Introduction: Metabolites are focal players in the host-microbiota crosstalk. Fecal metabolome represents the microbial metabolic output but the links between fecal and circulating metabolites remain unresolved. Deciphering the associations between fecal and plasma metabolomes may benefit the designing of tailored gut microbiota-targeting interventions.

Objective: To study common underlying associations between fecal and plasma metabolites after nutritional and exercise interventions.

Methods: Fecal and plasma samples from three separate interventions of alcohol use disorder (n = 44), obese (n = 27), or metabolic dysfunction-associated steatotic liver disease (MASLD) participants (n = 40) undergoing nutritional or exercise interventions were analyzed using a non-targeted LC-HRMS approach. Annotated features from feces and plasma were subjected to Spearman correlation analysis and fecal-plasma metabolite pairs were compared across studies in baseline, treatment or control groups. Chemical diversity was assessed by over-representation analysis and compound class prediction in the nutritional intervention trials.

Results: The number of nominally significant (p < 0.05) metabolite pairs among the alcohol use disorder, obese and MASLD participants were 4250, 5901 and 6981, respectively. Out of the significant metabolite pairs, less than 1% were common among all studies. Assessment of chemical diversity suggested study-specific molecular fingerprints after the nutritional interventions.

Conclusion: Wealth of study- and group-specific correlations were observed between the fecal and plasma metabolites. Lack of significant commonalities between interventions and the divergent chemical landscapes suggests large inter-individual variations in the fecal-plasma metabolite interactions. Distinctive composition of the fecal and plasma metabolomes warrants caution when inferring findings from feces to circulation and further to host health.