The expanding knowledge of the role of genetic variants involved in the susceptibility to IBD heralds an era of disease categorization beyond Crohn's disease and ulcerative colitis. A more robust molecular definition of the spectrum of IBD subtypes is likely to be based on specific molecular pathways that determine not only disease susceptibility but also disease characteristics such as location, natural history and therapeutic response. Evolving diagnostic panels for IBD will include clinical variables and genetic markers as well as other indicators of gene function and interaction with environmental factors, such as the microbiome. Multimodal algorithms that combine clinical, serologic and genetic information are likely to be useful in predicting disease course. Variation in IBD-susceptibility and drug-related pathway genes seems to influence the response to anti-TNF therapy. Furthermore, gene expression signatures and composite models have both shown promise as predictors of therapeutic response. Ultimately, models based on combinations of genotype and gene expression data with clinical, biochemical, serological, and microbiome data for clinically meaningful subgroups of patients should permit the development of tools for individualized risk stratification and treatment selection.
Ten children at our institution received single-infusion fecal microbiome transplant (FMT) using healthy, related screened donor stool to treat recurrent Clostridium difficile infection (RCDI) via nasogastric tube (2 patients) or colonoscopic delivery. Nine of the 10 (90%) children had resolution of their symptoms after a single-infusion FMT with follow-up of 1 month to 4 years. No concerning related adverse events were recognized during short- or long-term follow-up. Three of these children had concomitant inflammatory bowel disease and 2 of these 3 (66%) patients cleared RCDI with no clinical change in their underlying inflammatory bowel disease clinical activity as assessed by Physician's Global Assessment. All of the patients who had clinical improvement of gastrointestinal symptoms of RCDI while treated with antibiotics had lasting return of baseline health after FMT.
BACKGROUND: In patients with ulcerative colitis (UC), alterations of the intestinal microbiota, termed dysbiosis, have been postulated to contribute to intestinal inflammation. Fecal microbiota transplantation (FMT) has been used as effective therapy for recurrent Clostridium difficile colitis also caused by dysbiosis. The aims of the present study were to investigate if patients with UC benefit from FMT and if dysbiosis can be reversed.
METHODS: Six patients with chronic active UC nonresponsive to standard medical therapy were treated with FMT by colonoscopic administration. Changes in the colonic microbiota were assessed by 16S rDNA-based microbial community profiling using high-throughput pyrosequencing from mucosal and stool samples.
RESULTS: All patients experienced short-term clinical improvement within the first 2 weeks after FMT. However, none of the patients achieved clinical remission. Microbiota profiling showed differences in the modification of the intestinal microbiota between individual patients after FMT. In 3 patients, the colonic microbiota changed toward the donor microbiota; however, this did not correlate with clinical response. On phylum level, there was a significant reduction of Proteobacteria and an increase in Bacteroidetes after FMT.
CONCLUSIONS: FMT by a single colonoscopic donor stool application is not effective in inducing remission in chronic active therapy-refractory UC. Changes in the composition of the intestinal microbiota were significant and resulted in a partial improvement of UC-associated dysbiosis. The results suggest that dysbiosis in UC is at least in part a secondary phenomenon induced by inflammation and diarrhea rather than being causative for inflammation in this disease.
A dense mucus layer in the large intestine prevents inflammation by shielding the underlying epithelium from luminal bacteria and food antigens. This mucus barrier is organized around the hyperglycosylated mucin MUC2. Here we show that the small intestine has a porous mucus layer, which permitted the uptake of MUC2 by antigen-sampling dendritic cells (DCs). Glycans associated with MUC2 imprinted DCs with anti-inflammatory properties by assembling a galectin-3-Dectin-1-FcγRIIB receptor complex that activated β-catenin. This transcription factor interfered with DC expression of inflammatory but not tolerogenic cytokines by inhibiting gene transcription through nuclear factor κB. MUC2 induced additional conditioning signals in intestinal epithelial cells. Thus, mucus does not merely form a nonspecific physical barrier, but also constrains the immunogenicity of gut antigens by delivering tolerogenic signals.
BACKGROUND AND OBJECTIVE: Colonic dysbiosis contributes to the development of colonic inflammation in ulcerative colitis (UC). Fecal microbial transplantation (FMT) is being proposed as a novel treatment for UC because it can eliminate dysbiosis; however, no prospective data exist. We initiated a pilot study to evaluate feasibility and safety of FMT in children with UC.
METHODS: Ten children, 7 to 21 years of age, with mild-to-moderate UC (pediatric UC activity index [PUCAI] between 15 and 65) received freshly prepared fecal enemas daily for 5 days. Data on tolerability, adverse events, and disease activity were collected during FMT and weekly for 4 weeks after FMT. Clinical response was defined as decrease in PUCAI by >15, and decrease in PUCAI to <10 was considered clinical remission.
RESULTS: No serious adverse events were noted. Mild (cramping, fullness, flatulence, bloating, diarrhea, and blood in stool) to moderate (fever) adverse events were self-limiting. One subject could not retain fecal enemas. Average tolerated enema volume by remaining 9 subjects was 165 mL/day. After FMT, 7 of the 9 (78%) subjects showed clinical response within 1 week, 6 of the 9 (67%) subjects maintained clinical response at 1 month, and 3 of the 9 (33%) subjects achieved clinical remission at 1 week after FMT. Median PUCAI significantly improved after FMT (P = 0.03) compared with the baseline.
CONCLUSIONS: Fecal enemas were feasible and tolerated by children with UC. Adverse events were acceptable, self-limiting, and manageable by subjects. FMT indicated efficacy in the treatment of UC.
Studies of the genetics underlying inflammatory bowel diseases have increased our understanding of the pathways involved in both ulcerative colitis and Crohn's disease and focused attention on the role of the microbiome in these diseases. Full understanding of pathogenesis will require a comprehensive grasp of the delicate homeostasis between gut bacteria and the human host. In this review, we present current evidence of microbiome-gene interactions in the context of other known risk factors and mechanisms, and describe the next steps necessary to pair genetic variant and microbiome sequencing data from patient cohorts. We discuss the concept of dysbiosis, proposing that the functional composition of the gut microbiome may provide a more consistent definition of dysbiosis and may more readily provide evidence of genome-microbiome interactions in future exploratory studies.
Given the known dysbiosis of gut microflora in inflammatory bowel disease, there has been great enthusiasm about the potential for fecal microbiota transplantation (FMT) as a treatment. This editorial accompanies a prospective series of five patients with ulcerative colitis who underwent FMT, but did not achieve remission. I discuss the important observations from this study and point out that the lack of clinical efficacy and observed side effects warrant caution in the ongoing pursuit of this treatment option.
