Recent Mendelian randomization studies have uncovered the relationship between specific gut microbiota and Non-Alcoholic Fatty Liver Disease (NAFLD). However, reports on the facilitator mediating this causal relationship are scarce. Therefore, we analyzed the GWAS data of 207 gut bacterial taxa, 731 types of immune cells, and NAFLD together. From this analysis, we concluded that CD64 on CD14 + CD16 + Monocytes partially mediates the causal effect of the genus Collinsella on NAFLD, a finding not previously reported.
Our results align with those from earlier observational studies. Stuart et al. observed a 12-fold increase in Collinsella abundance in the NASH group, from 0.29–3.44%, and up to 4.38% in NASH-cirrhosis patients14. Moreover, they discovered a negative correlation between Collinsella abundance and serum HDL-C levels, but a positive correlation with triglycerides and total cholesterol, suggesting Collinsella's role in affecting lipid metabolism, potentially leading to lipid-related disorders14. Accordingly, Collinsella levels were higher in patients with obesity, atherosclerosis, and hypercholesterolemia15. Additionally, Collinsella contributes to NAFLD development through its association with insulin resistance and secondary bile acid production14.
CD64, or FcγRI, a high-affinity IgG antibody receptor, is mainly found on monocytes and macrophages16. CD14, a co-receptor for bacterial lipopolysaccharide (LPS), marks classical monocytes, while CD16 (FcγRIII), another IgG Fc receptor, distinguishes classical (CD14 + CD16-) from intermediate (CD14 + CD16+) monocyte subsets17. The presence of CD64 on CD14 + CD16 + monocytes suggests their activation or an inflammatory state, often linked to enhanced phagocytic and inflammatory capabilities. Monitoring CD64 across monocyte subsets provides valuable insights into immune responses, particularly in conditions like inflammatory disorders, infections, and autoimmune diseases. Research has linked monocyte/macrophage activation in the liver with NAFLD severity, where increased cell infiltration associates with the disease's advanced stages18. Monocytes can evolve into either pro-inflammatory (M1) or anti-inflammatory (M2) macrophages in the liver, with M1 types releasing cytokines like TNF-α and interleukins, exacerbating NAFLD-related liver damage19. Conversely, these cells may also foster insulin resistance by emitting inflammatory mediators. It is hypothesized that CD64 expression on CD14 + CD16 + monocytes, indicative of a pro-inflammatory subset, plays a crucial role in advancing NAFLD.
Although current research has not definitively associated the genus Collinsella with monocytes, insights from previous studies suggest a potential link. Increasing evidence supports the gut-liver axis's role in developing Non-Alcoholic Fatty Liver Disease (NAFLD), often related to heightened intestinal permeability and subsequent infiltration of Gram-negative bacteria into the liver via portal circulation20. Collinsella, a principal component of these bacteria, activates pro-inflammatory immune cells, including monocytes/macrophages and hepatic stellate cells21. This activation leads to a significant release of inflammatory cytokines and mediators, thereby contributing to NAFLD progression.
LIMITATIONS
Our study has several limitations. Firstly, despite Mendelian Randomization having an innate advantage in determining causal relationship, it's important to recognize that the estimates of Mendelian Randomization (MR) effects are based on lifelong genetic exposures and may not precisely capture the extent of the benefits associated with short-term changes in the microbiome. Secondly, the limited sample size in the GWAS data of immune cells may not be sufficient to adequately detect potential causal relationships. However, this is the largest GWAS of immune cells to date, encompassing 731 immunophenotypes across 5 planes, and providing more precise traits of immune cells. Finally, as our analysis focused on the European population, its relevance to other populations might be limited because of varying genetic backgrounds.