微塑料 (MP) 已成为一个全球性的环境问题，作为污染物出现，可能带来令人震惊的后果。然而，长期暴露于聚苯乙烯微球（PS-MS）及其对饮食引起的肥胖的影响尚未完全了解。我们旨在研究PS-MS暴露对高脂饮食（HFD）引起的肥胖的影响在本研究中，C57BL/6J 小鼠在不存在或存在 PS-MS 的情况下通过口服给药正常饮食 (ND) 或 HFD 喂养 8 周。进行微生物群抗生素消耗和粪便微生物群移植 (FMT)，以评估 PS-MS 对肠道微生物生态的影响。我们进行了 16S rRNA 测序来剖析微生物差异，并研究了与生态失调相关的肠道完整性和血清炎症。与 HFD 小鼠相比，喂食 HFD 和 PS-MS 的小鼠表现出更高的体重、肝脏重量和代谢功能障碍相关的脂肪变性肝病（MASLD）活动评分和白色脂肪组织质量，以及较高的血糖和血脂浓度。此外，粪便微生物群的 16S rRNA 测序显示，喂食 HFD 和 PS-MS 的小鼠具有更高的 α 多样性，并且 Lachnospiraceae、Oscillospiraceae、Bacteroidaceae、Akkermansiaceae、Marinifilaceae、Deferribacteres 和 Desulfovibrio 的相对丰度更高，但 Atopobiaceae 的相对丰度较低、双歧杆菌和副拟杆菌。用 PS-MS 饲喂 HFD 的小鼠表现出较低的 MUC2 粘蛋白表达和较高水平的脂多糖和炎症细胞因子 [肿瘤坏死因子-α (TNF-α)、白介素-6 (IL-6)、IL-1β 和 IL- 17A]血清中。相关分析显示，暴露于 PS-MS 的小鼠微生物菌群的差异与肥胖有关。有趣的是，微生物群耗尽的小鼠在 HFD 和 HFD PS-MS 之间的远端结肠 Muc2 和 Tjp1 表达、血清中炎症细胞因子表达或肥胖结果方面并未表现出相同的 PS-MS 相关差异。重要的是，将 HFD PS-MS 小鼠的粪便移植到微生物群耗尽的 HFD 喂养小鼠中，导致粘液蛋白表达降低、炎症细胞因子表达升高以及肥胖结果，与 HFD PS-MS 小鼠中的发现类似。研究结果为 PS-MS 诱导的 HFD 喂养小鼠肥胖提供了一种新的肠道微生物驱动机制，表明需要重新评估日常生活中常见的 MP 对健康的不利影响，特别是在易感人群中。 https://doi.org/10.1289/EHP13913。

Microplastics (MPs) have become a global environmental problem, emerging as contaminants with potentially alarming consequences. However, long-term exposure to polystyrene microspheres (PS-MS) and its effects on diet-induced obesity are not yet fully understood.We aimed to investigate the effect of PS-MS exposure on high-fat diet (HFD)-induced obesity and underlying mechanisms.In the present study, C57BL/6J mice were fed a normal diet (ND) or a HFD in the absence or presence of PS-MS via oral administration for 8 wk. Antibiotic depletion of the microbiota and fecal microbiota transplantation (FMT) were performed to assess the influence of PS-MS on intestinal microbial ecology. We performed 16S rRNA sequencing to dissect microbial discrepancies and investigated the dysbiosis-associated intestinal integrity and inflammation in serum.Compared with HFD mice, mice fed the HFD with PS-MS exhibited higher body weight, liver weight, metabolic dysfunction-associated steatotic liver disease (MASLD) activity scores, and mass of white adipose tissue, as well as higher blood glucose and serum lipid concentrations. Furthermore, 16S rRNA sequencing of the fecal microbiota revealed that mice fed the HFD with PS-MS had greater α-diversity and greater relative abundances of Lachnospiraceae, Oscillospiraceae, Bacteroidaceae, Akkermansiaceae, Marinifilaceae, Deferribacteres, and Desulfovibrio, but lower relative abundances of Atopobiaceae, Bifidobacterium, and Parabacteroides. Mice fed the HFD with PS-MS exhibited lower expression of MUC2 mucin and higher levels of lipopolysaccharide and inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and IL-17A] in serum. Correlation analyses revealed that differences in the microbial flora of mice exposed to PS-MS were associated with obesity. Interestingly, microbiota-depleted mice did not show the same PS-MS-associated differences in Muc2 and Tjp1 expression in the distal colon, expression of inflammatory cytokines in serum, or obesity outcomes between HFD and HFD + PS-MS. Importantly, transplantation of feces from HFD + PS-MS mice to microbiota-depleted HFD-fed mice resulted in a lower expression of mucus proteins, higher expression of inflammatory cytokines, and obesity outcomes, similar to the findings in HFD + PS-MS mice.Our findings provide a new gut microbiota-driven mechanism for PS-MS-induced obesity in HFD-fed mice, suggesting the need to reevaluate the adverse health effects of MPs commonly found in daily life, particularly in susceptible populations. https://doi.org/10.1289/EHP13913.