From Association to Causality: the Role of the Gut Microbiota and Its Functional Products on Host Metabolism

Abstract

Many genomic studies have revealed associations between the gut microbiota composition and host metabolism. These observations led to the idea that a causal relationship could exist between the microbiota and metabolic diseases, a concept supported by studies showing compositional changes in the microbial community in metabolic diseases and transmissibility of host phenotype via microbiota transfer. Accumulating data suggest that the microbiota may affect host metabolic phenotypes through the production of metabolites. These bioactive microbial metabolites, sensitive fingerprints of microbial function, can act as interkingdom signaling messengers via penetration into host blood circulation and tissues. These fingerprints may be used for diagnostic purposes, and increased understanding of strain specificity in producing microbial metabolites can identify bacterial strains or specific metabolites that can be used for therapeutic purposes. Here, we will review data supporting the causal role of the gut microbiota in metabolism and discuss mechanisms and potential clinical implications.

Effect of diet and intestinal AhR expression on fecal microbiome and metabolomic profiles

“…Advances in metagenomic sequencing methodologies have enabled the characterization of the gut microbiome composition and structure under different disease states and to identify differentially abundant microorganisms [37]. However, the functional redundancy in the microbiome makes it difficult to ascribe causal roles for differentially abundant taxa in disease [38]. Therefore, it is necessary to go beyond the characterization of the intestinal microbiome composition to the profiling of the functional output of the microbiome (i.e., the metabolome) to develop a more comprehensive understanding of the role of different microbial taxa in disease [39].…”

Microbiome-Aware Ecotoxicology of Organisms: Relevance, Pitfalls, and Challenges

“…Metabolomics, which map metabolites, are another important tool that profiles ongoing metabolisms, and thus informs functions (64,65) although, as for all of the above, the improvement of databases supporting metabolite identifications will be critical (66). The integration of these approaches in multi-omics appears challenging, yet particularly promising for revealing the causal role of the microbiome and mechanisms involved in contaminants metabolism and toxic effects (67,68). This will be key in integrating the microbiome in adverse outcome pathways (AOPs) and risk assessment [ Figure 2; (22)].…”

“…It allowed the identification of metabolites located at the hostsymbiont interface on tissue sections at the micrometer scale (79). Such a method is promising to monitor small-scale interactions between contaminants, the microbiome and the host and further explore causality (68). Co-occurrence networks that are based on positive or negative correlations between the occurrence of microorganisms, functions, and environmental parameters also help in exploring interactions and formulating hypotheses [reviewed in (80)].…”

Neonatal intestinal dysbiosis

“…In some cases, the compositional shift and associated phenotype can be ascribed to changes in a small collection of microbes. Disease causality for such changes can be tested in model systems by demonstrating transmissibility of host disease phenotype with microbiota transfer [5,6]. In other cases, an association is more nuanced.…”