Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene–metabolite associations, many previously unreported. Complementary approaches (genetic, computational (in silico gene knockouts in whole-body models of human metabolism) and one experimental proof of principle) provided orthogonal evidence that studies of rare, damaging variants in the heterozygous state permit inferences concordant with those from inborn errors of metabolism. Allelic series of functional variants in transporters responsible for transcellular sulfate reabsorption (SLC13A1, SLC26A1) exhibited graded effects on plasma sulfate and human height and pinpointed alleles associated with increased odds of diverse musculoskeletal traits and diseases in the population. This integrative approach can identify new players in incompletely characterized human metabolic reactions and reveal metabolic readouts informative of human traits and diseases.

Microbial metabolites measured using NMR may serve as markers for physiological or pathological host–microbe interactions and possibly mediate the beneficial effects of microbiome diversity. Yet, comprehensive analyses of gut microbiome data and the urine NMR metabolome from large general population cohorts are missing. Here, we report the associations between gut microbiota abundances or metrics of alpha diversity, quantified from stool samples using 16S rRNA gene sequencing, with targeted urine NMR metabolites measures from 951 participants of the Study of Health in Pomerania (SHIP). We detected significant genus–metabolite associations for hippurate, succinate, indoxyl sulfate, and formate. Moreover, while replicating the previously reported association between hippurate and measures of alpha diversity, we identified formate and 4-hydroxyphenylacetate as novel markers of gut microbiome alpha diversity. Next, we predicted the urinary concentrations of each metabolite using genus abundances via an elastic net regression methodology. We found profound associations of the microbiome-based hippurate prediction score with markers of liver injury, inflammation, and metabolic health. Moreover, the microbiome-based prediction score for hippurate completely mediated the clinical association pattern of microbial diversity, hinting at a role of benzoate metabolism underlying the positive associations between high alpha diversity and healthy states. In conclusion, large-scale NMR urine metabolomics delivered novel insights into metabolic host–microbiome interactions, identifying pathways of benzoate metabolism as relevant candidates mediating the beneficial health effects of high microbial alpha diversity.

COVID-19, a systemic multi-organ disease resulting from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is known to result in a wide array of disease outcomes, ranging from asymptomatic to fatal. Despite persistent progress, there is a continued need for more accurate determinants of disease outcomes, including post-acute symptoms after COVID-19. In this study, we characterised the serum metabolomic changes due to hospitalisation and COVID-19 disease progression by mapping the serum metabolomic trajectories of 71 newly hospitalised moderate and severe patients in their first week after hospitalisation. These 71 patients were spread out over three hospitals in Switzerland, enabling us to meta-analyse the metabolomic trajectories and filter consistently changing metabolites. Additionally, we investigated differential metabolite–metabolite trajectories between fatal, severe, and moderate disease outcomes to find prognostic markers of disease severity. We found drastic changes in serum metabolite concentrations for 448 out of the 901 metabolites. These results included markers of hospitalisation, such as environmental exposures, dietary changes, and altered drug administration, but also possible markers of physiological functioning, including carboxyethyl-GABA and fibrinopeptides, which might be prognostic for worsening lung injury. Possible markers of disease progression included altered urea cycle metabolites and metabolites of the tricarboxylic acid (TCA) cycle, indicating a SARS-CoV-2-induced reprogramming of the host metabolism. Glycerophosphorylcholine was identified as a potential marker of disease severity. Taken together, this study describes the metabolome-wide changes due to hospitalisation and COVID-19 disease progression. Moreover, we propose a wide range of novel potential biomarkers for monitoring COVID-19 disease course, both dependent and independent of the severity.

Bilophila wadsworthia, a sulfite-reducing bacterium stimulated by bile acids and enriched under high-fat diets, has been linked to several neurological disorders involving disturbances of motor function and basal ganglia circuitry. However, its potential association with alterations of brain structure remains unclear. Here, we investigated relationships between Bilophila (wadsworthia) abundance and basal ganglia volumes in two independent population-based cohorts combining gut microbiome profiling and brain MRI. Genus-level Bilophila abundance was assessed using 16S rRNA gene sequencing and complemented by species-level analyses of B. wadsworthia using whole-genome shotgun sequencing. Higher abundance of Bilophila (wadsworthia) was consistently associated with reduced volumes of basal ganglia regions, particularly the globus pallidus and nucleus accumbens. These associations were largely specific to basal ganglia regions when compared across a broad set of cortical thickness and other volumetric brain measures. Additionally, Bilophila (wadsworthia) was linked to elevated liver enzymes, elevated triglycerides, and pro-inflammatory states, confirming prior evidence from animal models while revealing novel associations in the general population. Constraint-based community modeling revealed that B. wadsworthia-enriched microbiomes exhibit increased functional redundancy for bile acid and sulfur metabolism and may modulate trimethylamine (TMA/TMAO) pathways. Together, these findings link variation in B. wadsworthia abundance to structural differences within basal ganglia regions and to unfavorable metabolic and inflammatory profiles in the general population, suggesting a potential role of this microbial species in gut-brain axis alterations relevant to neurodegenerative disease progression.

Proton pump inhibitors (PPIs) consistently alter the gut microbiome, but the contribution of these changes to systemic effects associated with PPI use remains unclear. Here, we show that PPI-associated microbiome remodelling induces systemic metabolic and transcriptional responses independently of direct drug exposure. Integrating human microbiome and metabolomics data with metabolic modelling, we identified consistent alterations in microbial metabolic functions and host-microbiome co-metabolism. Transfer of PPI-associated microbiota into germ-free mice reproduced key metabolic changes observed in humans, particularly in aromatic amino acid metabolism, and induced additional alterations in systemic lipid metabolism. These changes were accompanied by tissue-specific transcriptional responses in the colon, liver and brain, affecting metabolic and inflammatory pathways. Together, our findings identify transferable metabolic and transcriptional microbiome-mediated signatures that may contribute to the adverse systemic effects associated with PPI use.