Abstract
Previous work has demonstrated that intestinal bacteria, such as Fusobacterium varium (F. varium), contribute to the clinical activity in ulcerative colitis (UC); thus, an antibiotic combination therapy (amoxicillin, tetracycline, and metronidazole (ATM)) against F. varium can induce and maintain UC remission. Therefore, we investigated whether ATM therapy induces a long-term alteration of intestinal microbiota in patients with UC. Patients with UC were enrolled in a multicenter, randomized, double-blind, placebo-controlled study. Biopsy samples at the beginning of the trial and again at 3 months after treatment completion were randomly obtained from 20 patients. The terminal restriction fragment length polymorphism (T-RFLP) in mucosa-associated bacterial components was examined to assess the alteration of the intestinal microbiota. Profile changes of T-RFLP in mucosa-associated bacterial components were found in 10 of 12 patients in the treatment group and in none of 8 in the placebo group. Dice similarity coefficients using the unweighted pair group method with arithmetic averages (Dice-UPGMA) confirmed that the similarity of mucosal microbiota from the descending colon was significantly decreased after the ATM therapy, and this change was maintained for at least 3 months. Moreover, at 3 months after treatment completion, the F. varium/β-actin ratio, examined by real-time PCR using nested PCR products from biopsy samples, was reduced less than 40% in 8 of 12 treated patients, which was higher, but not significantly, than in 4 of 8 patients in the placebo group. Together, these results suggest that ATM therapy induces long-term alterations in the intestinal microbiota of patients with UC, which may be associated, at least in part, with clinical effects of the therapy.
Highlights
The etiology of ulcerative colitis (UC) is still unknown; increasing evidence suggests that the intestinal microbiota play important roles in the pathogenesis of inflammatory bowel disease (IBD), including: a) intestinal microbiota adhere to the crypt epithelium via Toll-like receptors (TLR)2 and TLR4 and invade the epithelium, resulting in inflammatory cytokine production; b) intestinal microbiota are necessary for the development of spontaneous colitis and immune system activation in IL-2- and IL-10-deficient mice; and c) an overly aggressive cellmediated immune response to endogenous intestinal bacterial constituents in genetically susceptible patients results in intestinal inflammation [1,2,3,4]
We show that the profile of the terminal restriction fragment length polymorphism (T-RFLP) in the mucosa-associated bacterial components is significantly changed at 3 months after the ATM therapy
The data presented here show that the 2-week triple-antibiotic therapy produced a long-term alternation of the intestinal microbiota that persisted at least 3 months compared to a placebo in a multicenter, randomized, double-blind, placebo-controlled study
Summary
The etiology of ulcerative colitis (UC) is still unknown; increasing evidence suggests that the intestinal microbiota play important roles in the pathogenesis of inflammatory bowel disease (IBD), including: a) intestinal microbiota adhere to the crypt epithelium via Toll-like receptors (TLR) and TLR4 and invade the epithelium, resulting in inflammatory cytokine production; b) intestinal microbiota are necessary for the development of spontaneous colitis and immune system activation in IL-2- and IL-10-deficient mice; and c) an overly aggressive cellmediated immune response to endogenous intestinal bacterial constituents in genetically susceptible patients results in intestinal inflammation [1,2,3,4]. Appropriate antibiotic therapy against microbial pathogens could alter the intestinal microbiota in patients with UC, resulting in the improvement and remission of active UC. We recently conducted a double-blind placebocontrolled multicenter trial to determine whether an antibiotic combination regimen (amoxicillin, tetracycline, and metronidazole (ATM) for 2 weeks) against the microbial pathogens of UC, including F. varium, induces and/or maintains remission of active UC [11]. In this study to assess the alteration of intestinal microbiota by the ATM therapy, biopsy samples that were randomly obtained from the clinical trial were analyzed
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