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Pharmacomicrobiomics in Anticancer Therapies: Comparison
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Please note this is a comparison between Version 2 by Amina Yu and Version 1 by Gabriele Conti.

The microbial community that inhabits the gastrointestinal tract is closely connected to human physiology, being fundamental among others for the synthesis of vitamins and the digestion of complex polysaccharides with production of short-chain fatty acids (SCFAs), key metabolites for host homeostasis, resistance to colonization by enteropathogens (i.e., the barrier effect) and, not least, the education and modulation of the immune system. The gut microbiota has also been attributed a role in the metabolism of numerous xenobiotics that can enter the human body, from environmental pollutants to therapeutic drugs. This interaction is bidirectional and multimodal, with xenobiotics being able to promote/inhibit the growth of certain taxa, induce a change in the natural pattern of microbial metabolites and influence virulence, with cascading repercussions on the mutualistic relationship with the host. It is therefore not surprising that the gut microbiota is increasingly suggested as a key factor influencing not only the onset and progression of various diseases, but also the response to therapies. In particular, more and more evidence is accumulating in the field of oncology, where the idea is taking hold that there is a more favorable configuration of the gut microbiota associated with enhanced anticancer responses, mitigated side effects, and longer disease-free survival. 

  • gut microbiota
  • pharmacomicrobiomics
  • anticancer drugs
  • multi-omics
  • tumor-associated bacteria
  • gut microbiota modulation

1. Gut Microbiome Impact on Immuno-Chemotherapeutics

1.1. Untargeted Traditional Chemotherapy

Traditional or broad-spectrum chemotherapy has been developed to target cell cycle phases, as cancer cells tend to have a shorter duplication time, making them a preferred target for chemotherapy drugs. Unfortunately, even normal cells can be damaged, thus causing several types of side effects. The gut microbiota has been shown to impact the efficacy and toxicity of some traditional anticancer agents (such as platinum drugs, alkylating agents, anthracyclines, camptothecins, and antimetabolites) through several mechanisms, as detailed below.
Regarding platinum drugs, it should be mentioned that patients responding to oxaliplatin showed elevated serum butyrate levels positively correlated to ID2 (inhibitor DNA-binding 2 protein HLH) and interferon-gamma (IFN-γ) expression by human CD8+ T cells, thus suggesting SCFA-driven promotion of anticancer immunity [36][1]. Furthermore, it has been shown that Bifidobacterium bifidum strains could work synergistically with oxaliplatin to reduce tumor growth, by increasing CD4+, CD8+, effector CD9+ T, and natural killer (NK) cells [37][2].
As for the alkylating agent cyclophosphamide (CTX), it is known to stimulate “pathogenic” TH17 (pTH17) cells through a complex circuitry involving gut microbes and MyD88. In particular, the translocation of Gram-positive bacteria into secondary lymphoid organs in response to CTX could polarize naïve CD4+ T cells towards a TH1 or pTH17 pattern activating bacterial-specific memory T cell responses [38][3].
