Functional relevance of microbiome signatures: The correlation era requires tools for consolidation

Abstract

Compelling research over the past decade identified a fundamental role of the intestinal microbiome on human health. Compositional and functional changes of this microbial ecosystem are correlated with a variety of human pathologies. Metagenomic resolution and bioinformatic tools considerably improved, allowing even strain-level analysis. However, the search for microbial risk patterns in human cohorts is often confounded by environmental factors (eg, medication) and host status (eg, disease relapse), questioning the prognostic and therapeutic value of the currently available information. In addition to a better stratification of human phenotypes, the implementation of standardized protocols for sampling and analysis is needed to improve the reproducibility and comparability of microbiome signatures at a meaningful taxonomic resolution. At the level of mechanistic understanding, the molecular integration of pleiotropic signals coming from this complex and dynamically changing ecosystem is one of the biggest challenges in this field. The first successful attempts to apply reverse genetics based on the available metagenomic information yielded identification of small molecules and metabolites with functional relevance for microbe-host interactions. Further expansion on the isolation of bacteria from the "unculturable biomass" will help characterize microbiome signatures in model systems, finally aiming at the development of clinically relevant synthetic consortia with safe and functionally well-defined strains. In conclusion and beyond reasonable enthusiasm, the mechanistic implementation and clinical relevance of microbiome alterations on disease susceptibility is still in its infancy, but the integration of all the above-mentioned strategies will help overcome the correlation era in microbiome research and lead to a rational evaluation of clinical strategies relevant for targeted microbial intervention.

Fungal Dysbiosis Correlates With the Development of Tumour-Induced Cachexia in Mice

“…A group of 10 animals was randomly chosen as a control group (CT), having received only subcutaneous injection with 200 μ l saline solution in their right flank. The others (20) were similarly inoculated with 3.5x10 5 LLC tumor cells (suspended in 200 μ l of Dulbecco´s modified Eagle´s medium). Next, the animals were transferred to sterile cages and kept, under the conditions described above, for a period of 28 days, when cachexia symptoms could be verified (23,24).…”

“…Studies aimed at characterizing the microbiota of mice, during the development of cancer-induced cachexia, revealed significant alterations in the composition of their gut bacterial population (dysbiosis), when compared to healthy control animals (6,7,8,9,10,11). The main characteristic of such dysbiosis involves an increased proportion of Enterobacteriaceae in CC-affected animals -a phenomenon also observed during the development of several diseases and syndromes associated with gut inflammation, such as celiac disease (12), food allergy (13), gastric cancer (14), diabetes (15,16), obesity (17,18,19) and inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD) (20), among others. More recently, cultivation of fecal material from cachectic mice in selective coliform media, identified Klebsiella oxytoca as the main representative of Enterobacteriaceae present in stool samples obtained from these animals (21).…”

The Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) ERS Clinical Research Collaboration: a new dawn in asthma research

“…subsets of asthma defined by molecular mechanisms rather than clinical or simple biomarker variables. This has been particularly true for forms of asthma with evidence of Type-2 cytokines being central to the disease, so called T2-high asthma, but there is increasing interest in T2-low forms, which may involve cytokines like IL-17 [23] or as yet unrecognised processes like mitochondrial stress [24] and defects in innate immunity leading to an altered lung metagenome [25].…”

Strain-Level Diversity in the Gut: The P. copri Case

“…Nevertheless, and beyond recent enthusiasm, the functional implementation of changes in composition and activity of the microbiome on human health is still in its infancy, and the search for disease-specific signatures is incomplete. One reason for this lack of understanding is the absence of strain-level resolution of microorganisms (Buttó and Haller, 2017).…”