with ADHD who use psychostimulants did not take longer to resolve symptoms than controls, suggesting that psychostimulants may have a positive influence on recovery. Regardless of time point, ADHD diagnosis was associated with an elevated number of concussion-related symptoms; however, this effect appears mitigated by having used ADHD-related psychostimulants.

Association of physical activity and fitness with executive function among preschoolers

It is well-documented in the literature that high levels of regular physical activity (PA), low levels of sedentary behavior (SB), and high levels of cardiorespiratory fitness (CRF) are associated with superior cognitive functioning, especially with regard to older populations. However, concerning other age groups (e.g., preschoolers) the available evidence documenting such a positive relationship is relatively scarce. Thus, this study aimed to investigate the association of time spent in different PA intensity zones and CRF with executive functions (EFs) in preschool-age children. To this end, preschoolers (n = 127) aged 3 to 6 years were recruited from 9 kindergarten classes in 2 districts of Shenzhen, China. The amount and the intensity of PA were assessed via accelerometry, and the CRF level was quantified by the 20-meter shuttle run test. EFs including inhibitory control and working memory were assessed using the one-on-one iPad-based Early Year Toolbox. Results suggested that children who had a higher CRF level (“impulse control” scores: β = 0.34, p < .001; “Go” accuracy: β = 0.31, p < .001; “No-Go” accuracy: β =0.28, < .001) and spentmore time in moderate-to-vigorous physical activity (MVPA) (“impulse control” scores: β = 0.50, p < .001; No-Go” accuracy: β = 0.52, p < .001) had higher scores on inhibitory control tasks, and those who had a higher CRF level had higher scores on a working memory task (β = 0.24, p < .05). The findings are discussed in light of the positive roles of MVPA and CRF for promoting EFs, but also consider the disproportionate association of PA and CRF with working memory relative to inhibition. (AU)

Increased anxiety and depression among collegiate athletes with comorbid ADHD and history of concussion.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is prevalent among student-athletes when compared to the general population. Mental health disruptions (i.e., depression or anxiety) are common among student-athletes, and risk of experiencing depressive and anxious symptoms may be even greater among student-athletes that have incurred concussion. OBJECTIVE: To examine the influence of pre-existing ADHD and history of concussion on mental health in collegiate student-athletes. DESIGN: Retrospective cross-sectional study. SETTING: National Collegiate Athletic Association Division-I (NCAA) athletics. PATIENTS: Between 2010 and 2017, student-athletes at a Southeastern NCAA Division-I institution were surveyed as part of a Performance, Health, and Wellness Program. Analyses were conducted using a sample of 324 student athletes (212 female) with either a prior diagnosis of ADHD, a prior history of a sport-related concussion, both prior diagnosis of ADHD and a history of sport-related concussion, or neither (controls). MAIN OUTCOME MEASURE(S): Symptomatology associated with ADHD was characterized using the Behavior Assessment System for Children Self-Report of Personality College Version. The State-Trait Anxiety Inventory and the Center of Epidemiological Studies-Depression Scale examined anxious and depressive symptomatology. RESULTS: Student-athletes with ADHD and a history of concussion had 16.4 times greater odds of exhibiting clinically significant symptoms of state anxiety and 7.9 times greater odds of exhibiting clinically significant symptoms of depression, relative to control student-athletes. Every participant with both a diagnosis of ADHD and a history of concussion exhibited clinically significant attentional problems. CONCLUSIONS: Having both ADHD and a history of concussion may have a synergistic effect on mental health beyond that of ADHD and/or concussion alone. Additional longitudinal research is necessary to verify current findings. However, athletic trainers and other health care professionals are encouraged to be mindful of student-athletes with ADHD, as they may be more vulnerable to experiencing symptoms of depression and state anxiety with elevated inattentive behaviors following a concussion.

Association of physical activity and fitness with executive function among preschoolers.

