Bacteria-Mediated Modulatory Strategies for Colorectal Cancer Treatment

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Mehdi Shakibaei	--	3140	2022-04-25 11:19:42	\|
2	format change	Peter Tang	Meta information modification	3140	2022-04-25 11:29:30	\|

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10040832

Colorectal cancer (CRC) is one of the most common tumors worldwide, with a higher rate of distant metastases than other malignancies and with regular occurrence of drug resistance. Therefore, scientists are forced to further develop novel and innovative therapeutic treatment strategies, whereby it has been discovered microorganisms, albeit linked to CRC pathogenesis, are able to act as highly selective CRC treatment agents. Consequently, researchers are increasingly focusing on bacteriotherapy as a novel therapeutic strategy with less or no side effects compared to standard cancer treatment methods. With multiple successful trials making use of various bacteria-associated mechanisms, bacteriotherapy in cancer treatment is on its way to become a promising tool in CRC targeting therapy.

colorectal cancer biotherapeutical toxins bacteriocins bacterial peptides bacteriotherapy microbiota

1. Introduction

Colorectal cancer (CRC) is globally among the most common causes of cancer-related death, whereby 50% of patients who are not showing metastasis when diagnosed, will develop metastases with the progressing course of the cancer disease ^[1]^[2]^[3]^[4], with the most common sites being liver and lungs ^[3]. CRC is known to be affected by environmental and lifestyle factors including poor diet, physical inactivity and a sedentary lifestyle ^[5]^[6]. The pathogenesis of CRC is characterized by multiple factors contributing to the disease, such as genetic mutations and epigenetic alterations as well as building of and interaction with the tumor microenvironment (TME) that promotes further tumor progression and metastasis ^[7]^[8]^[9]. Hereby, chronic inflammation, known as a risk factor for CRC development, plays a pivotal role, since diverse pro-inflammatory mediators such as cytokines, chemokines, carcinogens, chemotherapeutic substances or radiation, have been demonstrated to further stimulate inflammatory pathways (e.g., nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells, NF-κB), leading to tumor cell proliferation and invasion ^[10]^[11]^[12]^[13]. Moreover, it has been frequently shown that inflammatory bowel diseases and bowel-linked inflammation are not uncommonly associated with CRC tumor progression, highlighting the role of the gut’s inflammation-protective capability ^[14].

The gut, as a tissue hosting approximately 3 × 10¹³ colonic bacteria, is assumed to be responsible for the majority of known microbial immunomodulatory effects and immunity in the intestinal tract as well as for metabolism and inflammation and even shows cancer-protective properties ^[15]^[16]^[17]^[18]^[19]. This effect has already been discovered in the late 1800 s by William B. Coley, who was able to demonstrate tumor reduction and extended survival of CRC patients by using a mix of bacterial species Serratia marcescens and Streptococcus pyogenes for the treatment of sarcomas ^[20].

Today, bacterial therapy has been rediscovered as a potential treatment strategy for CRC ^[18]^[21]^[22]^[23], especially because tumor cells are capable of genetic mutations, and are thus able to escape from immune monitoring and can even develop resistance to standard immunotherapies. Moreover, current anti-tumor therapeutics are associated with high toxicity to normal cells, finally leading to severe side effects in patients, thus current cancer treatment is frequently exposed to a number of drawbacks ^[16]^[24]^[25]. Therefore, using bacteria strains possessing anti-cancer properties represents a promising strategy as preventative, concomitant or alternative treatment of CRC ^[18]^[20]^[21]^[22]^[23].

In particular, bacterial peptides, including toxins, show characteristics such as low molecular weight and hydrophobicity, facilitating their entry into tumor tissue, where they can unfold their anti-cancer effects ^[26]. Furthermore, taking advantage of the fact that some bacteria show tumor targeting specificity, they have also been used as carriers for anti-tumor agents and even for tumor and metastases detection in previous studies ^[27]^[28]^[29]^[30]^[31]. Besides, using bacteria as probiotics has been presented as another application strategy in the treatment of CRC and its prevention, showing direct effects by suppressing carcinogens and stimulating immune modulation ^[32]^[33]^[34]^[35]. This demonstrates again the various methods of bacterial application in CRC treatment approaches and its anti-cancer potential on various levels.

