Early Postoperative Endoscopic Recurrence in Crohn’s Disease Is Characterised by Distinct Microbiota Recolonisation

Abstract

Background and Aims Intestinal microbiota dysbiosis is implicated in Crohn’s disease [CD] and may play an important role in triggering postoperative disease recurrence [POR]. We prospectively studied faecal and mucosal microbial recolonisation following ileocaecal resection to identify the predictive value of recurrence-related microbiota. Methods Mucosal and/or faecal samples from 121 CD patients undergoing ileocaecal resection were collected at predefined time points before and after surgery. Ileal biopsies were collected from 39 healthy controls. POR was defined by a Rutgeerts score ≥i2b. The microbiota was evaluated by 16S rRNA sequencing. Prediction analysis was performed using C5.0 and Random Forest algorithms. Results The mucosa-associated microbiota in CD patients was characterised by a depletion of butyrate-producing species (false discovery rate [FDR] <0.01) and enrichment of Proteobacteria [FDR = 0.009] and Akkermansia spp. [FDR = 0.02]. Following resection, a mucosal enrichment of Lachnospiraceae [FDR <0.001] was seen in all patients but in POR patients, also Fusobacteriaceae [FDR <0.001] increased compared with baseline. Patients without POR showed a decrease of Streptococcaceae [FDR = 0.003] and Actinomycineae [FDR = 0.06]. The mucosa-associated microbiota profile had good discriminative power to predict POR, and was superior to clinical risk factors. At Month 6, patients experiencing POR had a higher abundance of taxa belonging to Negativicutes [FDR = 0.04] and Fusobacteria [FDR = 0.04] compared with patients without POR. Conclusions Microbiota recolonisation after ileocaecal resection is different between recurrence and non-recurrence patients, with Fusobacteria as the most prominent player driving early POR. These bacteria involved in the early recolonisation and POR represent a promising therapeutic strategy in the prevention of disease recurrence.

Gut Microbiota Profiles and Microbial-Based Therapies in Post-operative Crohn's Disease: A Systematic Review

“…Strömbeck et al detected higher Actinobacteria and lower Alistipes counts in the fecal microbiota of the PR group at their 1-year follow-up; Alistipes was found to correlate negatively with the Rutgeerts score ( 25 ). In another study tracking the trends in the fecal microbiota changes in patients with endoscopic recurrence, the relative Fusobacterium and Bifidobacterium abundances increased and decreased, respectively, in 1, 3, and 6 months after surgery compared to that in patients in remission ( 26 ). In addition, Hamilton et al found that bacterial clusters enriched with Enterobacteriaceae and Lachnospiraceae were associated with an increased risk of disease recurrence and the maintenance of remission, respectively ( 24 ).…”

“…In addition, increased Corynebacterium and decreased Ruminiclostridium 6 counts at baseline were identified as predictive factors of endoscopic recurrence for CD patients ( 27 ). Machiels et al reported that the Ralstonia, Haemophilus, Gemella , and Phascolarctobacterium abundances in resected specimens were good predictors using C5.0 classification tree analyses or random forest models ( 26 ). However, the considerable predictive power of Coprobacillus, unidentified Lachnospiraceae , and Dorea obtained from fecal samples before surgery could not be confirmed after validation using the forest model.…”

“…As has been shown in previous studies, the majority of the studies included in this review suggested that the ileal mucosa-associated microbiota in CD patients exhibited reduced bacterial richness and diversity, while there was a clustering of samples with statistically significant differences between CD patients and healthy controls. Only one study from Machiels et al simultaneously analyzed preoperative mucosal and fecal microbiota and found that CD patients had distinct characteristics of mucosal and fecal microbiota before surgery, which further confirmed that fecal and mucosal microbiota constitute different ecological environments ( 26 ). Although not even a single bacterial taxon had consistently altered counts across all included studies, we identified bacterial taxa obtained from surgical specimens that allowed us to discriminate between CD patients and healthy subjects, in several studies.…”

Medical therapies for postoperative Crohn’s disease

“…With recent emerging data on intestinal microbiome dysbiosis in the colonized neo-terminal ileum affecting POR, it has been postulated that modulation with antibiotics or probiotics may have a role in the management of postoperative CD. [35][36][37] Of these, nitroimidazoles have been well studied and demonstrated benefit. Compared with placebo, metronidazole (20 mg/ kg) reduces endoscopic recurrence at 3 months after surgery (13% versus 43%, p = 0.02) and clinical recurrence at 1 year (4% versus 25%, p = 0.04).…”

“…85,86 Finally, microbiome dysbiosis is being recognized as a risk factor with recolonization of microbiota, including Proteobacteria, Akkermansia spp., Fusobacteriaceae and a depletion of Streptococcaceae, Actinomycineae, Faecalibacterium. [35][36][37] Interestingly, active smoking was associated with elevated levels of Proteus, 37 and thus these risk factors may be interactive. The role of other "-omics", including ileal tissue transcriptomics, blood transcriptomics, and urinary metabolomics, is being evaluated.…”