It is well-documented in the literature that high levels of regular physical activity (PA), low levels of sedentary behavior (SB), and high levels of cardiorespiratory fitness (CRF) are associated with superior cognitive functioning, especially with regard to older populations. However, concerning other age groups (e.g., preschoolers) the available evidence documenting such a positive relationship is relatively scarce. Thus, this study aimed to investigate the association of time spent in different PA intensity zones and CRF with executive functions (EFs) in preschool-age children. To this end, preschoolers (n = 127) aged 3 to 6 years were recruited from 9 kindergarten classes in 2 districts of Shenzhen, China. The amount and the intensity of PA were assessed via accelerometry, and the CRF level was quantified by the 20-meter shuttle run test. EFs including inhibitory control and working memory were assessed using the one-on-one iPad-based Early Year Toolbox. Results suggested that children who had a higher CRF level ("impulse control" scores: ß = 0.34, p < .001; "Go" accuracy: ß = 0.31, p < .001; "No-Go" accuracy: ß =0.28, < .001) and spentmore time in moderate-to-vigorous physical activity (MVPA) ("impulse control" scores: ß = 0.50, p < .001; No-Go" accuracy: ß = 0.52, p < .001) had higher scores on inhibitory control tasks, and those who had a higher CRF level had higher scores on a working memory task (ß = 0.24, p < .05). The findings are discussed in light of the positive roles of MVPA and CRF for promoting EFs, but also consider the disproportionate association of PA and CRF with working memory relative to inhibition.

Sexual dimorphism in the context of nutrition and health.

Diets and dietary constituents that we consume have a considerable impact on disease risk. Intriguingly these effects may be modulated to some extent by sex. Lack of female representation in nutritional studies as well as a lack of stratification by sex has and continues to limit our understanding of these sex × diet interactions. Here we provide an overview of the current and available literature describing how exposure to certain dietary patterns (Western-style diet, Mediterranean diet, vegetarian/vegan, ketogenic diet) and dietary constituents (dietary fibre, PUFA and plant bioactive) influences disease risk in a sex-specific manner. Interestingly, these sex differences appear to be highly disease-specific. The identification of such sex differences in response to diet stresses the importance of sex stratification in nutritional research.

Role of mucin glycosylation in the gut microbiota-brain axis of core 3 O-glycan deficient mice.

Alterations in intestinal mucin glycosylation have been associated with increased intestinal permeability and sensitivity to inflammation and infection. Here, we used mice lacking core 3-derived O-glycans (C3GnT-/-) to investigate the effect of impaired mucin glycosylation in the gut-brain axis. C3GnT-/- mice showed altered microbial metabolites in the caecum associated with brain function such as dimethylglycine and N-acetyl-L-tyrosine profiles as compared to C3GnT+/+ littermates. In the brain, polysialylated-neural cell adhesion molecule (PSA-NCAM)-positive granule cells showed an aberrant phenotype in the dentate gyrus of C3GnT-/- mice. This was accompanied by a trend towards decreased expression levels of PSA as well as ZO-1 and occludin as compared to C3GnT+/+. Behavioural studies showed a decrease in the recognition memory of C3GnT-/- mice as compared to C3GnT+/+ mice. Combined, these results support the role of mucin O-glycosylation in the gut in potentially influencing brain function which may be facilitated by the passage of microbial metabolites through an impaired gut barrier.

The Influence of APOE Genotype, DHA, and Flavanol Intervention on Brain DHA and Lipidomics Profile in Aged Transgenic Mice.

The apolipoprotein E4 (APOE4) genotype is predictive of Alzheimer's disease (AD). The brain is highly enriched with the omega-3 polyunsaturated fatty acid (n3-PUFA), docosahexaenoic acid (DHA). DHA's metabolism is defective in APOE4 carriers. Flavanol intake can play a role in modulating DHA levels. However, the impact of flavanol co-supplementation with fish oil on brain DHA uptake, status and partitioning, and according to APOE genotype is currently unknown. Here, using a humanised APOE3 and APOE4 targeted replacement transgenic mouse model, the interactive influence of cocoa flavanols (FLAV) and APOE genotype on the blood and subcortical brain PUFA status following the supplementation of a high fat (HF) enriched with DHA from fish oil (FO) was investigated. DHA levels increased in the blood (p < 0.001) and brain (p = 0.001) following supplementation. Compared to APOE3, a higher red blood cell (RBC) DHA (p < 0.001) was evident in APOE4 mice following FO and FLAV supplementation. Although FO did not increase the percentage of brain DHA in APOE4, a 17.1% (p < 0.05) and 20.0% (p < 0.001) higher DHA level in the phosphatidylcholine (PC) fraction in the HF FO and HF FO FLAV groups, and a 14.5% (p < 0.05) higher DHA level in the phosphatidylethanolamine (PE) fraction in the HF FO FLAV group was evident in these animals relative to the HF controls. The addition of FLAV (+/- FO) did not significantly increase the percentage of brain DHA in the group as a whole. However, a higher brain: RBC DHA ratio was evident in APOE3 only (p < 0.05) for HF FLAV versus HF. In conclusion, our data shows only modest effects of FLAV on the brain DHA status, which is limited to APOE3.

