Abstract
The gut microbiome can influence host health by facilitating digestion, immune function, and xenobiotic metabolism. Microbial metabolites can influence mitochondrial function by shifting bioenergetic pathways, potentially altering sensitivity to mitochondrial toxicants. However, mechanisms through which the gut microbiota can alter mitochondrial function and susceptibility to mitochondrial toxicity are not well characterized. We used the model organism Caenorhabditis elegans and the microbiome kit CeMbio, a characterized collection of native gut commensals, to explore the interactions between gut microbiota, mitochondrial function, and chemical susceptibility. C. elegans grown on selected bacterial strains had varying levels of steady-state whole-body ATP, with an ∼3 fold difference between the highest and lowest strains, as well as 2- and 3-fold changes in antioxidant and mitochondrial unfolded protein gene induction. Further, C. elegans grown on selected bacterial strains showed differential sensitivity to short-term exposure to chemicals that inhibit mitochondrial electron transport chain Complexes I, II, and V, and fatty acid oxidation. To test mechanistically how microbiome-mediated sensitivities could result in chemical susceptibility, we carried out follow-up experiments using the Complex I inhibitor rotenone. We found that C. elegans grown on BIGb0170 (Sphingobacterium multivorum) had much higher lethality after 24- and 48-hour exposures than when grown on MYb10 (Acinetobacter guillouiae), MYb11 (Pseudomonas lurida), and OP50 (Escherichia coli) strains. Metabolomic analysis revealed that C. elegans grown on BIGb0170 had lower amounts of triglycerides and acylcarnitines. ATP levels were partially rescued by supplementing BIGb0170 with pyruvate. This work suggests that BIGb0170 can impact mitochondrial function through changes in metabolite abundance, which can increase sensitivity to the Complex I inhibitor rotenone.