๐ก This review explores the intricate relationship between the host, oral medications, and gut microbiota, emphasizing the profound impact of microbial drug metabolism on drug absorption, bioavailability, efficacy, and toxicity. The bidirectional interaction between oral medications and gut microbes is discussed, highlighting the potential of drugs to shape microbial communities. Computational tools and machine learning approaches for predicting microbial drug metabolism are also explored, emphasizing the challenges and prospects in this evolving field.
๐ Microbial Influence on Drug Metabolism: Gut microbiota, housing over 3 million unique genes, significantly contributes to drug metabolism, impacting drug absorption, bioavailability, stability, efficacy, and toxicity. Microbial enzymatic reactions in the gut, distinct from hepatic metabolism, create a vast array of drug metabolites, influencing pharmacological effects.
๐ Variability in Drug Response: Microbial deactivation of drugs, such as gemcitabine, can lead to chemotherapeutic resistance. Gut microbes play a crucial role in modulating the efficacy of anticancer drugs like cyclophosphamide, introducing variability in drug responses.
๐ Drug-Microbiota Bidirectional Interactions: Drugs can shape the composition, function, and gene expression of the gut microbial community.
Bidirectional interactions complicate predictions of drug-microbiota outcomes, challenging our ability to anticipate the consequences of drug administration.
๐ Functional Groups Susceptible to Microbial Metabolism:
Certain functional groups within oral medications are susceptible to microbial metabolism, influencing drug activation, inactivation, or toxicity.
Examples include ester, amide, nitro, and azo groups, with specific drugs like albiflorin, benzodiazepines, and antibacterial agents exhibiting susceptibility to microbial enzymatic degradation.
๐ Specific Examples of Microbial Drug Metabolism:
-Albiflorin, containing an ester group, undergoes hydrolysis by certain ๐๐ช๐ง๐ช๐ฅ๐ฐ๐ฃ๐ข๐ค๐ต๐ฆ๐ณ๐ช๐ข.
-Benzodiazepines are metabolized due to the presence of a nitro group.
-Antibacterial activities of various drugs, including prontosil and sulfasalazine, involve microbial azo reduction.
-Loperamide oxide’s antidiarrheal effect is mediated by gut bacteria cleaving N-oxide bonds.
-Levamisole incubation with human gut microbes results in thiazole ring-opened metabolites with anti-colon cancer activity.
๐ Microbial metabolism based on the intended use of xenobiotics, encompassing anticancer drugs, central nervous system (CNS) drugs, cardiovascular drugs, steroids, supplements, and natural products.
๐ Anticancer Drugs:
๐ Microbial Resistance and Metabolism:
Inconsistent responses and resistance to anticancer therapeutics are linked to the gut microbiome microenvironment.
๐. ๐ค๐ฐ๐ญ๐ช ๐ข๐ฏ๐ฅ ๐๐ช๐ด๐ต๐ฆ๐ณ๐ช๐ข ๐ธ๐ฆ๐ญ๐ด๐ฉ๐ช๐ฎ๐ฆ๐ณ๐ช have been associated with resistance to chemotherapeutics.
๐. ๐ค๐ฐ๐ญ๐ช degrades anticancer drugs, including tretazicar, gemcitabine, and doxorubicin, impacting drug efficacy.
๐ Immune Checkpoint Inhibitors (ICIs) and Gut Microbes:
Antibiotics with anti-PD-1 ICIs reduce progression-free survival (PFS) and overall survival (OS), highlighting the impact of gut microbes.
Specific microbial species, such as ๐๐ญ๐ช๐ด๐ต๐ช๐ฑ๐ฆ๐ด ๐ช๐ฏ๐ฅ๐ช๐ด๐ต๐ช๐ฏ๐ค๐ต๐ถ๐ด, ๐๐ฌ๐ฌ๐ฆ๐ณ๐ฎ๐ข๐ฏ๐ด๐ช๐ข ๐ฎ๐ถ๐ค๐ช๐ฏ๐ช๐ฑ๐ฉ๐ช๐ญ๐ข, ๐ข๐ฏ๐ฅ ๐๐ฏ๐ต๐ฆ๐ณ๐ฐ๐ค๐ฐ๐ค๐ค๐ถ๐ด ๐ฉ๐ช๐ณ๐ข๐ฆ, restore ICI efficacy.