Another group of traditional chemotherapeutic drugs are anthracyclines, antitumor antibiotics. Doxorubicin (DOX), a member of this class, has several adverse side effects including damage to the kidney, liver, and gastrointestinal mucosa [39][4], as well as cardiotoxicity, which limit its clinical doses and application [40,41][5][6]. DOX also induces gut microbiota imbalance (i.e., dysbiosis), with possible translocation of microbial components across the compromised intestinal barrier [42][7]. In particular, it has been shown that lipopolysaccharide (LPS), a molecule of the outer membrane of Gram-negative bacteria, can enter the bloodstream and promote the toll-like receptor 4 (TLR4)-mediated production of a wide range of proinflammatory factors (e.g., tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6), thus contributing to systemic damage [43][8]. On the other hand, several enterobacteria capable of inactivating DOX, through deglycosylation to 7-deoxydoxorubicinol and 7-deoxydoxorubicinolone, have been identified, including the predominantly environmental species Raoultella planticola [44][9]. Microbial detoxification of DOX could influence its therapeutic concentration in patients, significantly limiting its off-target toxicity.
Gut microbial residents have also been involved in drug reactivation processes and thus in undesirable side effects. Two examples of drugs with increased off-target toxicity due to reactivation by gut microbiota enzymes are irinotecan (IRT) and 5-fluorouracil (5-FU). Irinotecan, a camptothecan analog that blocks DNA replication, is administered for the treatment of pancreatic cancer and colorectal cancer (CRC) [45,46][10][11]. IRT is administered in the inactive form, converted to the biologically active form SN38 by hepatic and small intestinal carboxylesterases, and then detoxified in the liver by host UDP-glucuronosyltransferases (in the inactive form SN38-G) before being secreted in the intestine. At the intestinal level, SN38-G can be reactivated by specific microbial enzymes, β-glucuronidases, with severe diarrhea [47][12]. IRT treatment is also accompanied by an alteration of the gut microbiota composition, with a reduction in health-associated genera such as Lactobacillus and Bifidobacterium [48][13], and increased levels of Clostridium and Enterobacteriaceae taxa including Escherichia coli. Such a dysbiotic profile could contribute to toxicity due to mucosal injury/and or inflammation and higher levels of β-glucuronidases in the gastrointestinal tract [49,50][14][15]. The drug 5-FU is one of the best studied pyrimidine antagonist agents in CRC therapies, which interferes with thymidylate synthesis, thus inhibiting DNA elongation during DNA replication and repair processes. To improve oral bioavailability, 5-FU can be administered in the form of prodrug such as doxifluridine, which can be converted to 5-FU within cells by pyrimidine phosphorylase. Nonetheless, this prodrug can also be deglycosylated in the active form by microbial thymidine or uridine phosphorylases, resulting in premature intestinal activation and toxicity [28][16]. Furthermore, bacterial dihydropyrimidine dehydrogenase (e.g., expressed by E. coli and Salmonella enterica) is able to catalyze the inactivation of 5-FU to 5,6-dihydro-5-fluoruracil in the gastrointestinal tract [51][17]. Treatment using 5-FU has also been associated with dysbiosis in mouse models, with reduced intra-individual diversity and altered composition [52][18].
Finally, the gut microbiota has been implicated in the detoxification of the folic acid antagonist methotrexate (MTX). The metabolism of MTX to non-toxic 2,4-diamino-N(10)-methylpteroic acid is carried out by the bacterial enzyme carboxypeptidase glutamate 2. This activity has been correlated positively with the relative abundance of Prevotellaceae and Anaeroplasmataceae, which could help explain the intra-individual variability in therapy efficacy and toxicity [53,54][19][20]. At the same time, administration of MTX can alter the gut microbiota profile in a dose-dependent manner, which can lead to changes in immune cell levels and activity [55,56][21][22].

