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Dietary changes associated with industrialization increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease. This relationship is often attributed to an ‘evolutionary mismatch’ between human physiology and modern nutritional environments. Western diets enriched with foods that were scarce throughout human evolutionary history (e.g. simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to ancestral human hunter-gatherer diets, such as a Mediterranean diet. Peripheral blood monocytes, precursors to macrophages and important mediators of innate immunity and inflammation, are sensitive to the environment and may represent a critical intermediate in the pathway linking diet to disease. We evaluated the effects of 15 months of whole diet manipulations mimicking Western or Mediterranean diet patterns on monocyte polarization in a well-established model of human health, the cynomolgus macaque (Macaca fascicularis). Monocyte transcriptional profiles differed markedly between diets, with 40% of transcripts showing differential expression (FDR < 0.05). Monocytes from Western diet consumers were polarized toward a more proinflammatory phenotype. The Western diet shifted the co-expression of 445 gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans, and dramatically altered behavior. For example, Western-fed individuals were more anxious and less socially integrated. These behavioral changes were also associated with some of the effects of diet on gene expression, suggesting an interaction between diet, central nervous system activity, and monocyte gene expression. This study provides new molecular insights into an evolutionary mismatch and uncovers new pathways through which Western diets alter monocyte polarization toward a proinflammatory phenotype.

Dietary changes associated with industrialization substantially increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease, which are major contributors to the public health burden. The high prevalence of these chronic diseases is often attributed to an “evolutionary mismatch,” between human physiology and modern nutritional environments. In support of this idea, Western diets enriched with foods that were scarce throughout human evolutionary history (e.g., simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to hunter-gatherer diets, such as a Mediterranean diet; however, the mechanisms linking dietary mismatch to inflammation and chronic disease are poorly understood. We used a macaque model and whole diet manipulations to evaluate one possible mechanism – inflammatory polarization of monocytes – that potentially leads to this evolutionary mismatch. After consuming a Western- or Mediterranean-like diet for 15 months, monocytes from Western diet consumers exhibited a more proinflammatory phenotype, with 40% of their genes differentially expressed (FDR