Successful treatment of ulcerative colitis (UC) is highly dependent on several parameters, including dosing regimen and the ability to deliver drugs to the disease site. In this study two strategies for delivering mesalazine (5-aminosalicylic acid, 5-ASA) to the colon were compared in an advanced in vitro model of the human gastrointestinal (GI) tract, the SHIME® system. Herein, a prodrug strategy employing bacteria-mediated drug release (sulfasalazine, Azulfidine®) was evaluated alongside a formulation strategy that utilised pH and bacteria-mediated release (5-ASA, Octasa® 1600 mg). SHIME® experiments were performed simulating both the GI physiology and colonic microbiota under healthy and inflammatory bowel disease (IBD) conditions, to study the impact of the disease state and ileal pH variability on colonic 5-ASA delivery. In addition, the effects of the products on the colonic microbiome were investigated by monitoring bacterial growth and metabolites. Results demonstrated that both the prodrug and formulation approaches resulted in a similar percentage of 5-ASA recovery under healthy conditions. On the contrary, during experiments simulating the GI physiology and microbiome of IBD patients (the target population) the formulation strategy resulted in a higher proportion of 5-ASA delivery to the colonic region as compared to the prodrug approach ( < 0.0001). Interestingly, the two products had distinct effects on the synthesis of key bacterial metabolites, such as lactate and short chain fatty acids, which varied according to disease state and ileal pH variability. Further, both 5-ASA and sulfasalazine significantly reduced the growth of the faecal microbiota sourced from six healthy humans. The findings support that the approach selected for colonic drug delivery could significantly influence the effectiveness of UC treatment, and highlight that drugs licensed for UC may differentially impact the growth and functioning of the colonic microbiota.

中文翻译：

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美沙拉秦药物的结肠靶向功效及其对肠道微生物组的影响


溃疡性结肠炎 (UC) 的成功治疗高度依赖于几个参数，包括给药方案和将药物输送到疾病部位的能力。在这项研究中，在先进的人体胃肠道 (GI) 体外模型 SHIME® 系统中比较了两种向结肠输送美沙拉嗪（5-氨基水杨酸，5-ASA）的策略。在此，评估了采用细菌介导的药物释放（柳氮磺吡啶、Azulfidine®）的前药策略以及利用 pH 值和细菌介导的释放的制剂策略（5-ASA、Octasa® 1600 mg）。 SHIME® 实验模拟健康和炎症性肠病 (IBD) 条件下的胃肠道生理学和结肠微生物群，以研究疾病状态和回肠 pH 值变化对结肠 5-ASA 递送的影响。此外，通过监测细菌生长和代谢物来研究产品对结肠微生物群的影响。结果表明，在健康条件下，前药和制剂方法均导致 5-ASA 回收率相似。相反，在模拟 IBD 患者（目标人群）胃肠道生理学和微生物组的实验中，与前药方法相比，该制剂策略导致 5-ASA 递送到结肠区域的比例更高 (< 0.0001)。有趣的是，这两种产品对关键细菌代谢物（例如乳酸和短链脂肪酸）的合成具有明显的影响，这些代谢物根据疾病状态和回肠 pH 值变化而变化。此外，5-ASA 和柳氮磺吡啶均显着减少了六名健康人粪便微生物群的生长。 研究结果表明，选择的结肠药物输送方法可能会显着影响 UC 治疗的有效性，并强调获得许可用于 UC 的药物可能会对结肠微生物群的生长和功能产生不同的影响。