小檗碱联合生活方式干预对轻中度高甘油三酯血症受试者粪便短链脂肪酸、炎症指标及血脂谱的影响：一项随机、开放标签、盲法终点评估的探索性临床研究

Effects of Berberine plus Lifestyle Intervention on Fecal Short-Chain Fatty Acids, Inflammatory Markers, and Lipid Profiles in Adults with Mild-to-Moderate Hypertriglyceridemia: A Randomized, Open-Label, Blinded-Endpoint Exploratory Clinical Study

摘要: 目的：探索小檗碱联合生活方式干预对轻中度高甘油三酯血症受试者粪便短链脂肪酸(SCFAs)、炎症指标及血脂谱的影响，并评价其短期可行性与安全性。方法：采用随机、开放标签、盲法终点评估的探索性临床研究设计，纳入轻中度高甘油三酯血症受试者20例，随机分为小檗碱组和生活方式对照组，每组10例。两组均接受标准化生活方式指导；小檗碱组在此基础上口服盐酸小檗碱0.3 g，每日3次，连续8周。于基线和第8周采集粪便及血液样本，检测粪便SCFAs、血脂谱、炎症指标、肝肾功能及体格指标。采用线性混合效应模型估计组别 × 时间交互作用。结果：共19例受试者完成第8周随访，小檗碱组完成随访者的平均服药依从性为92.6%。与对照组相比，小檗碱组粪便丁酸水平显著升高，组间变化差为3.31 μmol/g湿重(95% CI: 1.13~5.49, P = 0.005)。小檗碱组hs-CRP、TNF-α、IL-6及IL-1β的下降幅度均大于对照组，组间变化差分别为−0.56 mg/L、−3.22 pg/mL、−1.61 pg/mL和−1.18 pg/mL (均P < 0.05)；IL-10的升高幅度大于对照组[1.46 pg/mL (95% CI: 0.31~2.61, P = 0.015)]。血脂方面，小檗碱组TG、TC及非HDL-C的下降幅度大于对照组，组间变化差分别为−0.56 mmol/L (P = 0.028)、−0.39 mmol/L (P = 0.049)和−0.44 mmol/L (P = 0.041)。两组肝肾功能指标均未见具有临床意义的异常变化。小檗碱组2例受试者报告3例次轻度胃肠道不良事件，经调整服药时间、增加饮水及观察后均缓解；未发生严重不良事件。结论：在本项小样本探索性研究中，8周小檗碱联合生活方式干预具有较好的短期可行性和耐受性，并与粪便丁酸水平升高、炎症指标改善及部分血脂指标下降相关。上述结果尚不能确证小檗碱的降脂疗效或“肠道菌群-SCFAs-免疫”因果机制，仍需开展多中心、随机、安慰剂对照及充分样本量的研究进一步验证。

Abstract: Objective: To explore the effects of berberine combined with lifestyle intervention on fecal short-chain fatty acids (SCFAs), inflammatory markers, and lipid profiles in adults with mild-to-moderate hypertriglyceridemia, and to evaluate its short-term feasibility and safety. Methods: This exploratory clinical study used a randomized, open-label, blinded-endpoint (PROBE) design. Twenty adults with mild-to-moderate hypertriglyceridemia were randomly assigned to a berberine group or a lifestyle control group (10 participants per group). Both groups received standardized lifestyle guidance. In addition, participants in the berberine group received oral berberine hydrochloride (0.3 g, three times daily) for 8 weeks. Fecal and blood samples were collected at baseline and week 8 to assess fecal SCFAs, lipid profiles, inflammatory markers, liver and kidney function, and anthropometric measures. Group-by-time interactions were estimated using linear mixed-effects models. Results: Nineteen participants completed the week-8 follow-up. Among participants completing follow-up in the berberine group, mean medication adherence was 92.6%. Compared with the control group, the berberine group showed a greater increase in fecal butyrate concentration, with a between-group difference in change of 3.31 μmol/g wet weight (95% confidence interval [CI]: 1.13 to 5.49; P = 0.005). Greater reductions in hs-CRP, TNF-α, IL-6, and IL-1β were also observed in the berberine group, with between-group differences in change of −0.56 mg/L, −3.22 pg/mL, −1.61 pg/mL, and −1.18 pg/mL, respectively (all P < 0.05). The increase in IL-10 was greater in the berberine group than in the control group (1.46 pg/mL, 95% CI: 0.31 to 2.61; P = 0.015). In terms of lipid parameters, reductions in triglycerides, total cholesterol, and non-high-density lipoprotein cholesterol were greater in the berberine group, with between-group differences in change of −0.56 mmol/L (P = 0.028), −0.39 mmol/L (P = 0.049), and −0.44 mmol/L (P = 0.041), respectively. No clinically meaningful abnormalities in liver or kidney function were observed. Two participants in the berberine group reported three mild gastrointestinal adverse events, all of which resolved after adjustment of dosing time, increased fluid intake, and observation. No serious adverse events occurred. Conclusion: In this small exploratory study, 8 weeks of berberine combined with lifestyle intervention showed acceptable short-term feasibility and tolerability and was associated with increased fecal butyrate levels, improved inflammatory markers, and favorable changes in selected lipid parameters. These findings do not establish the lipid-lowering efficacy of berberine or a causal gut microbiota-SCFAs-immune mechanism. Larger, multicenter, randomized, placebo-controlled trials with adequate sample sizes are required for confirmation.