1.2. Targeted Immuno-Chemotherapy

Targeted immuno-chemotherapeutic agents can be divided into two groups: small-molecule drugs and macromolecules (e.g., monoclonal antibodies, polypeptides, antibody–drug conjugates, and nucleic acids). Here wthe focus sis specifically on monoclonal antibodies and small-molecule inhibitors, as they are the main approaches for targeted therapy today. Monoclonal antibodies (mAbs) are high-molecular-weight glycoproteins with high selectivity for their targets, which are typically confined to the cell surface. They are generally administrated intravenously and recognizable thanks to the suffix “-mab” (e.g., bevacizumab, an angiogenesis inhibitor that slows the growth of new blood vessels [57][23]). On the other hand, small-molecule (<1000 Dalton) inhibitors are able to cross cell membranes and act inside cancer cells, directly promoting cell death, have better patient compliance (having a non-mandatory intravenous route of administration) and are mostly identifiable by the suffix “-ib” (e.g., imatinib, a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia and other different types of cancer [58][24]).

1.3. Monoclonal Antibodies

In the last two decades, advances in biotechnology and molecular biology have led to the development of cancer immunotherapy, a milestone in cancer treatment [59][25]. In particular, immune-checkpoint blockers (ICBs) have become the forefront of immunotherapy approaches, because of their broad activity in distinct histopathological cancer types and their efficacy against tumor metastasis. The most explored ICBs have two important targets: (i) programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1), and (ii) cytotoxic T-lymphocyte-associated protein 4/B7-1 (CD80) or B7-2 (CD86) ligands (CTLA-4/B7-1/B7-2) [60,61,62][26][27][28]. All these proteins are related to T cell inactivation, therefore to a decreased immune activity and reduced anticancer response. Unfortunately, however, less than 30% of patients respond to ICB therapy, showing a heterogeneous outcome. In this context, a large body of evidence is accumulating on the role of the gut microbiota in influencing the success of therapies [63,64][29][30].
As regards anti-CTLA-4 therapy, oral administration of Bacteroides fragilis, combined with Burkholderia cepacia or Bacteroides thetaiotaomicron, has been shown to promote a TH1-mediated immune response and intratumoral maturation of dendritic cells in mice, thus favoring a better anticancer immune response [65][31]. Additionally, FMT from melanoma patients to murine models confirmed that high levels of B. fragilis were associated with improved antitumor response. Similar results have been published for PD-1/PD-L1 blockers. In particular, higher microbial diversity and increased relative abundance of Bifidobacterium, Fecalibacterium and other Ruminococcaceae taxa have been correlated with improved mAb efficacy, probably due to increased antigen presentation and improved effector T cell activity in the local tumor microenvironment as well as systemically [66,67][32][33]. Ruminococcaceae, together with other Clostridiales and Akkermansia muciniphila have also been shown to establish “homeostatic” consortia capable of supporting the integrity of the intestinal barrier, thus favoring intestinal and immunological health, fundamental for recovery from cancer [66][32]. However, it should be noted that a high production of SCFAs, particularly propionate and butyrate (produced by Ruminococcaceae members among others), appeared to limit the antitumor activity of anti-CTLA-4, with reduced systemic inflammation and immune activation in tumor-bearing mice [68][34].

1.4. Small-Molecule Inhibitors

Since the approval of the first small-molecule inhibitor (imatinib) in 2001, around 90 targeted antitumor small-molecule drugs have been accepted by the US Food and Drug Administration and the National Medical Products Administration of China [69][35]. These drugs cover a wide range of target proteins, including kinases, epigenetic regulatory proteins, DNA damage repair enzymes, and proteasomes hitting cancer cells in different metabolic pathways [70,71][36][37].
As for the gut microbiota role, Bacteroides ovatus and Bacteroides xylanisolvens have been shown to exert a synergistic activity on tumor size reduction in mice treated with erlotinib, another tyrosine kinase inhibitor used to treat lung cancer [72][38]. In particular, oral gavage of these gut microbes increased the chemotherapy effect, with a 46% reduction in tumor volume compared to the control. Other tyrosine kinase inhibitors, such as sorafenib (SFN) and regorafenib, can undergo intestinal deglucuronidation, which implies enterohepatic recirculation and consequent improvement in the plasma half-life of such inhibitors [73][39]. As discussed above for IRT, genes coding for β-glucuronidases are widely present in the gut microbiota [74][40] and the related MDM event may partly explain the inter-individual pharmacokinetic variability observed for these drugs. Furthermore, the staphylococcal superantigen-like protein 6 enhances SFN sensitivity in hepatocellular carcinoma by inhibiting glycolysis and blocking CD47 signaling [75][41]. Glycolysis inhibition can be particularly effective against cancer cells with a mitochondrial defect or in hypoxic conditions, and the CD47 pathway can also work as a “don’t eat me” signal to macrophage cells, promoting immune escape in certain types of cancer [76,77][42][43].

