High-fat diet-induced resistance to helminth infection via alternative induction of type 2 immunity

Gastrointestinal nematode infections cause morbidity and socioeconomic loss in the most deprived communities. The shift in the context of obesity has led to spatial overlap with endemic gastrointestinal nematode regions resulting in the emergence of a novel comorbidity. Despite this, the impact of a high-fat diet (HFD) on immune-regulated protection against gastrointestinal infections remains largely unknown. We employed the murine model of nematode infection, Trichuris muris, to investigate the effect of an HFD on the immune response against chronic infection. Surprisingly, diet-induced obesity drove parasite expulsion in both single and repeated trickle low doses of T. muris eggs. Mechanistically, an HFD increased the expression of the ST2 receptor on CD4+ T cells, priming an enhanced type 2 helper T (Th2) cell cytokine production following interleukin (IL)-33 stimulation ex vivo. Despite IL-33-/- mice demonstrating that IL-33 is not critical for host protective immunity to T. muris under a conventional diet, HFD-fed Tcell deplete mice adoptively transferred with ST2-/- CD4 T cells were unable to expel a T. muris infection unlike those transferred with ST2-sufficient cells. Collectively, this study demonstrates that an HFD primes CD4+ T cells to utilize the IL-33-ST2 axis in a novel induction of type 2 immunity, providing insights into the emerging comorbidities of obesity and nematode infection.

Automated summary

Gastrointestinal nematode infections cause significant harm and economic losses in impoverished communities. The rise of obesity has led to the coexistence of obesity with endemic gastrointestinal nematode regions, resulting in a new comorbidity. However, the impact of a high-fat diet on the immune response against gastrointestinal infections is not well understood. A mouse model of nematode infection was used to study the effect of a high-fat diet on the immune response. Surprisingly, the high-fat diet led to parasite expulsion. Mechanistically, the high-fat diet increased the expression of the ST2 receptor on CD4+ T cells, promoting an enhanced type 2 immune response. This study provides insights into the emerging comorbidities of obesity and nematode infection.