• Gastrointestinal Microbiome V

• Indirect Drug Effects by Gut Microbes and Influences of the Microbiome on Pharmacodynamics etc.

  Indirect Drug Effects:  In addition to microbiome direct effects on drugs due to, for example, bacteria-elaborated enzymes, there also indirect effects.16 These indirect effects occur when gut microbiome metabolites change either the expression of important hepatic enzymes (e.g. cytochrome P450 systems) or change their function. Accordingly, clinically used drugs may be influenced either by direct or indirect consequences of the gastrointestinal microbiome.16 In summary then, bacteria constituting the gut microbiome affect drug action by both direct and indirect influences. Evaluation of microbiome influences on the hepatic cytochrome P450 drug metabolizing system, studied mainly in mice, demonstrates various influences. In comparing "germ-free" mice with mice with their gut microbiome intact, both reduced and enhanced mRNA as well as protein synthesis have been reported.16 (Table 2). Some human data, however, are available. In one example healthy volunteers were treated with a cephalosporin antibiotic (cefprozil), expected to reduce gut microbiota. A reduction in certain cytochrome P450 isoform enzymic activity was reported (reduced CYP1A2, CYP2C19, CYP3A4).15,18  Generally, changing the microbiome utilizing antibiotics slightly reduced enzyme activity. This result may suggest that a "healthy and diverse" microbiome promotes optimal drug-metabolizing enzyme function.15   Pharmacodynamics: Microbiome and Cancer Immune checkpoint inhibitors are drugs that inhibit cytotoxic T-lymphocytes from continued cancer cell targeting. Normally, cytotoxic T-lymphocytes undergo programmed cell death (apoptosis) following a period of anticancer activity. The checkpoint inhibitors extend the anticancer T-lymphocytes duration of cytotoxic action. The gut microbiome composition influences the effectiveness of immune checkpoint inhibitor drugs. In a study that evaluated immune checkpoint inhibitor (ICI) effectiveness in melanoma patients as a function of microbiome composition reported differences in progression free survival.13,17 Melanoma patients with higher levels of Faecalibacterium benefited from a longer progression-free survival. By contrast, a reduced progression-free survival was noted in those melanoma patients with higher levels of Bacteroidales.13,17   Comparison of Progression Free Survival in Melanoma Patients Receiving Immune Checkpoint Inhibitor Therapy and Relative Abundance of Faecalibacterium and Bacteroidales in Gut Microbiome17 Attribution: Figure 3C from reference 17 https://www.science.org/doi/epdf/10.1126/science.aan4236 Attribution: Figure 3C from reference 17 https://www.science.org/doi/epdf/10.1126/science.aan4236     Colorectal cancer: A reduction in therapeutic effectiveness with an attendant increase in mortality is an important chemotherapeutic issue in oncology.13   Chemotherapy resistance associated with the gut microbiome may in some circumstances be partially responsible. One such example is the apparent association with intestinal microbiota and colorectal carcinogenesis. The bacteria, Fusobacterium nucleatum, appear to both promote colorectal tumor growth while inhibiting T-cell associated immune responses against these tumors. Higher levels of Fusobacterium nucleatum DNA found in colorectal cancer tissue seem associated with reduced survival.13,19 "Kaplain-Meier curves for colorectal cancer-specific survival."19 Attribution: Figure 1 (A): "Kaplain-Meier curves for colorectal cancer-specific survival." reference 19 Mima K Nishihara R Qian ZR et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut 2016 December; 65(12):  1973-1980. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769120/pdf/nihms714636.pdf Another study found that Fusobacterium nucleatum was highly represented in colorectal cancer in those patients exhibiting disease recurrence postchemotherapy.13 Chemotherapeutic failure in this context influenced response to the chemotherapeutic drugs 5-fluorouracil (5-FU,Adrucil, others), oxaliplatin (Eloxatin), and capecitabine (Xeloda and others). All of these drugs figure prominently in treating colorectal cancer.13,20 . The underlying mechanism affected by Fusobacterium nucleatum involve both innate immune signaling and specific microRNAs involved in autophagy pathway activation. Changes in chemotherapeutic responses were noted "F. Nucleatum  Is Associated with Cancer Recurrence and Patient Outcome"20 Attribution: Figure 1: "Taxa enriched in recurrent (Red) and non-recurrent (Blue) patients are indicated with negative (Red) or positive (Blue) LDA scores, respectively. LDA (Linear discriminant analysis) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767127/pdf/nihms930192.pdf The reader is directed elsewhere to discussions of several topics related to pharmacology and the microbiome. Click on this LINK (https://link.springer.com/article/10.1007/s40262-021-01032-y) These topics include: Pharmacology and the Gut Microbiome:  Additional Topics (Click on topic) Enterohepatic Recycling Drug Effects on the Microbiome Diet in the Microbiome Future of Drugs and the Microbiome

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