2. Bacteriotherapy in CRC Treatment

In recent decades, the mortality rate of various cancers has remarkably increased, forcing scientists to further develop novel and innovative therapeutic treatment strategies, whereby bacterial therapy has been shown to be a very promising one ^[36], especially regarding CRC, which ranks among the most prevalent life-threatening types of cancer, bacteriotherapy provides an attractive novel and cost-efficacious treatment approach. Accordingly, research has shown that the microbiome of patients suffering from CRC has a significantly different composition than that of healthy individuals ^[37]^[38]. Moreover, it is known that pathogenic bacteria and microorganisms can greatly contribute to the development of CRC, but on the other hand, others were found to act as effective therapeutic agents with less or even no side effects compared to standard cancer treatment ^[20]^[39]. Based on this background further research on bacteria’s role in the treatment of patients suffering from CRC appears to be very promising.

2.1. Mechanisms Used in Bacteriotherapy in CRC

There have been several mechanisms of bacteria described to date that researchers are taking advantage of in the treatment of CRC via bacteriotherapy, such as formation of pores in the cell membrane, inhibition of metastasis, tumor necrosis or apoptosis ^[20]^[40].

In particular, apoptosis has been known as a key goal in cancer treatment for several decades in order to eradicate tumor tissue that is characterized by a loss of balance between cell proliferation and death ^[41]^[42]. The term apoptosis or programmed cell death, describes a very complex process, which includes various pathways and mechanisms (Figure 1) ^[42]^[43]. In general, it is distinguished between the intrinsic (mitochondrial-dependent) pathway and the extrinsic (receptor-dependent) pathway, both finally leading to Caspase activity and apoptosis. Programmed cell death, stimulated by the intrinsic pathway, is characterized by cytochrome c release from pro-apoptotic proteins (B-cell lymphoma 1-Bcl-1, Bcl-2-associated X protein-Bax, Bcl-2-Antagonist of Cell Death-Bad and BCL2 Antagonist/Killer 1-Bak)-stimulated mitochondria from the intermembrane space into the cytosol, subsequently forming the apoptosome complex together with Caspase-9, eventually leading to apoptosis. The extrinsic pathway on the other hand is stimulated by cell membrane death receptors such as Tumor necrosis factor receptor (TNF-R) binding to natural ligands, whereby initiator Caspase-8 is induced, which promotes cleavage of further downstream caspases, finally inducing apoptosis ^[41]^[42]^[44]^[45]. Moreover, receptor-ligand binding induces several cellular responses, including the activation of NF-κB, which can activate pro-apoptotic proteins depending on the cellular context ^[44]^[45]. However, the two main apoptotic pathways must not be considered separately, since previous research showed that they are linked with each other and metabolites of one pathway can have an impact on the other ^[45].

Figure 1. Schematic diagram showing the mechanisms of apoptosis triggered by bacterial peptides in cancer cells. (A) Bacterial toxins, secreted by various bacterial strains can cause apoptosis via the mitochondria-dependent pathway by causing cell injury, for example, by cell membrane pore formation. Induction of the intrinsic pathway leads to activation of pro-apoptotic proteins (Bcl-1, Bad, Bax, Bak), which in turn stimulates the release of cytochrome c molecules from the mitochondrial intermembrane space into the cytosol. Cytochrome c, together with Caspase-9 forms a complex called the “apoptosome”, finally stimulating executioner caspases (e.g., Caspase-3) leading to cancer cell apoptosis. (B) Bacterial proteins and peptides can have a modulatory impact on cytokines such as TNF-α, resulting in activation or blockage of NF-κB. With suppression of NF-κB, which stimulates anti-apoptotic proteins Bcl-2 and Bcl-xL, which in turn regulates apoptosis by blocking cytochrome c release, pro-apoptotic Bax and Bak-proteins remain stimulated and apoptosis is induced. (C) Besides stimulating the intrinsic pathway of apoptosis, probiotics are capable of apoptosis induction through stimulation of the extrinsic receptor-dependent pathway. Here, so called cell death receptors, such as TNF-R, bind to natural ligands, whereby initiator Caspase-8 and -10 are activated to cleave further downstream caspases, such as Caspase-3, which in turn induces cell apoptosis ^[41]^[42]^[43]^[44]^[45].