2. Modulation of the Gut Microbiota to Improve the Therapeutic Outcome

2.1. Prebiotics

Prebiotics are defined as “a substrate that is selectively utilized by host microorganisms, conferring a health benefit” [80][44]. The most used prebiotics include carbohydrates such as galactooligosaccharides (GOS), xylooligosaccharides (XOS), fructooligosaccharides (FOS), fructans, and inulin, as well as other compounds such as polyphenols and polyunsaturated fatty acids (PUFAs). Their beneficial effects are attributable to various mechanisms, including: (i) expansion of beneficial bacteria, (ii) reduction of overt pathogens or pathobionts, and (iii) anti-inflammatory and immunomodulatory activities [79][45].
In the cancer context, García-Peris et al. [81][46] conducted a randomized, double-blind, placebo-controlled trial, in which 31 patients with gynecological cancer were given a mixture of fibers (50% inulin and 50% FOS), twice daily from one week before to three weeks after post-surgery radiotherapy (NCT01549782). The prebiotic mixture counteracted the radiotherapy-related drop in Lactobacillus and Bifidobacterium counts, while reducing tissue damage at the enterocyte level. Many other clinical trials using prebiotics in cancer patients have been designed over the years and some are still ongoing. Among those started in the last two years, it is worth mentioning a clinical trial in the United States, in which researchers aim to evaluate the impact of daily dietary supplementation with a prebiotic based on soluble corn fiber on the gut and tumor-associated microbiota, the immune profile and the therapeutic outcome in 20 patients with stage II and III CRC (NCT05516641). In a Canadian clinical study of 45 patients with advanced non-small cell lung cancer and metastatic melanoma (NCT05303493), researchers will evaluate the safety and tolerability of the Camu-Camu prebiotic in combination with ICBs, as well as the impact on response. Interestingly, the Camu-Camu berry, also known as Myrciaria dubia, has recently been shown to lead to the enrichment of A. muciniphila, a bacterium associated with favorable clinical outcome in melanoma patients undergoing PD-1 immunotherapy [66][32], and the improvement of ICB efficacy in preclinical models [82,83][47][48]. In the context of a randomized, double-blind, placebo-controlled (maltodextrin) American clinical trial in 30 patients with myeloma or lymphoma undergoing autologous stem cell transplantation (NCT05135351), the authors will evaluate the impact of prebiotic supplementation with resistant starch on the diversity of the gut microbiota at the time of stem cell engraftment. It should be remembered that higher microbiota diversity has been associated with better survival after autologous stem cell transplantation in multiple myeloma and lymphoma [84,85][49][50] In particular, the prebiotic intervention will begin 10 days before the infusion of the stem cells and will continue until the first day of engraftment of the neutrophils or for about 30 days in total. The impact on intestinal permeability will also be evaluated. Another American clinical trial in 29 patients undergoing hematopoietic stem cell transplantation will evaluate the benefits of following a diet rich in prebiotics before and during the first 100 days after transplantation, especially in terms of reduction of acute graft-versus-host disease and risk of Clostridioides difficile infection (NCT04629430).

2.2. Probiotics

Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [86][51]. Due to the multiple effects on the host, including nutrient metabolism, improved barrier function, alteration of the gut microbiota, direct and/or indirect pathogen antagonism, influence on the gut-brain axis and immunomodulation [87][52], probiotics are also gaining increasing attention in cancer therapy, and their use has been proposed as non-invasive therapeutic adjuvants or protective agents [88,89][53][54].
In 2010, the interaction between probiotics, gut microbiota and immune functions in cancer patients undergoing colorectal resection was evaluated for the first time [90][55]. In a subsequent phase IV randomized clinical trial, the authors observed that daily oral administration of the probiotic yeast Saccharomyces boulardii for seven days prior to colorectal resection reduced the levels of pro- and anti-inflammatory cytokines, including IL-10, IL-23A and IL-1β, in the intestinal mucosa and at the same time the incidence of infectious complications (13.3% in patients receiving probiotics vs. 38.8% in the control group) [91][56]. A few years later, Zaharuddin and colleagues [92][57] determined the effect of consuming probiotics (Lactobacillus acidophilus, Lactococcus lactis, Lactobacillus casei, Bifidobacterium longum, B. bifidum, B. longum subsp. infantis) for 6 months on clinical outcomes and levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6, IL-10, IL-12, IL-17A, IL-17C and IL-22) in 52 patients with CRC. Although chemotherapy-induced diarrhea was observed, CRC patients who received probiotics showed a significant reduction in pro-inflammatory cytokine levels (except IFN- γ) compared to the control group. According to the authors, the combination of probiotic strains could therefore be safely consumed four weeks after surgery in CRC patients, leading to an overall benefit on the intestinal microenvironment and inflammatory profile.

