Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
Department of Gastroenterology, Clinic of Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
Aliment Pharmacol Ther. 2019 May;49(10):1301-1313. doi: 10.1111/apt.15227. Epub 2019 Mar 20.
5-aminosalicylic acid (5-ASA) is the first-line therapy for ulcerative colitis (UC). 5-ASA acts locally in the colonic mucosa by numerous proposed mechanisms, and is metabolised by N-acetyltransferase (NAT). Large variations in mucosal 5-ASA concentrations have been reported, but the underlying mechanisms are not understood.
To study the relationship between 5-ASA concentration, 5-ASA formulation, NAT genotype and bacterial microbiome in patients with UC.
Patients with quiescent UC, using monotherapy of Mezavant (n = 18), Asacol (n = 14) or Pentasa (n = 10), 4.0-4.8 g/day were included. 5-ASA was measured in colonic mucosal biopsies and serum by ultra-high performance liquid chromatography. NAT genotypes were determined by Sanger sequencing. Bacterial microbiome was sequenced from faeces and mucosa by 16S rRNA sequencing using Illumina Miseq.
Mezavant provided the highest mucosal 5-ASA levels (geometric mean 2.39 ng/mg), followed by Asacol (1.60 ng/mg, 33% lower, P = 0.50) and Pentasa (0.57 ng/mg, 76% lower, P = 0.033). Mucosal 5-ASA concentration was not associated with NAT genotype, but serum 5-ASA concentration and NAT1 genotype was associated (P = 0.044). Mucosal 5-ASA concentration was positively associated with mucosal bacterial diversity (P = 0.0005) and bacterial composition. High mucosal 5-ASA concentration was related to reduced abundance of pathogenic bacteria such as Proteobacteria, and increased abundance of several favourable bacteria such as Faecalibacterium.
Mucosal 5-ASA concentration is positively associated with bacterial diversity and a mucosal bacterial composition that are perceived favourable in UC. Mezavant yielded higher mucosal 5-ASA concentrations than Pentasa. 5-ASA may have beneficial effects on the mucosal microbiome, and high concentrations possibly amend dysbiosis in UC.
5-氨基水杨酸（5-ASA）是溃疡性结肠炎（UC）的一线治疗药物。5-ASA 通过多种提出的机制在结肠黏膜中发挥局部作用，并被 N-乙酰基转移酶（NAT）代谢。已经报道了黏膜 5-ASA 浓度的大量变化，但基础机制尚不清楚。
研究 UC 患者中 5-ASA 浓度、5-ASA 制剂、NAT 基因型和细菌微生物组之间的关系。
纳入使用 Mezavant（n=18）、Asacol（n=14）或 Pentasa（n=10）单药治疗、每天 4.0-4.8g 的静止期 UC 患者。通过超高效液相色谱法在结肠黏膜活检和血清中测量 5-ASA。通过 Sanger 测序确定 NAT 基因型。通过 Illumina Miseq 对粪便和黏膜进行 16S rRNA 测序，以确定细菌微生物组。
Mezavant 提供了最高的黏膜 5-ASA 水平（几何平均值 2.39ng/mg），其次是 Asacol（1.60ng/mg，低 33%，P=0.50）和 Pentasa（0.57ng/mg，低 76%，P=0.033）。黏膜 5-ASA 浓度与 NAT 基因型无关，但与血清 5-ASA 浓度和 NAT1 基因型相关（P=0.044）。黏膜 5-ASA 浓度与黏膜细菌多样性呈正相关（P=0.0005）和细菌组成。高黏膜 5-ASA 浓度与致病性细菌（如变形菌门）的丰度降低有关，与几种有利细菌（如粪杆菌属）的丰度增加有关。
黏膜 5-ASA 浓度与细菌多样性呈正相关，与 UC 中被认为有利的黏膜细菌组成呈正相关。Mezavant 产生的黏膜 5-ASA 浓度高于 Pentasa。5-ASA 可能对黏膜微生物组有有益影响，高浓度可能改善 UC 中的菌群失调。