Altogether, to make use of these mechanisms such as bacteria-induced apoptosis and metastasis suppression and to establish efficient therapy methods within using bacteria, it is important to meet several framework conditions such as maximum cytotoxicity against cancer cells with minimum cytotoxicity towards intact cell tissue and the ability to selectively attack carcinomas ^[20]^[40].

3. Microbiota in CRC

3.1. Influence of Microbiota on Drug Metabolism

With a bacteria-to-cell ratio of roughly 1:1 in the human body, microbes encode for 150 times more genes than the human genome ^[19]. The discovery of microbiota-specific metabolic signatures contributes to a better knowledge of the relation between bacteria and human cells and several studies have demonstrated that microbiota-dependent metabolites have a great impact on the immune function, therefore better understanding could aid in the prediction of drug effects and outcomes in their application.

Han and colleagues used a library of 833 metabolites to describe the metabolic identities of 178 gut bacteria with mass spectrometry and a machine learning workflow by using murine serum, urine, feces and caecal contents ^[46]^[47]. In this study, they could precisely map genes according to bacteria’s metabolism and their phenotypic variation as well as associate metabolites with microbial strains. For example, Firmicutes and Actinobacteria, which are two phylogenetically distant strains were found to produce high levels of ornithine, which is important for the regulation of several metabolic processes, whereas Enterococcus faecalis and Enterococcus faecium were demonstrated to accumulate high levels of tyramine that is known to modulate neurological functions. On the other hand, C. cadaveris has been shown to act as a consumer instead of a producer and to consume high levels of vitamin B5 that is linked to inflammatory bowel diseases ^[46]^[48]^[49].

These observations highlight the great potential of better knowledge about microbiota-dependent metabolites in drug therapy, because orally delivered chemicals are mainly absorbed in the gut and therefore represents the site where the majority of metabolic changes of medication takes place ^[47].

