Browsing by Author "Sharkey, Keith A"

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    Effect of a prebiotic supplement on knee joint function, gut microbiota, and inflammation in adults with co-morbid obesity and knee osteoarthritis: study protocol for a randomized controlled trial
    (2021-04-07) Fortuna, Rafael; Hart, David A; Sharkey, Keith A; Schachar, Rachel A; Johnston, Kelly; Reimer, Raylene A
    Abstract Background Osteoarthritis (OA) is a chronic and painful condition where the articular cartilage surfaces progressively degenerate, resulting in loss of function and progressive disability. Obesity is a primary risk factor for the development and progression of knee OA, defined as the “metabolic OA” phenotype. Metabolic OA is associated with increased fat deposits that release inflammatory cytokines/adipokines, thereby resulting in systemic inflammation which can contribute to cartilage degeneration. There is currently no cure for OA. Prebiotics are a type of dietary fiber that can positively influence gut microbiota thereby reducing systemic inflammation and offering protection of joint integrity in rodents. However, no human clinical trials have tested the effects of prebiotics in adults with obesity suffering from knee OA. Therefore, the purpose of this double-blind, placebo-controlled, randomized trial is to determine if prebiotic supplementation can, through positive changes in the gut microbiota, improve knee function and physical performance in adults with obesity and knee OA. Methods Adults (n = 60) with co-morbid obesity (BMI > 30 kg/m2) and knee OA (Kellgren-Lawrence grade II–III) will be recruited from the Alberta Hip and Knee Clinic and the Rocky Mountain Health Clinic and surrounding community of Calgary, Canada, and randomized (stratified by sex, BMI, and age) to prebiotic (oligofructose-enriched inulin; 16 g/day) or a calorie-matched placebo (maltodextrin) for 6 months. Anthropometrics, performance-based tests, knee pain, serum inflammatory markers and metabolomics, quality of life, and gut microbiota will be assessed at baseline, 3 months, 6 months (end of prebiotic supplementation), and 3 months following the end of the prebiotic supplementation. Clinical significance There is growing pressure on health care systems for aggressive OA treatment such as total joint replacement. Less aggressive, yet effective, conservative treatment options have the potential to address the growing prevalence of co-morbid obesity and knee OA by delaying the need for joint replacement or ideally preventing its need altogether. The results of this clinical trial will provide the first evidence regarding the efficacy of prebiotic supplementation on knee joint function and pain in adults with obesity and knee OA. If successful, the results may provide a simple, safe, and easy to adhere to intervention to reduce knee joint pain and improve the quality of life of adults with co-morbid knee OA and obesity. Trial registration Clinical Trials.gov NCT04172688 . Registered on 21 November 2019.
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    Effect of Bacterial Species Associated with Major Depressive Disorder on Emotionality Behaviors, Microbiome Structure, and Metabolism in Gnotobiotic Mouse Models
    (2021-08-17) Cooke, Noah C.A.; McCoy, Kathy D; Taylor, Valerie H; Hirota, Simon; McGirr, Alexander; Sharkey, Keith A; Savchenko, Alexei
    Major depressive disorder (MDD) is a prevalent disease, and antidepressants lack efficacy in many patients, motivating investigation for new therapeutic modalities. Altered microbiome composition and metabolism have been implicated in MDD, but the specific species and metabolites involved, and their mechanisms of effect, remain elusive. We set out to test whether two bacterial species correlated with MDD alter emotionality-related behaviors in stress-naïve and chronic stress-exposed mice, when added to the stable defined moderately diverse mouse microbiome 2 (sDMDMm2) consortium. We hypothesized that Lachnospiraceae bacterium would increase, and Faecalibacterium prausnitzii would decrease, these behaviors in both conditions. Further, we hypothesized that these behavioural effects would coincide with effects on microbiome composition and metabolism. To assess emotionality-like behavior, we established a gnotobiotic behavioral system comprised of five tests and the chronic variable stress (CVS) model for studying depression. L. bacterium did not alter depressive and anxiety-like behaviors in the stress-naïve condition. In the CVS condition, an increase in anxiety-like behavior was seen in one assay, the elevated plus maze test, in one preliminary experimental replicate. Illumina 16S V4 amplicon sequencing revealed that L. bacterium significantly altered microbiome composition. Hydrophilic interaction liquid chromatography with mass spectrometry (HILIC-MS/MS) also revealed a significant effect of L. bacterium on microbiome and serum metabolism. This thesis offers a novel methodological approach to investigate causal relationships between bacterial species and emotionality-related behaviors, and to identify microbial candidates for microbiome-targeted therapies for MDD.Keywords: microbiome, Lachnospiriceae bacterium, Major Depressive Disorder, Metabolism.
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    Impact of Alterations to Early Life Microbiota (Antibiotics, Prebiotics, and C-Section) on Body Weight and Brain Development
    (2021-09-21) Cho, Nicole A; Reimer, Raylene A.; Mychasiuk, Richelle; Sharkey, Keith A; Giesbrecht, Gerald
    Background: Communication between the gut microbiota, gut, and brain is now known to influence behavior, metabolic health, and immunity. Foods that improve the composition of the gut microbiota as well as factors that can disrupt it during early development are of interest to investigate the origins of and possible therapeutics for chronic diseases like obesity and mood and neurodevelopmental disorders. Objective: This dissertation examines how early life perturbations to gut microbiota, such as maternal antibiotic use, prebiotic consumption, maternal obesity, and C-section (CS) alter microbial, metabolic, behavioral, and brain outcomes. Specifically, the objectives of this thesis were to: 1) assess the impact of CS in offspring of lean and obese dams on offspring obesity risk; 2) examine the impact of CS and maternal prebiotic intake on offspring microglia and neuron morphology; 3) determine the effects of maternal antibiotic/prebiotic intake on offspring behavior and microglia reactivity; 4) investigate the effects of maternal and child antibiotic use on BMI z-score and temperament in 3-year-old children in a clinical cohort.Methods: Animal studies were conducted in Sprague-Dawley rats or NIH Swiss mice. Clinical participant data was accessed from the Alberta Pregnancy and Nutrition Outcomes (APrON) study. Body composition was measured with dual x-ray absorptiometry (DXA). Elevated Plus Maze (EPM), Novel Context Mismatch (NCM), and Sucrose Preference Tests (SPT) were used to assess behavior. Microglia were analyzed using the expression of IBA-1. Gut microbiota was assessed using 16S rRNA gene sequencing, and tissue gene expression was measured using RT-PCR. Temperament data was assessed using the Child Behavior Questionnaire (CBQ).Results: The primary findings from our study objectives were: 1) CS-associated obesity risk in offspring is dependent on maternal obesity status; 2) Maternal prebiotic intake reverses CS-induced alterations to microglia; 3) Antibiotic-induced alterations to microglia are reversed by maternal prebiotic intake; 4) Maternal and child antibiotic use is associated with increased BMI z-score in children. Conclusion: Our results provide evidence that early-life microbial perturbations alter obesity risk and microglia activation. We also demonstrated the potential for prebiotics to reduce the neuroinflammation that could modulate the risk for mood and neuropsychiatric disorders.