(A) Diet was significantly associated with the first principal component of gene expression (59% variance explained, t(25.1) = 4.4, p = 1.72 x 10−4). (B) The average effect size of diet on Western genes was 60% stronger than the effect size of diet on Mediterranean genes (Mann-Whitney U = 4.1 x 106, p = 6.1 x 10−117). (C) Western genes (orange) contained more M1 genes than expected by chance, indicating that the Western diet induced a shift toward a proinflammatory monocyte phenotype. Western genes were enriched for proinflammatory (M1-like) genes (fold-enrichment = 1.27, 95% CI = 1.09, 1.46), while Mediterranean genes (blue) were depleted of these same M1-like genes (fold-enrichment = 0.74, 95% CI = 0.61, 0.88). Regulatory (M2-like) genes were also under-represented in Mediterranean genes (fold-enrichment = 0.67, 95% CI = 0.40, 0.97), but not in Western genes (fold-enrichment = 0.95, 95% CI = 0.60, 1.35). Figure 1—figure supplement 1. The sets of Western and Mediterranean genes were compared to genes implicated in 103 complex human diseases and traits (Zhang et al., 2020). Fisher’s Exact Tests were used to calculate the enrichment of trait-associated genes in Western genes that are depicted here (FDR < 0.02, 95% CI) and no traits were enriched in Mediterranean genes. Figure 1—figure supplement 2. Western-diet fed animals exhibited significantly higher expression of pro-inflammatory genes involved in the conserved transcriptional response to adversity (CTRA Cole et al., 2015; Mann-Whitney U = 222, p = 0.016) and lower expression of antiviral- and antibody-related CTRA genes (Mann-Whitney U = 82, p = 0.023), both consistent with the CTRA. See Supplementary file 1A for CTRA categories.