Orm2 Deficiency Aggravates High‐Fat Diet‐Induced Obesity through Gut Microbial Dysbiosis and Intestinal Inflammation

SCOPE: Orosomucoid 2 (Orm2) is a hepatocyte-secreted protein that plays a crucial role in regulating obesity-type metabolic disease and immunity. The imbalance of gut microbiota is one of the causes of obesity, but the mechanism of the relationship between Orm2 and gut microbiota in obesity remains unclear. METHODS AND RESULTS: Orm2-/- (Orm2 knockout) mice on a normal diet developed spontaneous obesity and metabolic disturbances at the 20th week. Through 16S rRNA gene sequencing, the study finds that the gut microbiota of Orm2-/- mice has a different microbial composition compared to wild type (WT) mice. Furthermore, a high-fat diet (HFD) for 16 weeks exacerbates obesity in Orm2-/- mice. Lack of Orm2 promotes dysregulation of gut microbiota under the HFD, especially a reduction of Clostridium spp. Supplementation with Clostridium butyricum alleviates obesity and alters the gut microbial composition in WT mice, but has minimal effects on Orm2-/- mice. In contrast, co-housing of Orm2-/- mice with WT mice rescues Orm2-/- obesity by reducing pathogenic bacteria and mitigating intestinal inflammation. CONCLUSION: These findings suggest Orm2 deficiency exacerbates HFD-induced gut microbiota disturbance and intestinal inflammation, providing a novel insight into the complex bacterial flora but not a single probiotic administration in the therapeutic strategy of obesity.