The Footprints of Gut Microbial–Mammalian Co-Metabolism

TLDR

Gut microbiota influence human biology through a network of microbial–host co‑metabolism that shapes nutrient and drug processing and modulates multiple organ pathways linked to disease. We profiled normal Wistar rats treated with the broad‑spectrum β‑lactam imipenem/cilastatin (50 mg kg⁻¹ d⁻¹ for 4 days) followed by 14 days recovery using untargeted mass‑spectrometry metabonomics. Metabolic phenotyping uncovered 202 urinary and 223 fecal metabolites—many novel—significantly associated with functional metagenome endpoints, revealing gut microbiota modulation of host systemic metabolism (short‑chain fatty acids, tryptophan, tyrosine, indole‑melatonin) and offering a platform for therapeutic markers and mechanistic insights.

Abstract

Gut microbiota are associated with essential various biological functions in humans through a "network" of microbial–host co-metabolism to process nutrients and drugs and modulate the activities of multiple pathways in organ systems that are linked to different diseases. The microbiome impacts strongly on the metabolic phenotypes of the host, and hence, metabolic readouts can give insights into functional metagenomic activity. We applied an untargeted mass spectrometry (MS) based metabonomics approach to profile normal Wistar rats exposed to a broad spectrum β-lactam antibiotic imipenem/cilastatin sodium, at 50 mg/kg/daily for 4 days followed by a 14-day recovery period. In-depth metabolic phenotyping allowed identification of a panel of 202 urinary and 223 fecal metabolites significantly related to end points of a functional metagenome (p < 0.05 in at least one day), many of which have not been previously reported such as oligopeptides and carbohydrates. This study shows extensive gut microbiota modulation of host systemic metabolism involving short-chain fatty acids, tryptophan, tyrosine metabolism, and possibly a compensatory mechanism of indole–melatonin production. Given the integral nature of the mammalian genome and metagenome, this panel of metabolites will provide a new platform for potential therapeutic markers and mechanistic solutions to complex problems commonly encountered in pathology, toxicology, or drug metabolism studies.