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Significance The Western diet (WD) is high in fats and sucrose and low in fiber and is the most prevalent diet in westernized countries. We find that in our model of sepsis, mice fed WD had increased sepsis severity and poorer outcomes. WD-fed mice had higher baseline inflammation, increased sepsis-associated immunoparalysis, and altered neutrophil populations in the blood. The WD-dependent increase in sepsis severity and mortality was independent of the diet-associated microbiome, suggesting that diet may be directly regulating innate immunity. We used our identified disease factors and found WD-fed mice occupy a unique path in sepsis disease progression. Our data provide insight into diet-dependent reprogramming of the immune response and will be important in treating and diagnosing a WD-fed population.

Western diet regulates immune status and the response to LPS-driven sepsis independent of diet-associated microbiome