Parental high-fat diet induces upregulation of macrophage receptor with collagenous structure expression and exacerbates colorectal inflammation via the nuclear factor kappa-B pathway in offspring

Abstract

Parental high-fat diet (HFD) increases offspring's susceptibility to colorectal inflammation, but the underlying mechanism remains unclear. Using mouse models, we compared colorectal inflammation between offspring of HFD-fed and normal diet-fed parents. Histological analysis and immunostaining revealed that offspring of HFD-fed parents exhibited shortened colorectal length, decreased goblet cells, and reduced tight junction protein expression, particularly when maintained on HFD. RNA sequencing of colorectal tissue identified elevated expression of macrophage receptor with collagenous structure (MARCO) in these offspring. Immunofluorescence co-localization staining confirmed increased MARCO-positive macrophages in their colorectal tissue. Notably, switching offspring to normal diet partially alleviated these inflammatory responses, although some manifestations remained. Further investigation showed that high-lipid stimulation increased MARCO expression in macrophages and promoted inflammatory cytokine secretion through nuclear factor kappa-B (NF-κB) pathway activation. In vitro experiments demonstrated that MARCO knockdown inhibited the expression of inflammatory cytokines and prevented tight junction protein destruction in cocultured intestinal cells. Our findings reveal that parental HFD induces MARCO upregulation in offspring's colorectal macrophages and exacerbates colorectal inflammation through the NF-κB pathway, providing new insights into the mechanism by which parental HFD affects offspring's intestinal health.