WESTERN DIET DEPLETES SMALL INTESTINAL INTRAEPITHELIAL LYMPHOCYTES VIA FXR-TYPE I INTERFERON PATHWAY

Background: The prevalence of obesity has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar “Western” diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed adaptive immunity.
Methods: Small intestine samples from non-inflammatory bowel disease (IBD) subjects who underwent resection were used for CD3 immunohistochemistry (IHC), and the CD3+ intraepithelial lymphocytes (IEL) densities were correlated with the patients’ body mass index (BMI). Mice were fed with either standard diet (SD) or WD for various durations, and IELs were isolated for flow cytometry analysis.
Results: In non-IBD subjects, high BMI correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to deplete IEL (including major subsets CD4+, CD8+, CD8α+8β-CD4+, and γδCD8+ T cells) but not splenic lymphocytes, and the effect was reversible after another 4 weeks of SD washout. ob/ob mice that spontaneously developed obesity while fed with SD did not show IEL depletion, suggesting that the quality, not the quantity of the diet is key to this phenotype. Importantly, WD-associated IEL depletion was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL depletion. We previously showed that a key molecular pathway activated by WD in the ileum is the FXR pathway. Phagocyte-specific Fxr conditional knockout (cKO) mice were protected from WD-mediated IEL depletion, suggesting that FXR activation in the phagocytes is critical in mediating this phenotype. Activated FXR signaling stimulated phagocytes to secrete type I interferon (IFN), and inhibition of type I IFN signaling within the phagocytes (type I IFN monoclonal antibody treatment and Stat1 cKO mice) prevented WD-mediated IEL loss.
Conclusion: WD consumption depletes IEL by a FXR-IFN pathway mediated by gut phagocytes. These findings have significant clinical implications in understanding the pathogenesis of gut inflammatory disorders such as IBD.