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

and can modify the activity of different immune cells, ultimately affecting the spread of cancerous cells [23-25] .
Antibiotic treatment can reduce the effect of immune checkpoint inhibitors (ICI) treatment, such as PD-L1
or CTLA-4 blockade [26,27] . Moreover, clinical studies have unraveled differences in the microbiota
composition of individuals who respond to treatment compared to those who have not been reported in
several studies [23,28,29] . Differences in this response can be eliminated with fecal microbial transplantation
(FMT) administration. Additionally, oral administration of certain bacterial genera, such as
Bifidobacterium, Akkermansia, and Bacteroides, has been shown to improve the efficacy of anti-PDL1 and
CTLA-4 treatments [24,30,31] . Similar results were reported by Tanoue et al., in which administration of a mix
with 11 different strains, belonging to Alistipes, Bacteroides, Eubacterium, Fusobacterium, Parabacteroides,
[32]
Phascolarctobacterium, and Ruminococcaceae groups, enhanced therapeutic efficacy of ICI .

HOST-MICROBIOTA INTERACTIONS WITH THERAPEUTIC TREATMENTS
Even though there is increasing evidence demonstrating that the gut microbiota can affect drug efficacy, the
mechanisms by which this happens remain unexplained in many scenarios. Understanding the specific
ecological variables and mechanisms by which microbes can influence drug efficiency will aid in the
development of successful microbiome-based therapies. Below, we summarize the most relevant
microbiome-drug interaction mechanism known, with a special focus on oncological treatments, but we
also refer to others when necessary to illustrate a particular known mechanism.

The effect of host microbiota on drugs has been reported since the 80s, together with the discovery of the
[33]
extensive enzymatic repertoire of the gut microbiota . Pharmacogenomics is the way human genetic
variation affects drug action and their effectiveness. This idea was the foundation for
pharmacomicrobiomics (http://pharmacomicrobiomics.com), or the way variations in gut microbiome
composition affect the action and effectiveness of therapeutic drugs [34,35] . The modification of therapeutic
drugs by the microbiota can result in different types of effects, which is the base of some toxicity effects and
[35]
the phenomenon known as the “responder-no responder” effect .
Transformation of therapeutic drugs by the gut microbiota
In an extensive study, Zimmermann et al. evaluated the ability of 76 diverse human gut bacteria isolates to
metabolize 271 orally delivered drugs selected based on their clinical indication, physicochemical properties,
and predicted intestinal concentrations. This study shed light on the variability of these interactions and
how they affect their efficacy. Specifically, two-thirds of the drugs were partially or completely metabolized
by at least one bacterial strain and each bacterial strain was able to metabolize from 11 to 95 drugs . The
[36]
outcome of these metabolizations or interactions can be grouped into three types of effects (increased
bioavailability, increased toxicity, or drug inactivation), for which we illustrate some examples below, with a
special focus on oncological treatments.

First, the drug could augment its biological activity after metabolization, thus improving its effect.
Sulfasalazine, a prodrug used in arthritis, is metabolized by some members of the gut microbiota, improving
its bioavailability . Metformin is also a case in which microbiota plays a crucial role, but in this case, the
[37]
relationship is more complex. Metformin changes the composition of the gut microbiota, reducing the
abundance of proteobacteria and, simultaneously, changing the profile of short-chain fatty acids (SCFAs)
towards more production of butyrate and propionate, and bile acid metabolism resulting in an elevated
concentration of total bile acids. These changes are associated with beneficial effects on type-2 diabetes
patients, but also with the improvement in other aspects such as cognition and leaky gut [38-40] . Regarding
oncologic treatments, the chemotherapeutic cyclophosphamide effectivity is boosted by the ability of some
bacteria to recruit type 1 T helper (Th1), type 17 T helper (Th17), and CD8+ T cells. These effects have been