Quantifying the effects of diet and the microbiome

Host diet affects the structure and function of the gut microbiome, but these effects are far more context-dependent than is generally acknowledged. For instance, dietary changes drastically affect the microbiome in animal models, and in human infants during a shift to solid foods. In contrast, day-to-day dietary variation in healthy adults typically elicit only minor compositional shifts – although differences in pre-existing resident microbes among individuals can result in distinct chemical and metabolic responses to the same dietary intake. This indicates two separate mechanisms of action by which the microbiome interacts with diet: the first as a direct target, the second as a mediator. Here, we quantify these previously undifferentiated effects across different populations, life stages, environments, and dietary metadata. Seven publicly available metagenomic datasets spanning human adult, human infant, non-human primate, and mouse populations were reanalyzed through a standard bioinformatic workflow (total n=2,074 samples). The metagenomic profiles were accompanied by cohort-specific dietary information ranging from general diet types to resolved profiles of dietary components. To measure the effects of diet and the microbiome in these cohorts, we uniformly applied a set of models across studies. We assessed the relationship between overall dietary patterns or individual dietary compounds and microbial profiles, in addition to the specific interactions between dietary compounds and microbes. We found that, in a typical Western diet, the effect of day-to-day diet variation is small but significant, as expected. Instead, diet affects the microbiome indirectly via alterations in microbial transcription (but not, generally, organismal abundances), which in turn can have a mediating effect on host responses to diet. Applying the same models across populations, we also found that when the microbiome has not fully stabilized, as in human infants and laboratory animals, diet changes have a substantially larger effect on the gut community structure. Direct diet-driven variation thus depends largely on the resilience of the microbiome and on the extent of the dietary perturbation, while indirect interactions can be highly chemically and microbiologically specific.