Validation of the g.tec Unicorn Hybrid Black wireless EEG system.

Although dry and hybrid-style electrode technology has been well validated, systems utilizing these electrodes have not been widely adopted. One reason for this may be that the systems incorporating such technology present limitations that are fundamental to the EEG approach. The g.tec Unicorn Hybrid Black system, a low density Bluetooth EEG amplifier, however, attempts to address many of these limitations to allow greater flexibility to replicate methods used with traditional EEG amplifiers and extend them to more novel applications. The aim of the present investigation was to validate the g.tec Unicorn Hybrid Black amplifier to determine if it provides comparable data to a traditional laboratory-based system when no electrode preparation is utilized or if a saline-based solution is necessary to obtain sufficient signal quality. Stimulus-locked ERPs and EEG power spectrum data were concurrently recorded using both the Unicorn Hybrid Black amplifier and a traditional high-end laboratory-based low-impedance wired system. Findings suggest that the Unicorn Hybrid Black provides valid measures for investigations of frequency spectra even with no conductive solution applied. However, to obtain valid assessments of event-related brain potentials, it appears necessary to use a conductive solution for electrode preparation. This system appears well suited to allow for high-quality and flexible EEG measures available outside of traditional laboratory environments.

Look into my eyes: What can eye-based measures tell us about the relationship between physical activity and cognitive performance?

BACKGROUND: There is a growing interest to understand the neurobiological mechanisms that drive the positive associations of physical activity and fitness with measures of cognitive performance. To better understand those mechanisms, several studies have employed eye-based measures (e.g., eye movement measures such as saccades, pupillary measures such as pupil dilation, and vascular measures such as retinal vessel diameter) deemed to be proxies for specific neurobiological mechanisms. However, there is currently no systematic review providing a comprehensive overview of these studies in the field of exercise-cognition science. Thus, this review aimed to address that gap in the literature. METHODS: To identify eligible studies, we searched 5 electronic databases on October 23, 2022. Two researchers independently extracted data and assessed the risk of bias using a modified version of the Tool for the assEssment of Study qualiTy and reporting in EXercise (TESTEX scale, for interventional studies) and the critical appraisal tool from the Joanna Briggs Institute (for cross-sectional studies). RESULTS: Our systematic review (n = 35 studies) offers the following main findings: (a) there is insufficient evidence available to draw solid conclusions concerning gaze-fixation-based measures; (b) the evidence that pupillometric measures, which are a proxy for the noradrenergic system, can explain the positive effect of acute exercise and cardiorespiratory fitness on cognitive performance is mixed; (c) physical training- or fitness-related changes of the cerebrovascular system (operationalized via changes in retinal vasculature) are, in general, positively associated with cognitive performance improvements; (d) acute and chronic physical exercises show a positive effect based on an oculomotor-based measure of executive function (operationalized via antisaccade tasks); and (e) the positive association between cardiorespiratory fitness and cognitive performance is partly mediated by the dopaminergic system (operationalized via spontaneous eye-blink rate). CONCLUSION: This systematic review offers confirmation that eye-based measures can provide valuable insight into the neurobiological mechanisms that may drive positive associations between physical activity and fitness and measures of cognitive performance. However, due to the limited number of studies utilizing specific methods for obtaining eye-based measures (e.g., pupillometry, retinal vessel analysis, spontaneous eye blink rate) or investigating a possible dose-response relationship, further research is necessary before more nuanced conclusions can be drawn. Given that eye-based measures are economical and non-invasive, we hope this review will foster the future application of eye-based measures in the field of exercise-cognition science.