2.3. Antibiotics

The use of antibiotics in cancer patients has several pros and cons. For example, antibiotics have been shown to reduce the size and number of neoplastic lesions [94[58][59],95], and help eradicate the colonization of enterotoxigenic Bacteroides fragilis in a mouse model of intestinal neoplasia [96][60]. On the other hand, antibiotic treatment negatively impacts the gut microbiota, reducing biodiversity and contributing to select antibiotic-resistant microorganisms [97][61]. In this regard, a relevant issue is the co-administration of broad-spectrum antibiotics instead of selective ones against specific pathogens/pathobionts. Targeted antibiotic therapy could help to alter the gut microbiota less while preserving its diversity, which has proven crucial for patients’ response to chemotherapy and prognosis [12,13][62][63]. Antibiotic-induced alterations in the gut microbiota could also favorably modulate the pharmacokinetics and efficacy of anticancer drugs. In fact, specific antibiotics could be used to inhibit bacterial species carrying β-glucuronidase activity, thus reducing intestinal toxicity due to unwanted drug reactivation. This is the case of vancomycin, a glycopeptide antibiotic that has been shown to reduce the abundance of β-glucuronidase-expressing bacteria in mouse models, decreasing the gastrointestinal toxicity of several drugs including IRT [98][64]. Vancomycin could also prove useful in the specific context of 5-FU chemotherapy, since the alterations in the gut microbiota composition induced by its oral administration resulted in a reduced production of microbial-derived dihydropyrimidine dehydrogenase [99][65], which could counteract the local 5-FU deactivation as discussed above (see section “Untargeted traditional chemotherapy”).

2.4. FMT

Consisting of the transfer of fecal material from a healthy donor, FMT is arguably the most direct method of reshaping the gut microbiota. In recent years, FMT has been successfully applied for the treatment of recurrent C. difficile infection, achieving a 90% cure rate with acceptable side effects [102][66]. Several studies have provided evidence of the potential of FMT in treating inflammatory bowel disease, colitis, and digestive system cancer as well [103,104][67][68]. With specific reference to cancer, several seminal studies have shown that the microbiota from anti-PD-1 therapy responders, infused by FMT in refractory patients, enhanced tumor-infiltrating T cells and amplified the efficacy of immunotherapy [67,105][33][69]. Although large randomized controlled trials are needed, a pilot study has also shown satisfactory results on the feasibility of applying FMT in patients with chronic radiation enteritis [106][70]. In a randomized clinical trial of 20 patients with metastatic renal cell carcinoma (NCT04040712), Ianiro and colleagues [107][71] observed resolution of tyrosine kinase inhibitor-induced diarrhea four weeks after FMT with no serious adverse events.

