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. Turnbaugh^1,*

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

Description	Quantity	Units	HDDC	Internal	Academic	Commercial
Project Set Up	1	each	175.63	295.95	426.17	564.68
Short Chain Fatty Acids	61	each	24.53	41.34	59.53	78.87
Small Isolator Setup	13	each	671.48	1131.53	1629.41	2158.96
Small Supply Cannister	21	each	38.52	64.91	93.47	123.85
Germ Free Mice 3-6 Weeks Old	81	each	35.88	60.46	87.07	115.36
C57BL/6 Mice >3 weeks Old	18	each	35.88	60.46	87.07	115.36
Small Isolator Weekly Rental BL1	38	weekly	131.01	220.77	317.91	421.24
Other Germ Free Tech Support-Transfer mice from isolators	5	per unit	56.62	95.4	137.38	182.03
Other Germ Free Tech Support- Microbiology	2	per unit	56.62	95.4	137.38	182.03
Other Germ Free Tech Support- Ethyline Oxide	2	per unit	56.62	95.4	137.38	182.03
Other Germ Free Tech Support-Gavage	286		56.62	95.4	137.38	182.03
Food or Mouse Weight per weighing	121	per unit	19.57	32.98	47.5	62.93
Ear Notch	104	each	8.69	14.65	21.1	27.96
Aerobic Culture-Sterility Check	20	per unit	27.81	46.86	67.48	89.41
Anerobic Culture-ID and Quant	26	per unit	26.78	45.14	65	86.12
Total Project Cost**			40,911.11	68,938.11	99,274.43	131,537.35

*FY 2018 Fees
**Approximate cumulative costs reflected over a two year study period