Associations of meeting 24-h movement behavior guidelines with cognitive difficulty and social relationships in children and adolescents with attention deficit/hyperactive disorder.

BACKGROUND: Evidence-based 24-h movement behavior (24-HMB) guidelines have been developed to integrate recommendations for the time spent on physical activity, sedentary behavior, and sleep. For children and adolescents, these 24-HMB guidelines recommend a maximum of two hours of recreational screen time (as part of sedentary behavior), a minimum of 60 min per day of moderate to vigorous physical activity (MVPA), and an age-appropriate sleep duration (9-11 h for 5 to 13-year-olds; 8-10 h for 14 to 17-year-olds). Although adherence to the guidelines has been associated with positive health outcomes, the effects of adhering to the 24-HMB recommendations have not been fully examined in children and adolescents with attention eficit/hyperactive disorder (ADHD). Therefore, this study examined potential associations between meeting the 24-HMB guidelines and indicators of cognitive and social difficulties in children and adolescents with ADHD. METHODS: Cross-sectional data on 3470 children and adolescents with ADHD aged between 6 and 17 years was extracted from the National Survey for Children's Health (NSCH 2020). Adherence to 24-HMB guidelines comprised screen time, physical activity, and sleep. ADHD-related outcomes included four indicators; one relating to cognitive difficulties (i.e., serious difficulties in concentrating, remembering, or making decisions) and three indicators of social difficulties (i.e., difficulties in making or keeping friends, bullying others, being bullied). Logistic regression was performed to determine the associations between adherence to 24-HMB guidelines and the cognitive and social outcomes described above, while adjusting for confounders. RESULTS: In total, 44.8% of participants met at least one movement behavior guideline, while only 5.7% met all three. Adjusted logistic regressions further showed that meeting all three guidelines was associated with lower odds of cognitive difficulties in relation to none of the guidelines, but the strongest model included only screen time and physical activity as predictors (OR = 0.26, 95% CI 0.12-0.53, p < .001). For social relationships, meeting all three guidelines was associated with lower odds of difficulty keeping friends (OR = 0.46, 95% CI 0.21-0.97, p = .04) in relation to none of the guidelines. Meeting the guideline for screen time was associated with lower odds of being bullied (OR = 0.61, 95% CI 0.39-0.97, p = .04) in relation to none of the guidelines. While screen time only, sleep only and the combination of both were associated with lower odds of bullying others, sleep alone was the strongest predictor (OR = 0.44, 95% CI 0.26-0.76, p = .003) in relation to none of the guidelines. CONCLUSION: Meeting 24-HMB guidelines was associated with reduced likelihood of cognitive and social difficulties in children and adolescents with ADHD. These findings highlight the importance of adhering to healthy lifestyle behaviors as outlined in the 24-HMB recommendations with regard to cognitive and social difficulties in children and adolescents with ADHD. These results need to be confirmed by longitudinal and interventional studies with a large sample size.

Saffron extract (Safr'Inside™) improves anxiety related behaviour in a mouse model of low-grade inflammation through the modulation of the microbiota and gut derived metabolites.

Treatment of anxiety and depression predominantly centres around pharmacological interventions, which have faced criticism for their associated side effects, lack of efficacy and low tolerability. Saffron, which is reportedly well tolerated in humans, has been recognised for its antidepressant and anti-anxiety properties. Indeed, we previously reported upon the efficacy of saffron extract supplementation in healthy adults with subclinical anxiety. However, the molecular aetiology remains unclear. In a rodent model of low-grade chronic inflammation, we explored the impact of a saffron extract (Safr'Inside™) supplemented at a physiological dose, which equated to 22 ± 1.2 mg per day human equivalent dose for a person of 60 kg. Behavioural tests (Open Field task, Y maze, Novel object recognition), caecal 16S rRNA microbial sequencing, caecal 1H NMR metabolomic analysis and 2DE brain proteomic analyses were completed to probe gut-brain axis interactions. Time occupying the centre of the Open Field maze (OF) was increased by 62% in saffron supplemented animals. This improvement in anxiety-related behaviour coincided with gut microbial shifts, notably Akkermansia, Muribaculaceae, Christensenellacae and Alloprevotella which significantly increased in response to saffron supplementation. Akkermansia and Muribaculaceae abundance negatively correlated with the neurotoxic metabolite dimethylamine which was reduced in saffron supplemented animals. Brain proteomic analysis highlighted several significantly altered proteins including ketimine reductase mu-crystallin which also correlated with dimethylamine concentration. Both dimethylamine and ketimine reductase mu-crystallin were associated with OF performance. This may be indicative of a novel interaction across the gut-brain axis which contributes to anxiety-related disorders.

