Helminth infection induces malabsorption of dietary fat via STAT6-dependent intestinal MTTP suppression

Epidemiological studies link helminth infections to reduced obesity prevalence, but the mechanisms remain incompletely understood.

To determine whether and how Heligomosomoides polygyrus (H. polygyrus) infection impairs dietary fat absorption in fat mice.

H. polygyrus- infected wild-type (WT) and STAT6 knockout (KO) mice were used to assess the role of STAT6 in helminth-induced lipid metabolism changes. Complementary in vitro experiments were performed using cytokine-treated Caco-2 cells, and single-cell RNA sequencing (scRNA-seq) was conducted on intestinal epithelial cells (IECs) to further explore underlying molecular mechanisms.

We demonstrated that H. polygyrus infection impaired dietary fat absorption in mice via STAT6-dependent suppression of microsomal triglyceride transfer protein (MTTP), a key mediator of chylomicron assembly. WT mice infected with H. polygyrus exhibited increased fecal lipid excretion, reduced serum triglycerides, and enterocyte lipid retention, phenotypes absent in STAT6 KO mice. In vitro, IL4/IL13 treatment of polarized Caco-2 cells suppressed MTTP expression and lipid export, mirroring in vivo findings. Single-cell RNA sequencing of IECs revealed STAT6-dependent downregulation of lipid metabolism pathways and upregulation of immune responses.

These results identify a metabolic-immune trade-off in which helminth-induced Type 2 cytokines prioritize host defense over nutrient absorption, attenuating obesity, highlighting MTTP as a novel therapeutic target for metabolic disorders and underscores the role of helminth immunomodulation in systemic energy homeostasis.