OBJECTIVE The orphan nuclear receptor Nur77 is an important factor regulating metabolism. Nur77 knockout mice become obese with age, but the cause of obesity in these mice has not been fully ascertained. We attempted to explain the cause of obesity in Nur77 knockout mice from the perspective of the gut microbiota and to investigate the inhibitory effect of calcipotriol combined with BRD9 inhibitor (iBRD9) on obesity. METHODS Eight-week-old wild-type mice and Nur77 knockout C57BL/6J mice were treated with calcipotriol combined with iBRD9 for 12 weeks. Mouse feces were collected and the gut microbiota was assessed by analyzing 16S rRNA gene sequences. The bacterial abundance difference was analyzed, and the intestinal mucosal tight junction protein, antimicrobial peptide, and inflammatory cytokine mRNA levels of the colon and serum LPS and inflammatory cytokine levels were measured. RESULTS Calcipotriol combined with iBRD9 treatment reduced the body weight and body fat percentage in Nur77 knockout mice. In the gut microbiota of Nur77 knockout mice, the relative abundances of Lachnospiraceae and Prevotellaceae decreased, and Rikenellaceae increased; while Rikenellaceae decreased after treatment (p < 0.05). Correspondingly, the mRNA levels of intestinal mucosal tight junction proteins (occludin (Ocln), claudin3 (Cldn3)) in the colons of Nur77 knockout mice were significantly decreased, and they increased significantly after treatment (p < 0.001). The mRNA levels of inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β)) were significantly increased in Nur77 knockout mice, and TNF-α and IL-6 levels were significantly decreased after treatment (p < 0.05, <0.01, or <0.001). The levels of serum LPS, TNF-α, and IL-1β in Nur77 knockout mice were significantly increased (p < 0.05). Serum LPS, TNF-α, and IL-6 levels were significantly decreased after treatment (p < 0.05 or <0.01). CONCLUSIONS Calcipotriol combined with iBRD9 can regulate the gut microbiota, improve intestinal mucosal barrier function, reduce LPS absorption into the blood, and alleviate obesity in Nur77 knockout mice.

中文翻译：

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卡泊三醇和 iBRD9 通过调节肠道微生物群、改善肠黏膜屏障功能来减少 Nur77 基因敲除小鼠的肥胖。

目的孤儿核受体Nur77是调节代谢的重要因子。Nur77 基因敲除小鼠会随着年龄增长而变得肥胖，但这些小鼠肥胖的原因尚未完全确定。我们试图从肠道菌群的角度解释 Nur77 基因敲除小鼠肥胖的原因，并研究卡泊三醇联合 BRD9 抑制剂（iBRD9）对肥胖的抑制作用。方法 8周龄野生型小鼠和Nur77基因敲除C57BL/6J小鼠用卡泊三醇联合iBRD9治疗12周。收集小鼠粪便并通过分析 16S rRNA 基因序列评估肠道微生物群。分析细菌丰度差异，肠黏膜紧密连接蛋白、抗菌肽、测量结肠和血清 LPS 的炎性细胞因子 mRNA 水平和炎性细胞因子水平。结果 卡泊三醇联合 iBRD9 治疗降低了 Nur77 基因敲除小鼠的体重和体脂百分比。在Nur77基因敲除小鼠肠道菌群中，毛螺菌科和普氏菌科的相对丰度降低，理肯菌科的相对丰度增加；而 Rikenellaceae 处理后减少（p < 0.05）。相应地，Nur77基因敲除小鼠结肠中肠黏膜紧密连接蛋白（occludin（Ocln）、claudin3（Cldn3））mRNA水平显着降低，治疗后显着升高（p < 0.001）。炎性细胞因子（肿瘤坏死因子-α（TNF-α）、白介素-6（IL-6）、Nur77 基因敲除小鼠中白细胞介素-1β (IL-1β)) 显着升高，治疗后 TNF-α 和 IL-6 水平显着降低（p < 0.05、<0.01 或 <0.001）。Nur77基因敲除小鼠血清LPS、TNF-α和IL-1β水平显着升高（p < 0.05）。治疗后血清 LPS、TNF-α 和 IL-6 水平显着降低（p < 0.05 或 < 0.01）。结论 卡泊三醇联合 iBRD9 可以调节肠道菌群，改善肠黏膜屏障功能，减少 LPS 进入血液，减轻 Nur77 基因敲除小鼠的肥胖。TNF-α 和 IL-6 水平在治疗后显着降低（p < 0.05 或 <0.01）。结论 卡泊三醇联合 iBRD9 可以调节肠道菌群，改善肠黏膜屏障功能，减少 LPS 进入血液，减轻 Nur77 基因敲除小鼠的肥胖。TNF-α 和 IL-6 水平在治疗后显着降低（p < 0.05 或 <0.01）。结论 卡泊三醇联合 iBRD9 可以调节肠道菌群，改善肠黏膜屏障功能，减少 LPS 进入血液，减轻 Nur77 基因敲除小鼠的肥胖。