The immune system’s mediation of the protective effect of Parabacteroides against obesity: A Mendelian randomization study

Parabacteroides, a core component of the human gut microbiota, is closely associated with various diseases. While some studies have observed a decrease in the abundance of Parabacteroides in patients with obesity, the specific relationship and underlying mechanisms remain unclear. This study primarily employed 2-sample 2-step Mendelian randomization (MR), utilizing genetic data from 3 large publicly available genome-wide association studies. Within this framework, we applied 2-sample MR to assess the causal impact of Parabacteroides abundance in stool on obesity and used reverse MR to ensure the unidirectionality of the causal relationship. Additionally, we attempted to use 2-step MR to investigate the potential mediating role of immune cell phenotypes in this relationship. The results of the inverse variance weighted method indicated that Parabacteroides abundance in stool was negatively associated with obesity, with an odds ratio of 0.94 (95% CI: 0.88, 0.99). Additionally, 3 immune cell phenotypes-relative count-CD62L- CD86+ myeloi DC %DC (8.4%), MFI-CD25 on B cells (8.9%), and MFI-CD4 on activated and secreting Tregs (4.7%)-played a mediating role in this relationship. Our research findings suggest that elevated Parabacteroides abundance in stool may have a potential protective effect against obesity, with the immune system playing a mediating role in this relationship.