Humans are exposed to many small molecules foreign to the body, including dietary components, drugs, and environmental chemicals. The trillions of microorganisms that inhabit our gastrointestinal tract can directly or indirectly alter the chemical structures of such compounds, thus modifying their permanence in the body, biological effects, or toxicity. While most research has focused on drug-microbiome interactions, little is known about how the gut microbiome metabolizes dietary xenobiotics.
New findings from Yale University School of Medicine researchers provide insights into how the gut microbiome contributes to individual differences in dietary xenobiotics’ metabolism.
The authors studied inter-individual variability in response to food by systematically mapping the effects of chemically diverse dietary xenobiotics on bacterial growth and gut microbiome composition, and bacterial capacity for compound modification using estimated doses that reach the colon. The in vitro effects of 140 dietary xenobiotics-belonging to 37 structural classes-were surveyed in four gut microbial communities from unrelated healthy donors.
Interestingly, most of the tested glycosides were non-toxic. Yet, when their (non-glycosylated)-microbial metabolites were incubated with the different human fecal microbiomes, results showed community and compound-specific capacity to inhibit bacterial growth.
In some cases, further microbial transformation of bactericidal non-glycosylated forms revoked the inhibition of bacterial growth. Thus, microbial metabolic transformation of dietary xenobiotics may convert some compounds into antibiotics and detoxify others. Interestingly, the impact of individual dietary xenobiotics on a given community was not always readily predicted by toxicity observed in monocultures. In communities, both cross-protection and cross-sensitization occurred. These results showed the relevance of community interactions for compound metabolism and that different microbes share metabolites due to cross-feeding interactions.
Andrew L. Goodman and colleagues also identified enzymes involved in dietary xenobiotic toxification and detoxification. Specific enzymes that reduce resveratrol to dihydroresveratrol were restricted to selected bacteria species and strains. Moreover, altering the microbial gut communities in gnobiotic mice by adding or excluding individual members shaped the levels of microbial- and host-derived metabolites. The addition of Eggerthella lenta led to depleted serum resveratrol and related host-mediated metabolites and increased serum levels of host-mediated dihydroresveratrol metabolites. In contrast, the absence of E. lenta led to a disrupted gut microbiome with increased pathogenic E. coli resistant to growth inhibition by resveratrol.
While these findings are still far from being applied to improve the treatment of human disease and personalize dietetic advice based on the individual makeup of the gut microbiome, they explain why the same diet can have different effects on different people. Inter-individual variation of dietary xenobiotics’ metabolism depends not only on the presence of metabolites, but also on the presence or absence of specific gut commensals.
Reference:
Culp EJ, Nelson NT, Verdegaal AA, et al. Microbial transformation of dietary xenobiotics shapes gut microbiome composition. Cell. 2024 ; 187(22) :6327-6345.e20. doi: 10.1016/j.cell.2024.08.038.
