Leading article our disease understanding. In contrast Microbiomarkers in inflammatory bowel to the static human genome, micro- biome composition is more dynamic and Gut: first published as 10.1136/gutjnl-2016-313678 on 21 July 2017. Downloaded from diseases: caveats come with caviar can thus be more easily modified by, for example, probiotics, prebiotics, antibi- Felix Sommer,1 Malte Christoph Rühlemann,1 otics or faecal microbiota transfer (FMT) 1 1 1 2 from healthy donors to patients by enema Corinna Bang, Marc Höppner, Ateequr Rehman, Christoph Kaleta, or via the nasoduodenal route. The latter 3 4 5 Phillippe Schmitt-Kopplin, Astrid Dempfle, Stephan Weidinger, was demonstrated to be perhaps the best 1 2,6 7 method to treat life-threatening recurrent Eva Ellinghaus, Susanne Krauss-Etschmann, Dirk Schmidt-Arras, 6–8 1 8 1 1,8 Clostridium difficile infections, but is Konrad Aden, Dominik Schulte, David Ellinghaus, Stefan Schreiber, a controversial method for IBD and is Andreas Tholey,2 Jan Rupp,9 Matthias Laudes,8 John F Baines,2,10 therefore still regarded as an experimental Philip Rosenstiel,1 Andre Franke1 therapy. Nevertheless, a recent multi- centre placebo-controlled trial in Australia (the Faecal Microbiota Transplantation in The largest numbers of commensal gut, but also between luminal and mucosa- Ulcerative Colitis (FOCUS) study) demon- bacteria reside within our intestinal tract, attached communities of the same intes- strated efficacy of FMT for treating UC with an increasing density from mouth to tinal segment, and even along the crypt- (p=0.021; enemas given at 5 days a week anus. Recently, a new estimate for the total villus axis in the epithelium. Thus, for overall 8 weeks).9 Based on this finding, number of bacteria (3.8×1013) in the host–microbiota interactions are likely it was suggested that future work should 70 kg ‘reference man’ was reported.1 For regionally specific and the local crosstalk focus on defining the optimum treatment human cells, the same authors revised past determines intestinal function and physi- intensity and the role of donor–recipient estimates to 3.0×1013 cells, out of which ology. Probably each human individual matching based on microbial profiles. The approximately 90% belong to the haema- carries its own ‘microbial fingerprint’ growing body of studies using FMT and topoietic lineage. Hence, the widely cited (especially when considering genomic gnotobiotics started to move the field of 10:1 ratio of bacteria versus human cells variation within the bacterial species’ microbiota research away from correla- received an update, showing that the populations), which is why forensic scien- tion to causality by proving a functional number of bacteria in the body is actually tists started to exploit the use of this involvement of the microbiota for health of the same order as the number of human non-human organ.3 and disease.10–12 cells, and that the cumulative bacterial Recent large-scale analyses of popula- Microbiome studies in IBD have been mass is about 200 g. Still, this large number tion-based cohorts with >1000 samples consistent in finding reduced diver- of bacteria highlights their importance in validated that body mass index, age sity in patients compared with healthy maintaining health and metabolism. at sampling and gender are important controls (HC).13 14 A lack of microbial Different parts of the intestinal tract have covariates that need to be included in diversity seems to be a general theme in http://gut.bmj.com/ different functions, tissue structure varies microbiome association analyses.4 In several diseases (obesity, diabetes, asthma, accordingly and gradients exist for several sum, Falony et al identified 18 covari- atopic dermatitis, and so on), suggesting physicochemical parameters such as nutri- ates, including stool consistency, dietary that a species-rich ecosystem is more ents, pH or oxygen levels.2 Consequently, factors and blood traits, cumulatively robust against environmental influences, microbiota composition varies along the explaining 7.7% of the total variation in as functionally related microbes exist in the gut microbiota, leaving 92.3% of the an intact ecosystem that can compen- on October 2, 2021 by guest. Protected copyright. 1Institute of Clinical Molecular Biology, Christian- interindividual microbial variation unex- sate for the function of another species Albrechts-Universität zu Kiel, Kiel, Germany plained. In a recent host-microbiome that has disappeared. Consequently, 2Institute for Experimental Medicine, Christian Albrechts genome-wide association study, 42 diversity seems to be a good indicator University of Kiel, Kiel, Germany 15 3 genetic loci were identified that explain of a ‘healthy gut.’ A large study that Helmholtz Zentrum München, Research Unit Analytical 5 analysed the microbiota in 447 treat- BioGeoChemistry, Deutsches Forschungszentrum für another 10% of microbiome variability. Gesundheit und Umwelt (GmbH), Neuherberg, Germany Although these percentages need to be ment-naïve patients with new-onset CD 4Institute of Medical Informatics and Statistics, confirmed in other cohorts and for other (treatment effects on the microbiota can University Hospital Schleswig-Holstein, Kiel, Germany likely be excluded in this unique cohort) 5 ethnicities, both studies show that (A) a Department of Dermatology, University Hospital large portion of microbiome variability also identified different bacteria, which Schleswig-Holstein, Kiel, Germany 6Research Center Borstel, Leibniz-Center for Medicine remains to be explained and (B) any were more abundant in patients compared 16 and Biosciences, Airway Research Center North (ARCN), microbiome study needs to account for with controls and vice versa. Gevers German Center for Lung Research (DZL), Borstel, covariates to prevent false-positive and et al also developed a microbial dysbiosis Germany 7 false-negative results. This means for the index that was correlated with the paedi- Institute of Biochemistry, Christian-Albrechts- atric CD activity index. The dysbiotic Universität zu Kiel, Kiel, Germany field that the meta-data for a particular 8Clinic of Internal Medicine I, University Hospital sample is at least as important for the signal in their study was stronger in the Schleswig-Holstein, Kiel, Germany data analysis as the actual microbiome mucosa-attached microbial communities 9 Department of Infectious Diseases and Microbiology, data itself. compared with faecal bacteria, suggesting University of Lubeck, Lubeck, Germany The main subtypes of IBD are Crohn’s that disease-relevant and more adherent 10Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Plon, Germany disease (CD) and UC, affecting together bacteria are probably ‘diluted’ in the more than 2.5 million European indi- stool. The recently published longitudinal Correspondence to Mr Andre Franke, Institute IBD microbiome study of Halfvarson and of Clinical Molecular Biology, Christian-Albrechts- viduals. More than 200 genetic suscepti- University of Kiel, Rosalind-Franklin-Str. 12, 24105 Kiel, bility loci have been identified for IBD, a colleagues revealed that the microbiome Germany; a. franke@ mucosa. de contribution that significantly improved of patients with IBD varies more over time 1734 Sommer F, et al. Gut October 2017 Vol 66 No 10 Leading article dietary variance in microbiota-related data and to explore dietary modulation of the metabolic properties of the gut ecosystem Gut: first published as 10.1136/gutjnl-2016-313678 on 21 July 2017. Downloaded from (eg, enrichment of dietary fibre) as a possible therapeutic approach for IBD. Figure 1 provides a schematic overview on known gut microbiome changes in IBD. In the highlighted study, Pascal and colleagues29 report on an analysis of the faecal microbiome for a large IBD panel from four different countries (40 HC (unrelated HCs)/71 HR (healthy rela- tives from patients)/34 CD/74 UC from Spain, 54 CD from Belgium, 977 healthy twins from the UK and 158 patients with anorexia from Germany). In sum, they included about 1246 non-IBD and 162 IBD samples. The hypervariable region V4 of the 16S rRNA gene was targeted for microbiome profiling. Pascal et al replicate the findings of Gevers et al16 that F. prausnitzii is reduced/absent in patients with CD and that patients have Figure 1 Microbial signatures of a healthy gut and IBD. Under healthy homeostasis the a higher abundance of Escherichia and microbiota is diverse. Goblet cells produce a thick colonic mucus layer, which creates a physical Fusobacterium. barrier against the microbiota, but also harbours a specific mucus-resident microbiota enriched in, The key finding of their study is a for example, short-chain fatty acid producing bacteria Roseburia and Faecalibacterium prausnitzii. ‘microbial signature’ that may be used to Immune sensory cells such as DC and MΦ sample microbial patterns and induce a T cell profile discriminate between CD and non-CD dominated by IL-10 producing Treg lymphocytes leading to homeostasis. However, the composition by eight prokaryotic groups: Faecali- of the microbiota is less diverse in patients with IBD with fewer Bacteroidetes mainly attributed bacterium (genus from family Clostrid- to loss of Prevotella species and expansion of Actinobacteria, Proteobacteria such as adherent iaceae), Peptostreptococcaceae (family invasive Escherichia coli and Fusobacteria. Mucosal function is also altered, for example, lipid from order Clostridiales), Anaerostipes metabolism, illustrating a cometabolism