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Manrique et al. Microbiome Res Rep 2024;3:23 https://dx.doi.org/10.20517/mrr.2023.80 Page 5 of 20

Immunomodulation refers to the effect of certain bacterial groups on immune responses to ensure the
effectiveness of chemotherapy. For example, certain bacterial taxa influence the accumulation of Th1 and
[53]
Th17 cells in the tumor environment . In addition to this, understanding immunotherapy cancer drugs
becomes intriguing when considering the interplay with microbiota composition. This is because the
efficacy of these drugs heavily relies on the activation of specific immune cells driven by certain members of
the gut microbiota. As an example, one of the main differences found in responders to immunotherapy of
several cancers was their ability to recruit CD8+ cells into the tumor microenvironment [31,57] . The authors
hypothesized that this recruitment could be mediated by several bacterial populations, but further
investigations are needed to establish a robust relationship between bacterial composition and the
recruitment of immune cells [58,59] . On the other hand, immunomodulation by gut microbiome can result in
increased toxicity of chemotherapy and other drugs, leading to conditions such as severe intestinal
inflammation that often happens during chemotherapy [60,61] .

Bacterial metabolism can be particularly important in the modulation of drug effects. For example, vitamin
B from bacterial origin is related to the prevention of colitis during CTLA-4 blockade therapy in melanoma
[62]
patients . Regarding immunomodulation, SCFAs play a crucial role in the efficacy and side effects of
several drugs [40,63,64] . Acetic, propionic, and butyric acids are the major products of bacteria fermentation in
the colon and can result in the modulation of Th1, Th17, and regulatory T cell (Treg) responses . This
[65]
effect has been observed as well for drugs such as metformin or oxaliplatin [38,39,66] and preliminary data
suggest that this drug effect might be driven through changes in bacterial metabolites, such as SCFA, but
these interactions must be examined in depth. Other examples of microbial metabolites include
desaminotyrosine, which acts through the activation of T cells, and desoxythymidine triphosphate (dTTP),
produced by microbiota from dietary serine which could be potentially harmful due to the increasing
toxicity of chemotherapeutic 5-fluoridine-5’-monophosphate . Both examples are explored in the
[67]
preclinical state.

Bacterial Enzymatic activity, as we commented previously, can transform drugs into active and toxic forms
or metabolize active forms to other metabolic subproducts, leading to a loss of efficiency [34,36] .

Reduced diversity refers to the loss of several bacterial populations after the administration of drugs, such as
in some chemotherapy therapies . However, antibiotics are currently the drug that has the most dramatic
[60]
effect on microbial composition [68,69] . These effects include a reduction in SCFA metabolism, an increase in
stress response pathways, the emergence of pathogen infections, and the development of antimicrobial
resistance [9-11,70] . Other drugs, such as proton pump inhibitors, metformin, selective serotonin inhibitors, and
laxatives, also change the microbiome composition, leading to a reduced diversity .
[34]
Unlike host genes, the microbiome can be changed, as seen until now, to achieve a beneficial effect in
humans. Thus, the information about drug-microbiota interactions and its mechanisms are key to defining
the best strategies to develop microbiome-based therapies as treatments and/or coadjutants of therapeutic
drugs and confers some of the basis for personalized medicine [66,71] . In the next sections, we provide a
summary of the different strategies that have been developed to modulate the gut microbiota for our benefit.

1ST GENERATION PRODUCTS - INTERVENTIONS TO MODULATE GUT MICROBIOTA
Dietary interventions
A microbiome dietary intervention refers to dietary changes that aim to modulate the gut microbiota in
order to improve human health, including but not limited to chronic diseases, such as inflammatory bowel
disease and syndrome (IBD/IBS), Crohn’s disease (CD) and Type 2 diabetes [72-74] , and even to improve the