ß7-Integrin aggravates experimental Western diet-induced metabolic syndrome in mice by promoting intestinal fat absorption and colonic inflammatory monocyte infiltration

Background Western diet (WD)-induced metabolic syndrome (MetS) is a global health burden characterized by obesity, insulin resistance, dyslipidemia, and systemic low-grade inflammation. While a role for ß7 integrin-expressing adaptive immune cells in WD-induced MetS has already been described, the contribution of ß7 integrin-expressing innate immune cells remains unclear. Methods To elucidate the role of ß7 integrin in innate immune-mediated metabolic pathology, WD-induced MetS was investigated in recombination activating gene-2-deficient (RAG-2-/-) mice lacking adaptive lymphocytes and in RAG-2/ß7 integrin double-deficient (RAG-2-/-/ß7-/-) mice. Metabolic parameters, fat absorption, macrophage distribution and signaling, and fecal microbiota profiles were assessed through metabolic cage studies, fat absorption assay, flow cytometry, MALDI-MSI, bulk RNA sequencing, and 16S rRNA amplicon sequencing, respectively. Results RAG-2-/-/ß7-/- mice were protected from WD-induced obesity, dyslipidemia, and glucose intolerance, partially via the loss of ß7 integrin-MAdCAM-1 interactions. ß7 integrin-deficiency reduced diet-induced intestinal fat absorption and monocyte infiltration into the colon and adipose tissue. Adoptive transfer demonstrated that ß7 integrin-expressing monocytes promote metabolic dysfunction in WD-fed recipients. Transcriptomic and phospho-signaling analyses revealed that ß7 integrin-deficiency attenuated PI3K-Akt-pathway activation in colonic macrophages. Microbiota analysis revealed an enrichment of Akkermansia and reduction of Erysipelotrichaceae and Atopobiaceae in WD-treated RAG-2-/-/ß7-/- mice, correlating with improved metabolic outcomes. Conclusion ß7 integrin-expressing innate immune cells promote WD-induced MetS through integrin-dependent monocyte recruitment, macrophage activation, and modulation of intestinal fat metabolism and also affect microbiota composition. Targeting ß7 integrin on innate immune cells may represent a novel strategy to ameliorate metabolic inflammation and its systemic consequences.