Microbiome/Drug Interactions Abstracts
Identifying Gut Microbiome Contributions to Drug Metabolism
Individuals vary widely in their drug responses, which can be dangerous and expensive due to
significant treatment delays and adverse effects. Growing evidence implicates the gut microbiome in
this variability, however the molecular mechanisms remain mostly unknown. Using antiviral
nucleoside analogues and clonazepam as examples, we recently reported experimental and
computational approaches to separate host and gut microbiota contributions to drug metabolism. The
resulting pharmacokinetic models identified measurable physiological, microbial and chemical
parameters that dictate host and microbiome contributions to the metabolism of xenobiotics. To
systematically map the drug metabolizing capacity of the gut microbiota and assess its potential
contribution to drug metabolism, we further measured the ability of 76 diverse human gut bacteria to
metabolize each of 271 oral drugs. We found that two thirds of these drugs are chemically modified by
at least one of the tested microbes. Through combination of high-throughput bacterial genetics with
mass spectrometry, we systematically identified drug-metabolizing microbial gene products. These
gene products better explain the drug-metabolizing capacity of bacterial strains than their
phylogenetic classification. We further demonstrate that the abundance of homologs of these gene
products predict the capacity of complete human gut communities to metabolize the targeted drugs.
These causal links between microbiota gene content and metabolic activities connect inter-individual
microbiome variability to interpersonal differences in drug metabolism, which has translatable
potential on medical therapy and drug development across multiple disease indications.
New Approaches for Understanding Host-microbe-drug Interactions
In the past century, attempts to understand human disease were focused on identifying mutations in
the genome responsible or associated with a disease state. Despite great advances in our
understanding of disease from this genomic-centric approach, we still do not fully comprehend why
similar genetic architectures lead to a wide-range of disease manifestations. Recent evidence shows
that disease states arise from the complex interactions between the genetic make-up of the host and
its environment. Nutrition and the microbiome are key environmental factors regulating host
physiology but studying these in the context of drug efficacy remains a great challenge.
Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we are
currently unravelling the complexity underlying such interactions in the efficacy of fluoropyrimidine
anticancer drugs 1 and the anti-diabetic drug metformin 2,3,4. Currently, using a 4-way drug-microbe-
nutrient-host high-throughput screening approach combined with multi-omics at the host and microbe
level (the holobiont) we find that the microbiota integrates nutrition and drug cues through complex
signalling networks to drive unique phenotypical outputs in the host. Health benefits to the host
conferred by the impact of drugs on the microbiota can be recapitulated through targeted genetic
manipulation of signalling or metabolic pathways in bacteria. Importantly, metabolic modeling of the
microbiota in human patients supports our main findings.
Overall, our data shows that the mechanistic understanding of the effects of diet, drugs and intestinal
microbiota on host physiology allows their manipulation and may improve health in humans.
Bif195 Protects Against Enteropathy Caused by Acetylsalicylic Acid in Humans
Enteropathy and small-intestinal ulcers are common side effects of non-steroidal anti-inflammatory
drugs (NSAID) such as Acetylsalicylic Acid (ASA). We aimed to develop a live bacterial product to
alleviate impairment of the small intestine, caused by drugs such as ASA. Through a pre-clinical
screening and characterization process we identified the bacteria Bif195. We performed a clinical trial
with 75 heathy volunteers co-treated with 300 mg ASA daily (6 weeks) and oral capsules of Bif195; ≥
5*1010 cfu or placebo, daily for 8 weeks. We find that, daily intake of Bif195 is safe and confers
clinically significant reduced risk of small-intestinal enteropathy caused by ASA in humans.
Leveraging Microbiome Functional Capabilities for the Potentiation of Immune-Checkpoint Inhibitors
Biomica, a subsidiary of Evogene Ltd. (NASDAQ, TASE: EVGN), is an emerging biopharmaceutical
company. Biomica develops microbiome-based therapeutics utilizing a Computational Predictive
Biology platform (CPB) and focusing on 3 main therapeutic areas: Immuno-oncology, GI-related
disorders, and multidrug-resistant microorganisms.
The company’s most advanced program is focused on developing rationally-designed live bacterial
consortia that potentiate patients’ response to cancer immune-checkpoint inhibitors (ICI).
Biomica is utilizing PRISM, a proprietary microbiome analysis platform combining unique algorithms
and internal comprehensive databases. PRISM Big-Data analysis enables comprehensive high-
resolution taxonomic and functional profiling of microbial communities, highlighting microbial entities
that can affect disease through various mechanisms-of-action. PRISM enables the development of rationally-designed microbial consortia comprised of a minimal number of strains achieving maximal efficacy and safety.
Biomica’s leading products BMC121 and BMC127 are rationally-designed live bacterial consortia
aimed at potentiating patients’ response to ICI. BMC121 and BMC127 have been designed based on
detailed functional microbiome analysis of cancer patients’ data. The combination of 4 different
microbial strains in each consortium is aimed to achieve robust anti-tumor immune activation through
several mechanisms-of-action. BMC121 and BMC127 have demonstrated improved response to ICI
in preclinical studies. Biomica expects to progress BMC121 and BMC 127 to phase 1 clinical studies