Because medications have a significant impact on microbiota composition and balance, it is critical to bring up the interacting relationship between drug components and the microbiome ^[50]. Anti-diabetics, proton pump inhibitors ^[50] and nonsteroidal anti-inflammatory medications are all representations of drug-induced toxicity on microorganisms ^[33]. However, bacteria have also been discovered to have the ability to digest medicines. In a previous study, Maier et al. applied 1197 medicines from various therapeutic classes to 40 distinct bacteria species, excluding antibiotics, in an attempt to widely and thoroughly address these effects ^[50]. The researchers found that almost 30% of the substances examined hindered the proliferation of at least one bacterial species, therefore they hypothesized that antibiotic resistance may also arise as a result of changes in the microbiota caused by non-antibiotic exposure ^[50]. Genetic screens, and enzymatic analysis to find enzymes promoting specific drug conversions, have been used to investigate the reasons and effects of drug-microbiota interactions ^[51]. Recently, the metabolism of gut microbiota has gained more attention since it may explain why individuals suffering from the same disease and undergo the same treatment, show different therapeutical outcomes. Moreover, it shows the complex and challenging task to find an efficient treatment strategy for every individual. In order to find appropriate drugs for every patient, machine-learning frameworks using network-based analyses and data to identify drug biomarkers predicting drug responses increasingly take place ^[52]. With machine learning models and artificial intelligence, individual-specific cancer therapy can be developed to help improve therapeutic outcomes ^[52]^[53]. Furthermore, identifying hazardous by-products of bacterial medication aids in the prediction of potential adverse effects in patients undergoing therapy. With the wide spectrum of impacts of bacteria-induced chemical metabolism, such as pharmacological activation ^[54], inactivation ^[55] or toxicity ^[51], pinpointing the bacteria or their characteristics causing a specific metabolic effect is currently one of the most challenging aspects of treatments. For example by influencing the TNF response or ROS production ^[56], metabolic processes of glucuronidation conjugating pharmaceuticals to glucuronic acid (GlcA) in the liver, inactivates and detoxifies medicines. These glucuronides are then taken to the gut and are eliminated from the body ^[57]. However, once in the colon, these compounds can be reactivated by gut bacterialglucuronidases (GUS) enzymes by removing the GlcA, resulting in local acute toxicity ^[58]. Furthermore, as customized medicine is becoming increasingly important, research is currently being conducted into the extent to which individual drug metabolism can be harnessed. Javdan et al. created a technique to find metabolites formed by microbiome-derived metabolism (MDM) enzymes in a series of 23 orally applied medicines in human healthy donors in order to describe metabolic interactions between microbiota and therapeutical agents ^[59]. This study included different methodologies, including microbial community cultures, small-molecule structural assay, quantitative metabolomics, metagenomics, mouse colonization and bioinformatic analysis, making it a very extensive and technically heavy approach. The authors demonstrated the efficacy of this technique in identifying MDM enzymes in a high throughput manner utilizing medicines from several groups with varying mechanisms of action ^[59]. Zimmermann et al. used a related attempt to assess the in vitro ability of 76 naturally occurring bacteria in the human gut to metabolize 271 orally administered pharmaceuticals from various groups based on their mode of action. Surprisingly, at least one of the microbes studied was shown to metabolize up to two-thirds of the medications tested ^[60]. Furthermore, a single microbe had the ability to digest up to 95 distinct medicines and they were able to discover distinct drug-metabolizing gene products that are accounting for the conversion of medicines into metabolites using metabolomics, mass spectrometry and DNA sequence analysis ^[60]. Finally, in silico techniques have been created to enable the characterization of pharmaceuticals and their metabolites by certain bacterium species ^[50] as well as the prediction of toxicity events using data on bacteria composition, drug activity and food preferences ^[61]. When it comes to medication metabolism in the human body, more evidence has pointing out the importance of gut microbiota, as bacteria and their metabolites can affect pharmacokinetics and pharmacodynamics, which is a significant finding in context to therapy.

