Depleted gut microbiome α-diversity is associated with several human diseases, but the extent to which this is reflected in the host molecular phenotype is poorly understood. We attempted to predict gut microbiome α-diversity from ~1,000 blood analytes (laboratory tests, proteomics and metabolomics) in a cohort enrolled in a consumer wellness program (N = 399). Although 77 standard clinical laboratory tests and 263 plasma proteins could not accurately predict gut α-diversity, we found that 45% of the variance in α-diversity was explained by a subset of 40 plasma metabolites (13 of the 40 of microbial origin). The prediction capacity of these 40 metabolites was confirmed in a separate validation cohort (N = 540) and across disease states, showing that our findings are robust. Several of the metabolite biomarkers that are reported here are linked with cardiovascular disease, diabetes and kidney function. Associations between host metabolites and gut microbiome α-diversity were modified in those with extreme obesity (body mass index ≥ 35), suggesting metabolic perturbation. The ability of the blood metabolome to predict gut microbiome α-diversity could pave the way to the development of clinical tests for monitoring gut microbial health.