The microbiome seems to be involved in a number of human diseases, although the underlying mechanism remains to be elucidated.¹⁵  

• Diseases in which microbiome have been implicated includes:

  1. Autoimmune diseases

  2. Autism

  3. Hepatic disease

  4. Cancer

  5. Cardiovascular Disease.

• About 16% of all cancers in the United States appear closely related to elements of the microbiome. ¹⁵ 

  • Microbiome elements likely associated with cancer.:

    • hepatitis C

    • Heliobacter pylori

    • Human papilloma virus.

• DNA cleavage and potentially associated colorectal cancer may result from colibactin-producing Escherichia coli.¹⁵ 

  • Colibactin is considered a secondary metabolite associated with certain bacterial strains present in the human gut.¹⁷ 

  • Colibactin-producing bacteria appear correlated with human colorectal cancer.

  • Colibactin exhibits a heterodimeric structure with two DNA-reactive residues allowing formation of interstrand adenine cross-links (alkylation) between opposing DNA strands.¹⁷ 

  • Colibactin + E. coli → Colibactin-DNA Cross-link¹⁷ 

    Attribution: Wernke KM Xue M Tirla A Kim CS Crawford JM Herzon SB Structure and Bioactivity of Colibactin Bioorganic & Medicinal Chemistry Letters 30(15) 1 August 2020. https://www.sciencedirect.com/science/article/abs/pii/S0960894X20303905 ;

    
     

Drugs and their Interactions with the Bodies' Microbiome

• Variation in an individual's response to a drug is affected by the gut microbiome.

• The microbiome can influence almost every aspect of a drugs interaction in the body.

  • For example, the microbiome can affect:

    • Metabolism of Xenobiotics

    • Influence drug metabolism by modulating phase I (P450 drug metabolizing system) enzymes

      •  and phase II (e.g. conjugation reactions)

    • Influencing drug transporters

    • Affecting enterohepatic circulation Involvement in drug-pharmacodynamic interactions.^15,17,18 

• Gut bacteria can participate in direct drug metabolism.

• For example, digitoxin, a cardiac glycoside, can be inactivated by the microbe Eggerthella lenta and such inactivation could be important given that variability in drug concentration is especially important if the drug exhibits a narrow therapeutic index.

• Another example of a narrow therapeutic range agent, tacrolimus appears linked to Faecalibacterium prausnitzii in that patients (kidney transplant) requiring higher tacrolimus doses also exhibited elevated amounts of Faecalibacterium prausnitzii.^15,18

  •  

    Tacrolimus (left);  Digitoxin (right)

    Digitoxin Attribution:  MarinaVladivostok, CC0, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Digon_ball-and-stick.png	Tacrolimus Attribution:  Brenton, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Tacrolimus-1YAT-ball-and-stick-model.png

• An example in which microbiome gut bacteria enzymic activity is required for drug activation is illustrated by the prodrug sulfasalazine.

  • Prodrugs are defined as drugs that in their ingested form are not biologically active but upon metabolic transformation a pharmacologically active form results.

  • In this instance the azo bond of sulfasalazine is reduced by gut bacteria yielding the active form, 5-aminosalicylate (mesalamine).

    •  

      Sulfasalazine (left); Mesalamine (5-aminosalicylate; right)

      Sulfasalazine Attribution:  Unknown sourceUnknown source, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Sulfasalazine.svg	Mesalamine Attribution:  User:Mysid, Public domain, via Wikimedia Commons https://en.wikipedia.org/wiki/Mesalazine