Interplay between the human gut microbiome and host metabolism

Abstract

The human gut is inhabited by a complex and metabolically active microbial ecosystem. While many studies focused on the effect of individual microbial taxa on human health, their overall metabolic potential has been under-explored. Using whole-metagenome shotgun sequencing data in 1,004 twins, we first observed that unrelated subjects share, on average, almost double the number of metabolic pathways (82%) than species (43%). Then, using 673 blood and 713 faecal metabolites, we found metabolic pathways to be associated with 34% of blood and 95% of faecal metabolites, with over 18,000 significant associations, while species showed less than 3,000 associations. Finally, we estimated that the microbiome was involved in a dialogue between 71% of faecal, and 15% of blood, metabolites. This study underlines the importance of studying the microbial metabolic potential rather than focusing purely on taxonomy to find therapeutic and diagnostic targets, and provides a unique resource describing the interplay between the microbiome and the systemic and faecal metabolic environments.

Fig. 1

Gut microbiome composition. The composition of the gut ecosystem is unique to an individual while its functionality is maintained across the population. Pie charts represent the percentage of species (on the left) and microbial metabolic pathways (on the right) present in <1% of the population (dark blue), between 1% and 25% (light blue), between 25% and 50% (turquoise), between 50% and 75% (brown), and more than 75% (yellow)

Fig. 2

Study design and number of associations. The top of the figure reports the number of microbial species and metabolic pathways which were detected in at least 50 individuals with metabolomics and WMGS data, and that were used in the study, and the number of associations tested. The bottom of the figure reports the number of associations that were significant at a 5% FDR, along with the number and percentage of metabolites, microbial species, and microbial metabolic pathways involved. Association testing was performed using PopPAnTe, in order to model the resemblance between family members. Sex and age at the sample collection were included as covariates

Fig. 3

Potential mechanisms implicated in the interplay between the gut microbiome, the faecal metabolome, and the blood metabolome. (1) Small dashed lines: metabolites are produced by the microbiota and then absorbed, resulting in associations between the microbiome and both the blood and faecal metabolites. (2) Large dashed lines: the microbiome affects the gut barrier integrity, resulting in alterations of metabolites absorption (i.e., the same metabolite is associated with a species/pathway in both blood and faeces, but the directions of effects are opposite). (3) Light continuous line: metabolites produced by the host, such as bile acids, affect microbial growth. (4) Bold continuous line: direct microbiome to host cell interactions that result in host systemic modulation (i.e., species are associated with blood metabolites but not with faecal metabolites)