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Under physiological conditions the microbiota shows both: plasticity and high resilience. Upon short-term perturbations (e.g. temporal change in dietary-pattern) the microbial composition adapts to alterations in the intestinal milieu, though soon resembles a pre-disturbance state.7 The microbial ecosystem can also be changed without pathologic consequences for the host and stabilize within a new “alternative state”.35 Animal studies showed that the microbiota is capable to adapt to exposomal factors including diet, antibiotics or intrinsic factors like host genetics. Nevertheless, diet seems to overwrite the influence of genetic imprints.36, 37Rapid resilience to perturbations is a key requirement for intestinal homeostasis in order to maintain a health-associated composition of the ecosystem (“eubiosis”). However, this resilience is lost in some pathologic conditions, like IBD. It is important to note that dysbiosis displays several features, which will be categorized below in i) reduced bacterial diversity, ii) expansion of pathobionts, iii) changes in the microbial composition and iv) change in microbial functional capacity. The appearance of these characteristics may occur solitarily, successively or simultaneously (Figure 2). Upon short term perturbations the microbiota may shift in diversity, composition and function and stabilize again in its previous state, or an alternative state due to high resilience. However, in IBD the microbiota shows low resilience and is subjected to changes finally leading to dysbiosis.The widely discussed attribute of dysbiosis is reduced bacterial diversity. Based on numbers of bacterial species and their abundance found within one sample, the alpha diversity can be calculated. Many studies associated lowered bacterial diversity to disease, with the rationale of loss in metabolic redundancy.32, 38-41 Furthermore, the ability to outcompete pathogens by a low-diverse microbiota is diminished. In patients that underwent frequent antibiotic treatments, the deteriorated intestinal diversity was shown to increase the risk of infection by opportunistic pathogens, such as Clostridium difficile.42 In animal models, pathogens including Salmonella, Citrobacter rodentium or enterohaemorrhagic E. coli (EHEC) fail to colonize in the presence of a diverse, undisturbed microbiota, but elicit pathogenic traits if competing strains are missing.43-46 The mechanisms of competitive exclusion may correspond to rivalry for nutrients or virulence-modulation of intruding strains.47A further characteristic trait of dysbiosis is the expansion of pathobionts, i.e. single strains of the commensal microbiota that outgrow and cause detrimental effects in the host. The term pathobiont was defined by Chow and Mazmanian et al. as “…symbiont that is able to promote pathology only when specific genetic or environmental conditions are altered in the host”.48 While pathobionts are found only in low abundance in a healthy microbial setting, they overgrow in dysbiosis and cause disease in the susceptible (e.g. immune-compromised) host. Hereby, specificity in the combination of microbe and host-susceptibility is required. In animal studies Bacteroides vulgatus induced colitis in HLA/B27-ß2m rats, but not in interleukin (IL) 10 deficient (IL-10-/-) mice and even prevented colitis in IL2-/- mice.49, 50 Early studies regarded Mycobacterium avium subspecies paratuberculosis as the responsible pathobiont or even pathogen in IBD. However, this hypothesis could not be verified, as summarized by Packey and Sartor.51 An increased abundance of Enterobacteriaceae is repeatedly observed in stool samples and mucosal specimens from IBD patients. Among these, the Escherichia coli strain LF82 is discussed to be a pathobiont.23, 52, 53 The group around Darfeuille-Michaud was the first to describe adherent-invasive E. coli (AIEC), which selectively colonize the ileum of CD patients, suggesting that dysbiosis in IBD may also relate to strain-specific virulence factors.54, 55Apart from single pathobionts, dysbiosis is in most cases regarded as shifts in the overall microbial composition, i.e. simultaneously increased or decreased abundance of certain commensals. Due to the new sequencing techniques and improved databases, great progress has been made in characterizing the intestinal microbiome also in larger cohorts. However, most samples were taken from patients who already underwent some kind of treatment, which exerts changes in the ecosystem and thereby impedes conclusive interpretation of findings.56, 57 A study from Gevers et al. elegantly solved this issue by picturing the treatment naïve microbiome in children recently diagnosed for CD, before pharmaceutical or nutritional intervention.26 They described an increase in Enterobacteriaceae preceding the onset of CD, an observation made by others as well.34 However, one cannot