Gut microbial signatures serve as potential biomarkers for predicting ICIs’ treatment response.
๐ Microbial Impact on Ipilimumab Treatment:
Gut microbial variations predict poor ipilimumab treatment response in metastatic melanoma patients.
Bacterial operational taxonomic units (OTUs) act as potential biomarkers for ipilimumab-colitis free patients.
๐ Central Nervous System Drugs:
๐ Metabolism of Anti-Depressants and Anxiolytics:
๐๐ช๐ง๐ช๐ฅ๐ฐ๐ฃ๐ข๐ค๐ต๐ฆ๐ณ๐ช๐ถ๐ฎ strains metabolize the anti-depression drug albiflorin.
Microbes, including ๐. ๐ค๐ฐ๐ญ๐ช, metabolize clonazepam, nitrazepam, and flunitrazepam through nitro-reduction.
๐ Gut Microbes and Levodopa Response:
Gut microbes, including ๐๐ฏ๐ต๐ฆ๐ณ๐ฐ๐ค๐ฐ๐ค๐ค๐ถ๐ด ๐ง๐ข๐ฆ๐ค๐ข๐ญ๐ช๐ด ๐ข๐ฏ๐ฅ ๐๐จ๐จ๐ฆ๐ณ๐ต๐ฉ๐ฆ๐ญ๐ข ๐ญ๐ฆ๐ฏ๐ต๐ข, metabolize levodopa, affecting treatment response.
Levodopa metabolites produced by ๐๐ญ๐ฐ๐ด๐ต๐ณ๐ช๐ฅ๐ช๐ถ๐ฎ ๐ด๐ฑ๐ฐ๐ณ๐ฐ๐จ๐ฆ๐ฏ๐ฆ๐ด exhibit variable deamination, influencing therapeutic outcomes.
๐ Cardiovascular Drugs:
Digoxin is reduced by ๐๐จ๐จ๐ฆ๐ณ๐ต๐ฉ๐ฆ๐ญ๐ข ๐ญ๐ฆ๐ฏ๐ต๐ข in the gut.
Gut microbes, affected by antibiotics, influence the response to quinapril and amlodipine in hypertension patients.
Lovastatin treatment response is altered due to microbial metabolism.
๐ Steroids and Corticosteroids:
Microbial enzymes in ๐๐ณ๐ฐ๐ต๐ฆ๐ฐ๐ฃ๐ข๐ค๐ต๐ฆ๐ณ๐ช๐ข ๐ข๐ฏ๐ฅ ๐๐ค๐ต๐ช๐ฏ๐ฐ๐ฃ๐ข๐ค๐ต๐ฆ๐ณ๐ช๐ข degrade steroids.
Gut microbes, including ๐๐ญ๐ฐ๐ด๐ต๐ณ๐ช๐ฅ๐ช๐ถ๐ฎ ๐ด๐ค๐ช๐ฏ๐ฅ๐ฆ๐ฏ๐ด, impact the metabolism of external corticosteroids.
Estrogen is reactivated by gut microbes through B-glucuronidase activity.
๐ Miscellaneous Xenobiotics and Natural Substances:
Gut microbes affect vitamin D levels, with conflicting results on vitamin D supplementation.
Microbial impact on natural substances like chlorogenic acid involves cinnamoyl esterase activity.
๐ Computational Prediction of Microbial Drug Metabolism:
Tools like MASI and MagMD provide databases for experimentally determined drug-microbe interactions. Machine learning models, including Drug Bug and others, predict drug degradation by gut microbes, considering microbial diversity variations. Meta-analysis studies reveal associations between specific drugs and microbial species, emphasizing the bidirectional nature of drug-microbiome interactions.
This comprehensive exploration of microbial metabolism of xenobiotics underscores the need for personalized approaches in drug development and treatment strategies, considering the intricate interplay between drugs, gut microbes, and host responses. Advances in computational prediction tools hold promise for enhancing our understanding of pharmacomicrobiomics.
Link to the article : http://tinyurl.com/3c3smutu
