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Xenobiotics Affect Composition, Gene Expression in Human Gut Microbiome

NEW YORK (GenomeWeb News) – Exposure to xenobiotics affects the makeup of the human gut microbiome and what genes it expresses, researchers from Harvard University reported in Cell today.

By combining a number of techniques, including flow cytometry and 16S rRNA sequencing, Harvard's Peter Turnbaugh and his colleagues characterized the active portion of the human gut microbiome and studied how it reacted to perturbations from antibiotics and other drugs targeted to the human host.

"Short-term exposure to xenobiotics not only alters bacterial physiology, but also significantly alters the structure of the overall microbial community and each physiological fraction, in addition to gene expression," Turnbaugh and his colleagues wrote. "These responses may provide some clue as to which microorganisms, genes, and pathways are involved in xenobiotic metabolism and as to how the gut microbiota resists damage from these molecules."

Over the course of nine months, the researchers examined the microbiota contained within 21 fecal samples from three unrelated people. The microorganisms in the samples fell into four broad physiological subsets — cells with a loss of membrane integrity, cells with a loss of polarity, and cells with either high or low nucleic acid content. The levels of nucleic acid correspond to active and less active subsets, the researchers said, and the active subset comprised a little more than half of the microbiome.

Then by combining fluorescence-activated cell sorting and 16S rRNA sequencing, the researchers identified the microorganisms present in each of those physiological categories — finding that the active portion of the gut microbiome contains a distinct set of microorganisms that is dominated by the Firmicutes phylum, particularly Clostridiales.

Then focusing on the active microbiome, the researchers sought to determine how it responds to antibiotics as compared to host-targeted drugs. Antibiotics, particularly ones targeted to cell walls like ampicillin, had a great effect on the active microbiome, and led to differences in the microbial community structure, the number of damaged cells, and temporal variation. Drugs targeted to the host, like digoxin, did not have such effects.

Additionally, the researchers looked at how antibiotics and other drugs affected gene expression throughout the microbiome. Using RNA-seq, they found that antibiotic treatment led to increased transcription of tRNA biosynthesis-, translation-, and phosphate transport-related genes. Other drugs induced expression of membrane transport, the pentose phosphate pathway, and xenobiotic metabolism/biodegradation genes. Further, they noted that antibiotic exposure also led to the expression of genes involved in stress response, including antibiotic resistance genes.

"Elucidating the underlying mechanisms for xenobiotic resistance and metabolism in the active human gut microbiome will not only provide insight into host-microbial interactions and biochemistry, but may also provide indications for unexplained patient-to-patient variations in drug efficacy and toxicity," Turnbaugh and his colleagues wrote.