3.2. Influence of Microbiota on Conventional CRC Therapy

In conventional CRC therapy, chemotherapeutic agents and radiation are used and, due to their insufficiency, co-treatment with supplements, phytopharmaceuticals or feces transplantation, with its influence on the microbiome, are becoming increasingly interesting. Chemotherapeutics have been utilized for decades to treat a variety of human tumors and still represent typical first-line treatment for CRC ^[62], but are also used in combination with fluoropyrimidine-based substances and oxaliplatin as well as irinotecan ^[63] at the advanced, non-resectable CRC stage. Nonetheless, a substantial number of patients are likely to experience treatment-related morbidity and mortality due to these medications ^[62]. Given that CRC develops in close neighborhood to gut bacteria, new research has focused on how the gut microbiota influences the efficacy and toxicity of existing chemotherapeutic treatments ^[56]. Traditional CRC medicines such as irinotecan, 5-FU and cyclophosphamide have been demonstrated to alter the microbiome diversity of mice in pre-clinical models as well as in human patients. However, it is still unclear how this affects the prognosis, as some research revealed conflicting results when it comes to the role of microbiota in therapy. For example, in an animal experiment, germ-free mice were much more resistant ^[64] to powerful anti-cancer agent irinotecan ^[65] and had a higher lethal dose than holoxenic mice ^[64]. This could be due to the development of metabolites that are harmful to drugs as a consequence of bacterial metabolism. The authors have not thoroughly investigated the ultimate cause of death of these mice and did not identify the crucial bacterial species that accounted for this phenomenon. However, interestingly, irinotecan’s major side effect of diarrhea correlating with intestinal damage was very rarely observed in germ-free mice compared to holoxenic animals ^[64], while irinotecan-treated patients often show severe diarrhea as a side effect. In their liver, irinotecan is converted to its active form, human topoisomerase I poison SN-38, and then inhibited by DP-glucuronosyltransferases by adding GlcA (SN-38-G) ^[66]. This inactive compound is revived by GUS in the colon, resulting in acute poisoning. Jariwala et al. discovered the GUS enzymes responsible for SN-38 reactivation in the human gut using a combination of proteomics and bioinformatic analysis on human feces samples under the consideration that SN-38 is a harmful metabolite of irinotecan ^[58]. Meanwhile, it is known that removing GlcA from SN38-G causes SN38 reactivation, leading to the described disadvantages for the patients. Inhibition of the GUS enzyme synthesis thereby minimizes intestinal damage and maintains irinotecan’s anti-cancer activity ^[66]. These findings imply that the presence of some bacteria is responsible for an increase in treatment-associated adverse effects leading to the assumption that gut microbiome can influence therapeutic efficacy. Surprisingly, bacteria appear to have a dual function in cancer treatment, with studies reporting a synergistic impact of microbiota and therapeutic efficacy, while some others demonstrate the presence of bacteria as an barrier for the efficacy of drug ^[63]. With regard to diseases of the digestive organs, research is constantly being conducted into the potential effects of nutritional supplements. More than a decade ago, it was shown that supplementing a high-inulin or oligofructose diet inhibited the growth of a transplantable tumor in a mouse model. Inulin and oligofructose are fructans that have been found to increase Bifidobacteria proliferation in the stomach. The inclusion of these supplements to the animals’ food increased the efficacy of six different chemotherapy medicines, namely 5-FU, doxorubicine, vincristine, cyclophosphamide, methotrexate as well as cytarabine, implying a prebiotic impact of inulin and oligofructose ^[67]. An auspicious approach is offered by phytopharmaceuticals, safe secondary plant compounds with numerous health-promoting effects ranging from anti-inflammation to tumor containment. The treatment of CRC cells with resveratrol ^[7]^[68]^[69] or the components of Curcuma longa (turmeric) curcumin ^[70] and calebin A ^[13]^[71]^[72]^[73] is particularly promising, as these substances can extensively modulate tumor processes. In in vivo-like models, it was shown that all of the three phytopharmaceuticals mentioned above enhance the effect of the cytostatic drug 5-FU ^[73], and since they alter not only the CRC cells but also the immediate environment as part of their anti-tumor effect, it is obvious that they can also have an influence on the intestinal microbiome.

Another interesting approach is fecal microbiota transplantation (FMT), firstly introduced in 1958 for treatment of Clostridium difficile infection (CDI) ^[74]. Here, up to 80% of all CDI cases could be treated by assisting in the restoration of a beneficial microbiome in infected patients. In addition, FMT was found to be successful in a variety of other illnesses, including inflammatory bowel diseases, diabetes or even autism, thus it became a viable therapy option ^[75]. The benefits of this method were also addressed as a way to mitigate undesirable effects from radiation treatment due to its safety. For CRC treatment, radiation is utilized as a standard therapeutic strategy in conjunction with chemotherapy ^[6], where patients may have a variety of severe adverse effects, such as bone marrow and gastrointestinal damage, thus bacteria have been shown to reduce these adverse effects of radiation treatment in pre-clinical trials and, furthermore, in various pre-clinical cancer mouse models, the gut microbiota has been found to influence even the efficacy of radiation ^[76]^[77]. Furthermore, worth mentioning, it was shown that applying certain bacteria such as Lactobacillus rhamnosus to mice undergoing radiotherapy had a protective impact on the intestinal mucosa of the tested animals ^[78]. Moreover, probiotics were found to reduce radiation-induced gastrointestinal damage in cancer patients undergoing irradiation in clinical investigations such as diarrhea ^[60].

The future of cancer therapy will undoubtedly lie in the investigation of the dual function of microbiotica in medication outcomes: on the one hand, though bacteria is able to exacerbate therapy side effects as a result of their metabolism, on the other hand the existence of microorganisms is critical for the efficacy of cancer therapeutical agents ^[76]^[79], playing a special role in CRC and its treatment because of the bacteria-rich digestive organs.

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Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Mehdi Shakibaei

Anna-Lena Müller

Aranka M. Brockmueller

tahere ghotbi

Ajaikumar B. Kunnumakkara

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Update Date: 25 Apr 2022

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