The global incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has surged in recent years, potentially impacted by both high-energy food intake (e.g., high-fat diet, HFD) and environmental pollutants like microplastics (MPs). However, the combined impacts of MPs exposure and HFD feeding, particularly under long-time exposure, low concentrations MPs conditions, on the MASLD progression remain to be fully elucidated. In this study, C57BL/6 J male mice were fed either a normal chow diet or HFD with or without low-dose MPs (polystyrene) exposure (25-30 μg/kg body weight /day) for 14 weeks. The adverse health effects associated with MASLD development were evaluated, including intestinal permeability, gut microbiota composition, hepatic lipid metabolism, and the mediating role of the gut-liver axis. Additionally, HFD with or without low-dose MPs exposure was withdrawn to further verify this process. Our data demonstrated that low-dose MPs exposure or HFD feeding significantly increased the gut permeability, oxidative stress, pro-inflammatory response and apoptosis, while concurrently contributing to gut dysbiosis (e.g., reduced levels of Akkermansia) and MASLD development. Furthermore, low-dose MPs exposure exacerbated these effects in combination with HFD feeding, exhibiting a 'double hit' effect. Notably, the impacts of low-dose MPs exposure combined with HFD feeding on MASLD were difficult to reverse after two weeks withdrawing, likely due to the limited recovery potential of intestinal barrier integrity and gut microbiota homeostasis. These finding underscore the importance of avoiding MPs exposure in the pathogenesis of MASLD, particularly under a metabolic disorder conditions, and provide valuable insights for the developing therapeutic strategies to combat MASLD caused by MPs exposure.

It is well-documented that systemic lupus erythematosus (SLE) is associated with asthma. However, the causal relationship between SLE and asthma, and the potential mediator need to be explained. This study aims to confirm the cause-and-effect relationship between SLE and asthma, and evaluate the mediation effect of lipid in European ancestry. A Two-sample Mendelian randomization (MR) study was applied to analyze the causal relationships between SLE and asthma. A two-step MR design was used to explore whether low-density lipoprotein cholesterol (LDL-C) mediates the causal pathway from SLE to asthma outcome. Cochran’s Q statistic methods and MR-Egger regression were used to assess heterogeneity and pleiotropy. Leave-one-out (LOO) sensitivity test was adopted to estimate the effect of removing one of the selected individual SNPs on the overall results. Funnel and forest plots were also conducted to detect the pleiotropy directly. SLE was significantly associated with higher asthma risk according to inverse-variance weighted (IVW) method [OR (95%CI): 1.093 (1.024–1.166)] (P = 0.007), MR Egger method [OR (95%CI): 1.192 (1.077–1.319)] (P = 0.028) and Maximum likelihood [OR (95%CI): 1.094 (1.036–1.155)] (P = 0.001), which were robust across adequate sensitivity analysis. On the contrary, asthma has no causal relationship with SLE. In addition, LDL-C may mediate a proportion of 6.15% of the total effect between SLE and asthma. This study demonstrates that patients with SLE may have a higher risk of developing asthma, which may be mediated by LDL-C. Understanding this relationship provides insight into potential mechanisms underlying asthma development in SLE patients and offers a foundation for developing targeted treatment strategies to manage these risks effectively.