A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice.

Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its anti-tumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 70% carb, 14% protein, 16% fat), a KD (%kcal: 14% protein, 1% carb, 85% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood ß-hydroxybutyrate levels compared to mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared to KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data was disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation.

(-)-Epicatechin mitigates anxiety-related behavior in a mouse model of high fat diet-induced obesity.

Mounting evidence demonstrates that consumption of high fat diet (HFD) and subsequent development of obesity leads to alterations in cognition and mood. While obesity can affect brain function, consumption of select dietary bioactives may help prevent obesity-related cognitive decline. This study investigated the capacity of the dietary flavonoid (-)-epicatechin (EC) to mitigate HFD-induced obesity-associated alterations in memory and mood. Healthy 8-week old male C57BL/6J mice were maintained on either a control diet (10 kCal% from fat) or a HFD (45 kCal% from fat) and were supplemented with EC at 2 or 20 mg/kg body weight (B.W.) for a 24 week period. Between week 20 and 22, anxiety-related behavior, recognition memory, and spatial memory were measured. Underlying mechanisms were assessed by measuring the expression of selected genes in the hippocampus and by 16S rRNA sequencing and metabolomic analysis of the gut microbiota. 24 weeks of HFD feeding resulted in obesity, which was not affected by EC supplementation. HFD-associated increase in anxiety-related behavior was mitigated by EC in a dose-response manner and was accompanied by increased hippocampal brain-derived neurotrophic factor (BDNF), as well as partial or full restoration of glucocorticoid receptor, mineralocorticoid receptor and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) expression. Higher EC dosage (20 mg/kg B.W.) also restored aberrant Lactobacillus and Enterobacter abundance altered by HFD and/or the associated obesity. Together, these results demonstrate how EC mitigates anxiety-related behaviors, revealing a connection between BDNF- and glucocorticoids-mediated signaling. Our findings link changes in the hippocampus and the gut microbiota in a context of HFD-induced obesity and anxiety.

Chronic Consumption of Cranberries (Vaccinium macrocarpon) for 12 Weeks Improves Episodic Memory and Regional Brain Perfusion in Healthy Older Adults: A Randomised, Placebo-Controlled, Parallel-Groups Feasibility Study.

Background: Ageing is highly associated with cognitive decline and modifiable risk factors such as diet are believed to protect against this process. Specific dietary components and in particular, (poly)phenol-rich fruits such as berries have been increasingly recognised for their protection against age-related neurodegeneration. However, the impact of cranberries on cognitive function and neural functioning in older adults remains unclear. Design: A 12-week parallel randomised placebo-controlled trial of freeze-dried cranberry powder was conducted in 60 older adults aged between 50 and 80 years. Cognitive assessment, including memory and executive function, neuroimaging and blood sample collection were conducted before and after the intervention to assess the impact of daily cranberry consumption on cognition, brain function and biomarkers of neuronal signalling. Results: Cranberry supplementation for 12 weeks was associated with improvements in visual episodic memory in aged participants when compared to placebo. Mechanisms of action may include increased regional perfusion in the right entorhinal cortex, the accumbens area and the caudate in the cranberry group. Significant decrease in low-density lipoprotein (LDL) cholesterol during the course of the intervention was also observed. No significant differences were, however, detected for BDNF levels between groups. Conclusions: The results of this study indicate that daily cranberry supplementation (equivalent to 1 small cup of cranberries) over a 12-week period improves episodic memory performance and neural functioning, providing a basis for future investigations to determine efficacy in the context of neurological disease. This trial was registered at clinicaltrials.gov as NCT03679533 and at ISRCTN as ISRCTN76069316.