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OBJECTIVES: Poor diet and obesity often go hand-in-hand and are difficult to discern which variable is the major driver of the gut microbiome. The objective of this study was to determine the impact of obesity within dietary exposures on the gut microbiome and metabolic parameters using a non-human primate model. METHODS: Female M. fasicularis monkeys were fed a Western or Mediterranean diet for 2.5 years. We performed metagenomics sequencing on fecal samples obtained at 26 months. DNA was isolated from feces using Qiagen PowerSoil DNA extraction kit and metagenomics sequencing was performed for multikingdom microbiome analysis. DEXA scans for body adiposity and metabolic profiling were measured in each subject before the end of the study. Subjects were grouped by body fat composition (Lean (≤10% body fat) or Overweight/Obese (≥20% body fat)) and the impact of diet and adiposity was determine on the gut microbiome. Gut microbiota populations were correlated with metabolic parameters. RESULTS: Diet is the main determinant on gut microbiome α-diversity. Obesity had no significant outcome on Shannon diversity. Obesity within each dietary pattern can influence certain gut microbes. Lean Mediterranean diet-fed animals had significantly higher L. animals and C. comes that overweight animals fed the same diet. Obese Western diet-fed animals displayed elevated proportional abundance of S. infantarius and R. chanpaneliensis that lean Western diet-fed animals. Independent of adiposity, Western diet consumption lead to two distinct microbiome populations; P. copri high and P. copri low. P. copri(HIGH) displayed reduced α-diversity, increased abundance of other Prevotella species (P. stercorea, P. brevis, and P. bryantii), and increased F. prausnitzii. P. copri negatively correlated with α-diversity. P. copri(LOW) displayed increased proportional abundance of E. siraeum. Gut E. siraeum populations positively correlated with plasma HDL cholesterol levels. CONCLUSIONS: Our data indicates that diet is a potent regulator of the gut microbiome, while body adiposity can subtly shift specific gut microbiota taxa within subjects fed a specific dietary pattern. Moreover, our data indicates at a sub-group of metabolically healthier subjects on a Western diet characterized by low P. copri microbiota abundance. FUNDING SOURCES: NIH and DOD BCRP.

BackgroundWestern diets are associated with increased incidences of obesity, hypertension, diabetes, and hypercholesterolemia, whereas Mediterranean diets, richer in polyphenols, monounsaturated fats, fruits, vegetables, poultry, and fish, appear to have cardiometabolic health benefits. Previous work has included population-based studies with limited evidence for causation or animal studies focused on single macro- or micronutrients; therefore, primate animal models provide an opportunity to determine potential mechanisms underlying the effects of dietary patterns on health and disease.ObjectiveThe aim of this study was to determine the effects of whole dietary patterns, either a Western or Mediterranean diet, on skeletal muscle mitochondrial bioenergetics in cynomolgus macaques.MethodsIn this study, 22 adult female cynomolgus macaques (∼11-14 y by dentition) were fed either a Western or Mediterranean diet for 30 mo. The Western diet was designed to mimic the diet of a middle-aged American woman and the Mediterranean diet included key aspects of Mediterranean diets studied in humans, such as plant-based proteins and fat, complex carbohydrates, and fiber. Diets were matched on macronutrient composition (16% protein, 54% carbohydrate, and 31% fat) and cholesterol content. Skeletal muscle was collected for high-resolution respirometry, citrate synthase activity, and western blot measurements. Pearson correlation analysis between respirometry measures and measures of carbohydrate metabolism was also performed.ResultsWe found that consumption of a Western diet resulted in significantly higher mitochondrial respiration with fatty acid oxidation (FAO) (53%), FAO+complex I (52%), complex I+II (31%), max electron transport system (ETS) (31%), and ETS rotenone sensitive (31%) than did consumption of a Mediterranean diet. In addition, measures of respiration in response to fatty acids were significantly and positively correlated with both insulin resistance and plasma insulin concentrations.ConclusionsThis study highlights the importance of dietary composition in mitochondrial bioenergetics and that diet can influence skeletal muscle mitochondrial respiration independently of other factors such as macronutrient composition.

Age-related neurodegeneration associated with Alzheimer’s (AD) disease begins in middle age, well before the onset of symptoms. Therefore, translational models to identify modifiable risk factors in middle-age are needed to understand etiology and identify therapeutic targets. Vervet monkeys (Chlorocebus aethiops sabaeus), like humans, naturally develop several risk factors for AD with age, including obesity, prediabetes, and hypertension. Furthermore, older vervets exhibit accumulation of amyloid and tauopathies, decreased brain volumes, and physical declines in gait speed, suggesting that these NHPs may be useful models of early AD-like neuropathology. Currently, we are investigating the extent to which cognitive and physical decline co-occur in 20 elder (mean age=23 years, ~equivalent to a human age of 80 years) and 10 middle-aged (mean age=11 years) females through assessments of physical performance, executive function, social cognition, and short-term memory. These measures are part of a larger study to integrate physical, social, and cognitive function with measures of body composition, metabolic profiles, CSF, blood, neuroimages, and neuropathology. While tests of social cognition and short-term memory are ongoing, assessments of executive function indicate that performance declines with age (N=26; p

Social status is a powerful correlate of aging-related health decline. Observational data in humans suggest that disadvantaged social status may be associated with accelerated biological aging. But establishing causality in this relationship poses challenges; experimental manipulation of human social status is not possible. In contrast, social status can be experimentally manipulated non-human primates (e.g. Snyder-Mackler 2016 Science). We conducted analysis to reverse-translate blood-chemistry of biological aging to cynomolgus monkeys using data from several hundred animals in the Wake Primate Center breeding colony. We are applying these measures in an independent sample of monkeys with ascertained dominance rank to test replication in the non-human primate model of the human social gradient in biological aging. Parallel analysis of DNA methylation-based measures of biological aging are ongoing and should be available to present by Fall 2019. Results will inform potential to use this non-human primate model to study social determinants of biological aging.