Mucosal 5‐aminosalicylic acid concentration, drug formulation and mucosal microbiome in patients with quiescent ulcerative colitis

Abstract

Summary Background 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. Aim To study the relationship between 5‐ASA concentration, 5‐ASA formulation, NAT genotype and bacterial microbiome in patients with UC. Methods 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. Results 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. Conclusions 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.

Gut Microbiome Changes in Patients with Active Left-Sided Ulcerative Colitis after Fecal Microbiome Transplantation and Topical 5-aminosalicylic Acid Therapy

“…Xu et al [ 4 ] demonstrated a higher abundance of Firmicutes and lower levels of Proteobacteria in the inflamed mucosa of 5-ASA-treated patients. Olaisen et al [ 5 ] determined that the mucosal 5-ASA concentration was positively associated with mucosal bacterial diversity and bacterial compositions. A high mucosal 5-ASA concentration was also found to be related to the reduced abundance of pathogenic bacteria such as Proteobacteria and increased abundance of several favorable families (Lachnospiraceae and Ruminococcaceae) and genera such as Faecalibacterium and Coprococcus .…”

“…5-ASA may have beneficial effects on the mucosal microbiome, with high concentrations altering dysbiosis in UC. Olaisen et al [ 5 ] highlighted that mucosal 5-ASA concentration is associated with changes in mucosal bacterial composition, however, the fecal microbiota was not changed to the same extent.…”

Editorial: mesalamine and mucosal microbiome in quiescent ulcerative colitis—what can we learn? Authors' reply

“…The authors' declarations of personal and financial interests are unchanged from those in the original article …”

“…We welcome the interest expressed by Buchner and Lichtenstein in our work examining mucosal mesalazine concentration in relation to various factors, including the microbiome composition in mucosal biopsies and faecal samples from patients with ulcerative colitis (UC) …”

Editorial: mesalazine and mucosal microbiome in quiescent ulcerative colitis—what can we learn?

“…The recent study by Dr. Olaisen et al in AP&T adds a valid argument for the influence of 5‐ASA on the mucosal microbiome. The study aimed to evaluate the relationship between 5‐ASA concentrations, 5‐ASA formulations, N‐acyl transferase (NAT) genotype and bacterial microbiome in 42 patients with UC.…”