Multicenter analysis of fecal microbiota profiles in Japanese patients with Crohn's disease.
ABSTRACT BACKGROUND: We analyzed the fecal microbiota profiles of patients with Crohn's disease (CD) at 4 inflammatory bowel disease (IBD) centers located in different districts in Japan. METHODS: Terminal restriction fragment length polymorphism (T-RFLP) analysis was performed in 161 fecal samples from CD patients and 121 samples from healthy individuals. The bacterial diversity was evaluated by the Shannon diversity index (SDI). RESULTS: There were no regional differences in the fecal microbiota profiles of the healthy individuals in Japan. A setting of similarity generated three major clusters of T-RFs: one included almost all the healthy individuals (118/121), and the other two clusters were mainly formed by CD patients at different stages of disease activity. The changes in simulated bacterial composition indicated that the class Clostridia, including the genus Faecalibacterium, was significantly decreased in CD patients with active disease and those in remission as compared with findings in the healthy individuals. In contrast, the genus Bacteroides was significantly increased in CD patients during the active phase as compared with findings in the healthy individuals. The genus Bifidobacterium was significantly decreased during the active phase of CD and increased to healthy levels during the remission phase. The bacterial diversity measured by the SDI was significantly reduced in CD patients during the active and remission phases as compared with findings in the healthy individuals. From the clinical data and T-RFLP analysis, we developed a logistic model to predict disease activity based on the fecal microbiota composition. CONCLUSION: Dysbiosis in CD patients was shown by a multi-IBD center study. The feasibility of using the fecal microbiota profile as a predictive marker for disease activity is proposed.
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ABSTRACT: The predominantly anaerobic microbiota of the distal ileum and colon contain an extraordinarily complex variety of metabolically active bacteria and fungi that intimately interact with the host's epithelial cells and mucosal immune system. Crohn's disease, ulcerative colitis, and pouchitis are the result of continuous microbial antigenic stimulation of pathogenic immune responses as a consequence of host genetic defects in mucosal barrier function, innate bacterial killing, or immunoregulation. Altered microbial composition and function in inflammatory bowel diseases result in increased immune stimulation, epithelial dysfunction, or enhanced mucosal permeability. Although traditional pathogens probably are not responsible for these disorders, increased virulence of commensal bacterial species, particularly Escherichia coli, enhance their mucosal attachment, invasion, and intracellular persistence, thereby stimulating pathogenic immune responses. Host genetic polymorphisms most likely interact with functional bacterial changes to stimulate aggressive immune responses that lead to chronic tissue injury. Identification of these host and microbial alterations in individual patients should lead to selective targeted interventions that correct underlying abnormalities and induce sustained and predictable therapeutic responses.Gastroenterology 03/2008; 134(2):577-94. · 12.82 Impact Factor
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ABSTRACT: A decrease in the abundance and biodiversity of intestinal bacteria within the dominant phylum Firmicutes has been observed repeatedly in Crohn disease (CD) patients. In this study, we determined the composition of the mucosa-associated microbiota of CD patients at the time of surgical resection and 6 months later using FISH analysis. We found that a reduction of a major member of Firmicutes, Faecalibacterium prausnitzii, is associated with a higher risk of postoperative recurrence of ileal CD. A lower proportion of F. prausnitzii on resected ileal Crohn mucosa also was associated with endoscopic recurrence at 6 months. To evaluate the immunomodulatory properties of F. prausnitzii we analyzed the anti-inflammatory effects of F. prausnitzii in both in vitro (cellular models) and in vivo [2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced] colitis in mice. In Caco-2 cells transfected with a reporter gene for NF-kappaB activity, F. prausnitzii had no effect on IL-1beta-induced NF-kappaB activity, whereas the supernatant abolished it. In vitro peripheral blood mononuclear cell stimulation by F. prausnitzii led to significantly lower IL-12 and IFN-gamma production levels and higher secretion of IL-10. Oral administration of either live F. prausnitzii or its supernatant markedly reduced the severity of TNBS colitis and tended to correct the dysbiosis associated with TNBS colitis, as demonstrated by real-time quantitative PCR (qPCR) analysis. F. prausnitzii exhibits anti-inflammatory effects on cellular and TNBS colitis models, partly due to secreted metabolites able to block NF-kappaB activation and IL-8 production. These results suggest that counterbalancing dysbiosis using F. prausnitzii as a probiotic is a promising strategy in CD treatment.Proceedings of the National Academy of Sciences 11/2008; 105(43):16731-6. · 9.74 Impact Factor
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ABSTRACT: Results of recent genetic and immunologic studies have brought to the forefront several biologic pathways that allow for a better understanding of the mechanisms of tissue homeostasis, on the one hand, and inflammatory bowel disease (IBD) on the other. The explosion of research activity as a result of these newly identified targets is bringing the pathogenesis of these complex disorders into focus as well as creating new therapeutic opportunities. The greatest advances with perhaps the largest impact on our understanding of the etiology of Crohn's disease are those related to bacterial sensing, such as through nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and its relationships to autophagy and the unfolded protein response as a consequence of endoplasmic reticulum stress. Interestingly, it appears as though these pathways, which are rooted in microbial sensing and regulation, are interrelated. Genetic studies have also renewed interest in previously studied pathways in IBD, such as the formation and function of the inflammasome and its relationship to interleukin (IL) 1-beta signaling. With the recent success of therapeutic agents designed to block tumor necrosis factor, the IL-12/23 pathways, and lymphocyte homing, insights have been gained into the biologic relevance and impact of these various inflammatory pathways in IBD. In this review, the exciting recent advances in these biologic pathways of IBD are discussed, particularly in light of their therapeutic relevance.Journal of Gastroenterology 01/2012; 47(1):1-8. · 3.79 Impact Factor