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Nutrition affects all physiological processes, including those that regulate our immune system1. The link between nutrition and host immunity represents an important opportunity to develop therapeutic nutritional interventions in the context of various disease states, such as cancer or chronic inflammatory disorders. In support of a link between diet and disease state, a low-fat vegan or vegetarian diet has been previously associated with decreased inflammation, reduced risk for cardiovascular diseases and reduction in overall mortality2,3,4. On the other hand, high-fat, very low-carbohydrate diets (commonly referred to as ketogenic diets) have been associated with reduced symptoms in defined types of epilepsy and reduced neuroinflammation5,6,7,8,9,10,11,12,13,14. However, despite the preventive and therapeutic potential of nutritional interventions, how nutrition impacts human immunity remains largely unknown.

Nutrition can impact host physiology via the amount and quality of fuels but also via the microbiota15,16. The microbiota possesses the ability to reconfigure and alter its function in ways that are believed to promote host resilience. As such, nutrition plays a dominant role in shaping the composition and function of the microbiome17,18,19,20,21,22,23. While the connection between the microbiota and nutrition is clearly established in experimental models, how such a symbiotic dyad influences human immunity remains largely unexplored.

In addition to the paucity of data pertaining to the impact of nutritional intervention on the human immune system, previous studies have explored responses to only one diet at a time. Based on the highly variable responses of individuals to nutritional interventions24 and the high number of diets consumed, addressing how individuals respond to different diets remains an important line of research. Moving forward, in the absence of rigorously designed clinical interventions, harnessing nutrition to shape human health will remain an ongoing challenge.

We first assessed the cellular composition of peripheral blood mononuclear cells (PBMCs) via flow cytometry (Extended Data Figs. 1l and 2, Extended Data Tables 1 and 2 and ref. 26). PBMC analysis focused on all major immune cell types, except for neutrophils which do not survive sample processing. As expected, high variability was observed at baseline between participants (for example, frequency of naive CD4 T cells ranged from 5% of all CD45+ cells to almost 25%) (Fig. 1b).

Notably, change in diet itself, independent of diet order, induced significant changes, including a significant decrease in the level of naive CD8 T cells and a significant increase in the level of activated CD4 T cells, effector CD4 T cells and effector CD8 T cells following both ketogenic/vegan versus baseline diet (Fig. 1c and Extended Data Fig. 1m). Whether these changes resulted from the shift in diet, or an abrupt decrease in the consumption of highly processed food which is often represented in a standard Western diet, remains unclear but would be of interest for future investigation.

Some distinct changes were also observed following consumption of each diet, independent of diet order. For instance, we observed a significant increase in the frequency of activated regulatory T cells and CD16+ natural killer (NK) cells following consumption of a ketogenic diet compared with vegan diet (Fig. 1d and Extended Data Fig. 1n). Further, we observed a significant increase in the frequency of activated T helper cells and activated NK cells following vegan diet compared with ketogenic diet (Fig. 1d and Extended Data Fig. 1n). Thus, changes in diet itself had a significant impact on the host immune system. Further, both ketogenic and vegan diets imposed distinct changes in lymphoid composition and status of activation.

We next performed bulk RNA-seq of whole blood at baseline and following diets. Clustering of highly expressed genes showed marked differences in the expression of transcripts between all three conditions, as well as between individuals (Extended Data Fig. 3a). Principal component analysis (PCA) showed that principal component 1 (PC1) captured differences in the transcriptome between participants explaining 37.38% of variation, whereas PC2 captured differences between the diets explaining 34.45% of variation (Extended Data Fig. 3b). As expected, most variations resulted from interindividual differences; however, diet also had a significant impact on whole blood transcriptome.

We next assessed functional trajectories associated with each diet. To this end, we performed blood transcription module27 (BTM) analysis as well as Hallmark analysis of all genes differentially expressed between each diet comparison (Fig. 2a,b and Extended Data Fig. 3c,d), with previous diet referring to the diet consumed directly beforehand (see Methods for more details). This approach uncovered a striking polarization in overall pathway enrichment between ketogenic and vegan diets (Fig. 2a,b). For example, ketogenic diet was associated with an upregulation of pathways linked to adaptive immunity, including T cell activation and enrichment of B cells and plasma cells, as well as NK cells (Fig. 2a and Extended Data Fig. 3d). As such, oxidative phosphorylation, a fundamental pathway associated with T cell activation and memory formation (reviewed in refs. 28,29,30), was significantly enriched in ketogenic diet compared with vegan or baseline diet (Fig. 2b).

In contrast, a vegan diet was associated with upregulation of pathways associated with innate immunity, as well as antiviral responses (Fig. 2a,b and Extended Data Fig. 3c). Functional analysis further predicted upregulation of type I interferon signatures and responses (Fig. 2a,b). The order of diets did not affect transcriptional changes (Extended Data Fig. 3c,d). We and others have shown that sensing of endogenous retroviruses (ERVs) can contribute to host immunity and that changes in dietary lipids impact ERV expression31,32,33. Indeed, we observed distinct changes in ERV expression both between individuals and after dietary changes, where discrete sets of ERVs were uniquely upregulated in each participant after defined diets (Extended Data Fig. 3e).

To predict drivers of transcriptional changes, we evaluated the expression profiles of sorted cell populations from the blood35 and analyzed gene expression from enriched pathways. Using this approach, we found that upregulation of innate immunity following vegan diet was predicted to be driven mainly by neutrophils, whereas upregulation of adaptive immunity in ketogenic diet was predicted to be driven by B and T cells (Fig. 2d and Extended Data Fig. 3h).

We next analyzed the origin of differentially impacted proteins by downloading tissue annotations from the Human Protein Atlas35. Ketogenic diet impacted proteins predicted to originate from several tissues, including the blood, brain and bone marrow, while both diets affected proteins predicted to originate from the liver and secondary lymphoid organs (Fig. 3b). Thus, a ketogenic diet may have a broader impact on host protein secretion or clearance than a vegan diet.

We performed functional enrichment analysis with STRING36 based on fold change of all proteins (Fig. 3c). Consistent with results gained from transcriptomics analysis, we observed a significant enrichment in heme metabolism following vegan diet (Fig. 3c). Of note, we also observed an enrichment of insulin signaling pathway in baseline diet compared with ketogenic diet (Fig. 3c).

PCA did not show separation by diet but showed several outliers (Fig. 3d). Further analysis revealed that all outliers were female participants who showed substantially greater changes following ketogenic diet, highlighting potential sex-bias in responsiveness to diet (Fig. 3e). Sex-specific differences in protein abundance between diets included proteins associated with glucose metabolism, as well as immunity (Extended Data Fig. 4e).

Thus, proteomic data analysis revealed that a ketogenic diet may have the strongest effect on the proteome of study participants. Furthermore, proteomic data supported the idea that vegan diet can promote heme metabolism and that there is a sex-specific difference in the magnitude of response to diet.

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