3. Bacterial-Based Anticancer Technologies

The tumor microenvironment is another ecological niche where microorganisms can proliferate with an extracellular and intracellular localization, in both cancer and immune cells (Figure 3) [111] [72]. As for the gut microbiota, tumor-associated bacteria (TAB), present in primary or distal tumor sites, metastatic lymph nodes or liver metastases, can also influence the efficacy of chemotherapy and immunotherapy with pro- or anti-carcinogenic effects [27,112][73][74]. For example, it has recently been found that obligate or facultative anaerobes from Fusobacteriaceae, Enterobacteriaceae, Clostridiaceae, and Bifidobacteriaceae families can proliferate in hypoxic niches of solid tumors [111,113][72][75]. These localized microbes can alter the therapeutic effect of anticancer drugs through the expression of enzymes that are capable of metabolizing such drugs (e.g., dihydropyrimidine dehydrogenase [51][17]), by modulating autophagy [114][76], or enhancing tumor-infiltration and activation of CD8+ T cells [115][77]. In particular, induction of the autophagy pathway by TAB, such as Fusobacterium nucleatum, has been shown to reduce apoptotic cell death, thereby promoting chemoresistance [114][76]. Nowadays, microbial modulation approaches as described above do not specifically act on the tumor microenvironment, making it necessary to develop targeted intervention strategies [111,116,117,118][72][78][79][80].
Several TAB, such as the facultative anaerobe Salmonella typhimurium, are known to actively migrate to the tumor, colonizing hypoxic niches in in vitro studies [119,120][81][82]. The chemotaxic ability of these microorganisms could be useful for therapeutic delivery and local bacterial nanofactory technology [121,122][83][84]. Different targeted antimicrobial approaches have been developed, allowing for antimicrobials to be delivered to metastatic sites, in order to eliminate unwanted TAB and modulate the local microbial niche. For example, polylactic-co-glycolic acid nanoparticles, coated with the gastric epithelial cell membrane, could be used to deliver clarithromycin to target Helicobacter pylori, which is related to a higher risk of gastric cancer development and progression [123][85].
TAB metabolites and/or components could also be an interesting target for cancer treatment. A nanotechnology approach was able to induce LPS-binding fusion protein (LPS-trap) production by cancer cells, useful for limiting the LPS-TLR4 interaction at the tumor site [124][86]. Specifically, the researchers used a lipid-protamine-DNA nanoparticle gene delivery system to transfect selectively cancer cells, inducing transient expression and secretion of LPS-trap and thus LPS-TLR4 binding block in the tumor microenvironment. This treatment could increase the efficacy of immunotherapy and prevent oncogene activation. Similarly, a triple-layered nanogel DOX-loaded nanoparticle has been developed to be degraded by bacterial lipases, releasing DOX into the tumor, thereby allowing for better tissue specificity, targeted anticancer action and a reduction in side effects [125][87].
Furthermore, genetically modified TAB could be used as external inducible therapeutic agents. These types of bacteria, capable of growing in the tumor microenvironment, could be triggered through external stimuli such as: (i) electromagnetic waves, (ii) magnetic fields, and (iii) ultrasound, to express silent genes and work as a bacterial nanofactory. For example, photosynthetic bacteria or bacteria functionalized with photosensitizer nanoparticles, which can reach and accumulate in tumors, have been designed to generate oxygen under laser irradiation, thereby relieving tumor hypoxia and enhancing reactive oxygen species (ROS) production, with damage to tumor cells and contribution to primary tumor elimination [126,127][88][89]. Magnetotactic bacteria, capable of producing particular types of membranous structures, i.e., magnetosomes, have also been evaluated for magnetic hyperthermia cancer therapy. Bacterial magnetosomes could in fact be modified to carry drugs, such as DOX and/or oligotherapeutics, and release them at the cancer site through exposure to alternating external magnetic field [128][90]. Finally, some anaerobic TAB, which populate the necrotic core of solid tumors, could be engineered to express and secrete exogenous therapeutics molecules, such as anti-CTLA-4 and anti-PD-L1 proteins, under a thermal stimulus. For example, focused ultrasound was used to trigger a temperature-dependent operon that induced the expression of anti-CTLA-4 and anti-PD-L1 by engineered tumor-homing probiotic E. coli Nissle 1917 [129][91].
Another innovative biotechnological strategy consists of bacterial-derived antitumor vaccines. Cancer cell membrane vesicles could be used to stimulate immune system activity against related patient tumor cells, and bacterial outer membrane vesicles could be fused with them to enhance cancer-specific immunostimulation. In particular, eukaryotic-procaryotic engineered vesicles could trigger the activity of antigen-presenting cells and subsequent activation of cytotoxic T cells, promoting an enhanced antitumoral immune response. A propidium iodide core, added to the engineered vesicles, could convert near-infrared irradiation into cytotoxic heat, damaging cancer cells and generating supplementary tumor antigen, for a better anticancer response [130][92].
A final way to target the tumor microenvironment comes from bacteriophages directed against TAB. Due to their target selectivity and infection ability, phages represent very versatile vectors for drug delivery and gene therapy. In this context, some researchers have developed a nanotechnological approach based on bacteriophages that could be useful for eradicating CRC, thanks to a click-chemistry applied to phage and dextran nanoparticles containing chemotherapeutic agents (i.e., IRT) [131][93]. As observed in mouse models, these functionalized phages provided a multitiered strategy to treat CRC: (i) phage infection of the tumor-promoting TAB F. nucleatum, (ii) expansion of SCFA-producing species (e.g., Clostridium butyricum) thanks to the prebiotic function of dextran, and (iii) delivery of IRT to eliminate CRC cells in the tumor site.
With continuing technological advances, other more specific, targeted, and inducible cancer therapies that exploit biological bacterial processes are expected to be presented, as a very promising way to overcome actual therapeutic limitations.

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