16S rRNA gene amplicon sequencing of fecal microbiota in a Gpr183-deficient mouse model

Objectives: Excessive eating and intake of high fat and sugar content affect the intestinal immune system negatively resulting in compromised glucose homeostasis and lower bacterial diversity. The G protein-coupled receptor (GPR)183 regulates immune cell migration and intestinal immune response, and has been associated with tuberculosis, type 1 diabetes, and inflammatory bowel diseases. We hypothesized that with these implications, GPR183 has an important immuno-metabolic role and investigated this using a global Gpr183 knock-out mouse model.Methods: Wild-type (wt) and Gpr183-deficient (Gpr183-/-) mice were fed a high-fat high-sucrose diet (HFSD) for 15 weeks and challenged with an oral glucose tolerance test before and after the diet. We investigated weight, body composition, and fecal IgA levels and sequenced the microbiome before and after the diet. Macrophage infiltration into visceral fat was determined by flow cytometry. We moreover determined glucose-stimulated insulin secretion (GSIS) from pancreatic islets isolated from wt and Gpr183-/- mice.Results: Unexpectedly, a remarkable sexual dimorphism was discovered. Female Gpr183-/- mice showed adverse metabolic outcomes compared to wt counterparts with increased fat relative to lean body mass, lowered oral glucose tolerance and fecal IgA levels, and increased macrophage infiltration in adipose tissue, with no differences in fasting blood glucose regardless of diet. Male Gpr183-/- mice had significantly lower baseline body weight and fasting blood glucose after diet, compared to male wt mice. Islet area did not differ between the groups and Gpr183 contributed to insulin secretion independent of glucose in female mice.Conclusion: Gpr183 maintains metabolic homeostasis in female but not in male mice independent of diet. If confirmed in humans, future therapy targeting GPR183 should take this sexual dimorphism into consideration.