Microbiota Drug Metabolism

Despite numerous examples of the effects of the human gastrointestinal microbiome on drug efficacy and toxicity, there is often an incomplete understanding of the underlying mechanisms. Here, we dissect the inactivation of the cardiac drug digoxin by the gut Actinobacterium Eggerthella lenta. Transcriptional profiling, comparative genomics, and culture-based assays revealed a cytochrome-encoding operon up-regulated by digoxin, inhibited by arginine, absent in non-metabolizing E. lenta strains, and predictive of digoxin inactivation by the human gut microbiome. Pharmacokinetic studies using gnotobiotic mice revealed that dietary protein reduces the in vivomicrobial metabolism of digoxin, with significant changes to drug concentration in the serum and urine. These results emphasize the importance of viewing pharmacology from the perspective of both our human and microbial genomes.

Publication: 

Prediction and manipulating cardiac drug inactivation by human gut bacterium Eggerthella lenta

Henry J. Haiser,1 David B. Gootenberg,1 Kelly Chatman,1 Gopal Sirasani,2 Emily P. Balskus,2and Peter J. Turnbaugh1,*

Services provided: 

The MHMC provided microbiologic preparation of consortia to inoculate germ free mice. Longitudinal germ-free mouse studies were conducted by MHMC technical staff-with administration of drug and different colonizing microbes. Tissues were harvested and microbiologic assessment of colonized material was performed.

Microbiota Drug Metabolism Project Services and Costs

DescriptionQuantityUnitsHDDCInternalAcademicCommercial
Total Project Cost**40,911.1168,938.1199,274.43131,537.35
Project Set Up1each175.63295.95426.17564.68
Short Chain Fatty Acids 61each24.5341.3459.5378.87
Small Isolator Setup13each671.481131.531629.412158.96
Small Supply Cannister21each38.5264.9193.47123.85
Germ Free Mice 3-6 Weeks Old81each35.8860.4687.07115.36
C57BL/6 Mice >3 weeks Old18each35.8860.4687.07115.36
Small Isolator Weekly Rental BL138weekly131.01220.77317.91421.24
Other Germ Free Tech Support-Transfer mice from isolators5per unit56.6295.4137.38182.03
Other Germ Free Tech Support- Microbiology 2per unit56.6295.4137.38182.03
Other Germ Free Tech Support- Ethyline Oxide2per unit56.6295.4137.38182.03
Other Germ Free Tech Support-Gavage28656.6295.4137.38182.03
Food or Mouse Weight per weighing121per unit19.5732.9847.562.93
Ear Notch104each8.6914.6521.127.96
Aerobic Culture-Sterility Check20per unit27.8146.8667.4889.41
Anerobic Culture-ID and Quant26per unit26.7845.146586.12
*FY 2018 Fees
**Approximate cumulative costs reflected over a two year study period