Page 10 - Read Online

Page 4 of 20 Manrique et al. Microbiome Res Rep 2024;3:23 https://dx.doi.org/10.20517/mrr.2023.80

described in several bacteria, such as Lactobacillus johnsonii, Enterococcus hirae, and Barnesiella
[41]
intestinihominis, respectively . Regarding novel cancer therapies, such as ICI, several recent papers
associate the composition of the gut microbiota with the effectivity of these types of treatments [29,31] .

On the contrary, some drugs can be inactivated by bacterial metabolization, as is the case of the reduction of
digoxin to its inactivated form [42,43] . Levodopa, which has to be transformed into dopamine in the brain to
treat Parkinson’s disease, can be transformed prematurely by the gut microbiota, herein losing its biological
activity [44,45] . Gemcitabine, used in pancreatic ductal adenocarcinoma, presents chemoresistance because the
[46]
long isoform of the enzyme cytidine deaminase is present predominantly in Gammaproteobacteria .
Unfortunately, the gut microbiota also interacts with drugs, producing some toxic effects on the host .
[47]
This is the case with the intravenous drug Irinotecan (CTP-11), a drug to treat colorectal cancer. The
innocuous metabolic subproducts of CTP-11 (SN-38G) are released to the gut with the bile fluid and are
reconverted by the microbiota into their active toxic form (SN-38), causing epithelial damage and diarrhea.
An increase in Veillonella, Clostridium, Butryicicoccus, and Prevotella species was seen in the CTP-11 group.
This effect could be mitigated in a mouse model by modulating the composition of the microbiota with a
mix of Lactobacillus species, suggesting that modulation of the microbiota with microbiome-based
organisms can reduce the side effects caused by this therapy, and the development of such cotreatment
should be explored (see sections “1st Generation Products- Interventions to modify gut microbiota” and
“2nd Generation Products- Microbiome Based therapies” for more specific ways on how to achieve
this) [48-50] . Another example consists of the teratogenicity of nitrazepam, which is enhanced by microbial
nitroreductases that increase the production of 7-aminonitrazepam, its teratogenic derivative [51,52] .

Overall, it has been demonstrated that the gut microbiota composition and the resulting differences in
[35]
metabolic activity and immune regulation are crucial factors in the therapeutic effects of drugs . This effect
can be caused by direct metabolization of the drug or indirectly by influencing microbiome-based
modulation of the immune system [38-40] . Often, it is a two-way interaction between drugs and bacteria,
wherein the drug causes changes in gut microbiota composition, and these changes affect the performance
of the therapeutic drug [34,47,53] . The specific mechanisms by which the microbiota can influence the effect of
therapeutic drugs are truly diverse and are summarized in the following section.

Mechanisms of interaction between therapeutic drugs and gut microbiota
Alexander et al.’s review presents the TIMER framework to classify the mechanisms by which the
microbiota affects chemotherapy drugs. This classification could be applied to other types of drugs and/or
xenobiotic compounds with biological activity. TIMER stands for: Translocation, Immunomodulation,
Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation . Understanding these
[53]
mechanisms is essential to define strategies to modulate the microbiota and reduce the toxic effects of drugs,
enhance their beneficial effects, and avoid their inactivation which nullifies their effectiveness altogether.

Translocation, the process by which some bacteria cross the intestinal barrier, can be caused by many drugs.
Particularly, some chemotherapy drugs, such as cyclophosphamide or doxorubicin, provoke a local
inflammation effect on the gut due to the shortening of the villi, with concomitant changes in the
microbiota composition . Antiretroviral therapy can also cause inflammatory gut barrier damage and, in
[53]
[54]
addition, interfere with gut homeostasis recovery as they also change microbiota composition . Opioids
are another type of drug that provokes the translocation of bacteria due to the inhibition of myosin light
chain kinase (MLCK), a key protein in the maintenance of tight junctions [55,56] .