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The use of proton pump inhibitors (PPIs) has increased considerably in many Western countries, and there is concern that numerous conditions and diseases associated with PPI use may be adverse events. The main function of gastric acid is to defend the organism against orally ingested microorganisms, and there is also concern that alterations not only in the gastric microbiome but also the downstream intestinal microbiome may increase the risk of disease or alter the course of preexisting disease. The current study is a systematic review of the available evidence from experimental trials investigating the effects of PPIs on the gastrointestinal microbiota by next-generation sequencing. Thirteen studies were identified. The effects of PPIs were seen on alterations in diversity and richness in some of the studies, while a larger proportion of the studies detected alterations at various taxonomic levels. The general finding was that PPI use caused an increase in bacteria normally found in the oral microbiota in both the upper and lower GI tract. The most consistent taxonomic alterations seemed to be increases in oral flora along the axis Streptococcaceae and Streptococcus at genus level and various Streptococcus spp., as well as Veillonellaceae, Veillonella and Haemophilus.

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Introduction: Fungal microbiota's involvement in the pathogenesis of Crohn's disease (CD) is incompletely understood. The terminal ileum is a predilection site both for primary involvement and recurrences of CD. We, therefore, assessed the mucosa-associated mycobiota in the inflamed and non-inflamed ileum in patients with CD. Methods: The mucosa-associated mycobiota was assessed by ITS2 sequencing in a total of 168 biopsies sampled 5 and 15 cm proximal of the ileocecal valve or ileocolic anastomosis in 44 CD patients and 40 healthy controls (HC). CD patients with terminal ileitis, with endoscopic inflammation at 5 cm and normal mucosa at 15 cm and no history of upper CD involvement, were analyzed separately. The need for additional CD treatment the year following biopsy collection was recorded. Results: CD patients had reduced mycobiota evenness, increased Basidiomycota/Ascomycota ratio, and reduced abundance of Chytridiomycota compared to HC. The mycobiota of CD patients were characterized by an expansion of Malassezia and a depletion of Saccharomyces, along with increased abundances of Candida albicans and Malassezia restricta. Malassezia was associated with the need for treatment escalation during follow-up. Current anti-TNF treatment was associated with lower abundances of Basidiomycota. The alpha diversity of the inflamed and proximal non-inflamed mucosa within the same patients was similar. However, the inflamed mucosa had a more dysbiotic composition with increased abundances of Candida sake and reduced abundances of Exophiala equina and Debaryomyces hansenii. Conclusions: The ileal mucosa-associated mycobiota in CD patients is altered compared to HC. The mycobiota in the inflamed and proximal non-inflamed ileum within the same patients harbor structural differences which may play a role in the CD pathogenesis. Increased abundance of Malassezia was associated with an unfavorable disease course.

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BACKGROUND: Oral 5-aminosalicylic acid (5-ASA) is the mainstay treatment of ulcerative colitis (UC) and therapy with oral 5-ASA is associated with beneficial outcomes. We have examined factors associated with the persistence of oral 5-ASA treatment in a national cohort of UC patients. METHODS: Patients with newly diagnosed UC from 2010 to 2014 using oral 5-ASA monotherapy were identified by combining data from the Norwegian Patient Registry and the Norwegian Prescription Database. The median follow-up time was 1029 days. Drug persistence was defined as duration of oral 5-ASA preparation as monotherapy. Non-persistence of a oral 5-ASA preparation as monotherapy was defined as stopping oral 5-ASA, initiation of any further anti-inflammatory treatment including a course of glucocorticoids and a change to another oral 5-ASA preparation. Drug persistence was analyzed using the Kaplan-Meier method and influence of covariates on drug persistence was analyzed with the Cox proportional hazard model. RESULTS: A total of 3421 patients were identified. The overall median 5-ASA drug persistence was 179 days. In univariate analyses, persistence was associated with preparation type and high-dose treatment, while oral glucocorticoid use or hospitalization around the start of oral 5-ASA were associated with shorter 5-ASA persistence. In multivariate analyses, oral glucocorticoids [HR 1.67 (1.54-1.80), p < 0.005] and hospitalization around start of 5-ASA [HR 1.23 (1.14-1.34), p < 0.005] were associated with non-persistence, whereas high dose (⩾3 g/day) 5-ASA was associated with longer persistence [HR 0.68 (0.65-0.71), p < 0.005]. CONCLUSION: High-dose treatment with oral 5-ASA was associated with longer persistence of oral 5-ASA monotherapy, whereas the presence of factors indicating more severe disease around initiation of 5-ASA monotherapy was associated with a shorter persistence.

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BACKGROUND: Microbiota is most likely essential in the pathogenesis of Crohn's disease (CD). Fecal diversion after ileocecal resection (ICR) protects against CD recurrence, whereas infusion of fecal content triggers inflammation. After ICR, the majority of patients experience endoscopic recurrence in the neoterminal ileum, and the ileal microbiome is of particular interest. We have assessed the mucosa-associated microbiome in the inflamed and noninflamed ileum in patients with CD. METHODS: Mucosa-associated microbiome was assessed by 16S rRNA sequencing of biopsies sampled 5 and 15 cm orally of the ileocecal valve or ileocolic anastomosis. RESULTS: Fifty-one CD patients and forty healthy controls (HCs) were included in the study. Twenty CD patients had terminal ileitis, with endoscopic inflammation at 5 cm, normal mucosa at 15 cm, and no history of upper CD involvement. Crohn's disease patients (n = 51) had lower alpha diversity and separated clearly from HC on beta diversity plots. Twenty-three bacterial taxa were differentially represented in CD patients vs HC; among these, Tyzzerella 4 was profoundly overrepresented in CD. The microbiome in the inflamed and proximal noninflamed ileal mucosa did not differ according to alpha diversity or beta diversity. Additionally, no bacterial taxa were differentially represented. CONCLUSIONS: The microbiome is similar in the inflamed and proximal noninflamed ileal mucosa within the same patients. Our results support the concept of CD-specific microbiota alterations and demonstrate that neither ileal sublocation nor endoscopic inflammation influence the mucosa-associated microbiome.

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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.

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BACKGROUND: Ulcerative colitis (UC) can be complicated by reactivation of cytomegalovirus (CMV). CMV reactivation may change the course of UC and may require antiviral treatment. Some risk factors of CMV reactivation have previously been identified, whereas the association between CMV reactivation and postoperative complications has not been examined systematically. METHODS: Patients with UC operated with colectomy due to active UC were studied (n = 77). Patient and disease characteristics, as well as postoperative complications were recorded and CMV was detected by immunohistochemical examination of multiple sections from the colectomy specimen. RESULTS: CMV was found in nine (11.7%) colectomy specimens. CMV-positive patients received significantly higher doses of corticosteroids at colectomy than CMV-negative patients (61.1 ± 23 vs 32.5 ± 32 mg/day, p = 0.01). CMV-positive patients were also older, had a higher risk of severe complications, higher American Society of Anesthesiologists (ASA) score, longer preoperative stay, and a higher rate of acute surgery. Complications occurred in 30 (39%) patients after surgery, 8(10.4%) of whom were serious. Two CMV-positive patients (2.6%) died in-hospital after the colectomy. High ASA score was associated with the occurrence of serious complications. CONCLUSION: A relatively small proportion of patients with UC operated by colectomy were CMV positive. CMV positivity was associated with old age, high dose of corticosteroids at operation, high ASA score, acute surgery, and severe postoperative complications. Patients with such characteristics may be at risk of CMV infection and may require special management.

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