exclude that small inflammatory lesions can cause change in the microbiota, before the diagnosis of disease.58 Thus, prospective cohorts would be of high value, but too demanding due to the low incidence rates.Among the multitude of studies performed to detect IBD-associated bacterial taxa, little congruence is found between different cohorts. By combining the sequencing data from several studies, Walters et al. showed shifts in the bacterial composition at different taxonomic levels, which were at least partly consistent for several studies and cohorts.53 These single taxa may serve as indicator species with diagnostic value, comparable to a biomarker. Walters et al. showed higher abundance of Actinobacteria and Bacteroides and a loss of Prevotella in CD patients compared to healthy controls. They also described at lower taxonomic level the loss of Faecalibacterium prausnitzii, the best known indicator species in IBD. This health-associated species was found in significantly lower levels in the inflamed intestine compared to healthy specimens and exerts positive immune-regulatory effects on the host. Therefore, loss of F. prausnitzii is speculated to be indicative for increased IBD risk.59, 60 However, the use of only single indicator species as diagnostic tool may not be sufficient, as IBD-associated strains may be cohort or individual specific. Nevertheless, the novel approach of using overall drifts in the intestinal microbiota is a promising new tactic in diagnosis of IBD. Walters et al highlighted some universally valid disease-related shifts, which may be powerful enough to securely diagnose IBD, by combining the sequencing results from several studies.53 By using stool microbiota, this non-invasive approach is even more advantageous.Due to great progress in 16S ribosomal RNA sequencing methods, shifts in the prevailing bacterial members of the intestinal composition can be easily assessed and discussed (16S profiling). Hereby the gene amplicons of the V3/V4 region (approximately 450bp) of the 16S rRNA are assessed and identified via different databases. This finally allows the description of the bacterial profile in composition and diversity. However, most descriptions of intestinal dysbiotic communities fail to take fungal and viral contributions into consideration. Recently Chehoud et al. could show reduced fungal diversity in paediatric CD accompanied by increased Candida taxa.61 Norman et al. showed marked differences in the intestinal virome in CD and UC patients compared to healthy controls.62 The main difference was an increase in Caudovirales bacteriophages which was not secondary to bacterial dysbiosis. Interestingly, it is more likely to assume that viral dysbiosis contributes to pathology and changes in the bacterial ecosystem due to a “predator-prey” relationship.63, 64 Nevertheless, studies of the role of other microbial taxa in IBD pathogenesis are awaited and will be essential to unravel dysbiotic patterns.In addition to changes in composition and diversity, alterations in the functional capacities are characterizing a dysbiotic ecosystem. As shown by the human microbiome project, the healthy intestinal ecosystem may be exceedingly different in composition, while its metabolic activity is highly similar.9 An interesting study in IBD patients by Morgan et al. showed small perturbation of the intestinal composition, though quite distinct changes in microbial function.65 In dysbiotic conditions, microbial pathways for oxidative stress tolerance, immune evasion, metabolite uptake and carbohydrate as well as amino acid biosynthesis were upregulated. An increase in carbohydrate-metabolism and especially changes in the capacity to utilize fucose, was reported in dysbiotic settings in CD patients and animal models of intestinal inflammation.66, 67 Metaproteome analysis in a cohort of CD patients also proved a distinct signature, which was associated with CD.68 By correlating these functional shifts to the bacterial ecosystem, Bacteroides-derived proteins related to survival in challenging environments (e.g. DnaKs and other chaperones) were found overrepresented. Along with changes in the intestinal microbial function, the profile of produced metabolites varies.69 This leads to the assumption that dysbiosis may be more precisely characterized by changes in the microbial function rather than composition.Furthermore, the definition of dysbiosis should not be a mere one-sided, microbial consideration, but should undoubtedly take the host into account. Palm et al. showed that IBD patients display an altered immune recognition of a dysbiotic microbiota. This was correlating with increased and more divergent Immunoglobulin A (IgA) coating.70 By using an animal model of chemically induced colitis, they transferred disease-susceptibility and thereby proved the causal role of this IgA-coated ecosystem.

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