Microbiome and Resistance to Chemotherapy: History
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Subjects: Oncology
Contributor:
Aneta Ševčíková
,
Nikola Izoldova
,
Viola Stevurkova
,
Barbora Kasperova
,
Michal Chovanec
,
Sona Ciernikova
,
Michal Mego

Understanding the mechanisms of resistance to therapy in human cancer cells has become a multifaceted limiting factor to achieving optimal cures in cancer patients. Besides genetic and epigenetic alterations, enhanced DNA damage repair activity, deregulation of cell death, overexpression of transmembrane transporters, and complex interactions within the tumor microenvironment, other mechanisms of cancer treatment resistance have been recently proposed. Importantly, preclinical models and clinical studies highlight the critical role of the microbiome in the efficacy of cancer treatment.

  • microbiome
  • chemotherapy
  • treatment resistance
  • microbiota modulations

1. Introduction

Recent advances in cancer treatment and clinical implementation of precision medicine have brought about improvements in both the disease-free survival and quality of life in cancer patients. However, the failure of therapy due to the induced selection of resistant cells within the tumors or unfavorable immune responses are connected with poor patient outcomes and represent a huge challenge. Different mechanisms of drug chemoresistance have been described, related to genetic alterations, DNA damage repair, epigenetic modifications, deregulation of apoptosis, autophagy, and changes in the tumor microenvironment [1]. Importantly, increasing evidence supports the role of the gut microbiome in modulating the response to anticancer therapies. Altered composition of intratumoral and gut microbiota together with other mechanisms can influence the resistance of cancer cells to administered therapy.

2. Human gut microbiome

Trillions of bacteria inhabit the human gut ecosystem and mounting research has revealed the mechanisms of how the gut microbiota influences the host in health and disease. The gut microbiome represents the collection of intestinal microorganisms including bacteria, archaea, viruses, and fungi, together with their overall genetic material. During the last 30 years, progress in sequencing methods has generated data about the composition of the healthy gut microbiome, showing Bacteroidetes, Firmicutes, and Proteobacteria are dominant bacterial phyla. Moreover, other microorganisms including archaea, eukaryotic organisms, viruses, and fungi significantly contribute to the stability and diversity of the human gut [2][3]. The comprehensive metagenomics approach provides information on how individual bacterial species can affect the host´s health [4].

The human microbiome influences the hosts´ metabolism via several intrinsic pathways and plays an important role in both shaping and modulating immune system responses. Maintaining healthy gut homeostasis is critical for the host [5] since disturbing the homeostatic crosstalk between the microbiota and the host immune system leads to severe pathological conditions. The gut is a producer of intestinal mediators which can enter the blood circulation, and affect the vital internal organs such as the brain and liver [6]. Due to its interactions with microbiota, the intestinal epithelium plays a role in the recognition of specific bacterial ligands (lipopolysaccharide, lipoproteins, flagellin) allowing the tolerance to commensal bacteria which form the intestinal symbiotic ecosystem [7][8]. Disruption of gut microbiota leads to an abnormal immune response against invasive and inflammation-inducing bacteria. The recognition of microbial pathogen-associated molecular patterns (PAMPs) from translocated bacteria allows activation of the TLR signaling pathway and triggers oxidative stress and inflammation [9][10]. In addition, gut dysbiosis is associated with the development of many intestinal disorders including Crohn's disease, antibiotic-associated diarrhea, inflammatory bowel disease, and increased risk of gastrointestinal malignancies [11][12][13][14].

Animal models, as well as clinical studies, suggest the involvement of gut microbiota in cancer initiation and progression through immune system modulation [15]. At the same time, the ability of the microbiome to potentiate the host immune response against tumors has been reported [16]. Growing evidence from preclinical and clinical findings highlights the fact that the host´s microbiome can affect the potential response to different anticancer modalities, mainly chemotherapy and immunotherapy. Recently, the link between the gut microbiome and late effects of anticancer therapies has been also proposed [17].

3. The Relationship between Microbiome and Resistance to Chemotherapy

The successful use of systemic chemotherapy dates back to the 1940s when nitrogen mustard proved to be an effective alkylating agent in the treatment of malignant lymphoma [18]. Several cytotoxic drugs that significantly improve cancer treatment and patient survival have been introduced in the last decades. However, the occurrence of adverse effects and acquired drug resistance represent the main challenges in recently administered chemotherapeutical regimens [19].  The microbiota-derived metabolic activation of some azo prodrugs has been described almost 60 years ago [20]. The gut microbiota co-develops with the host, playing a role in the interface of antitumor and carcinogenic metabolic, inflammatory and immune pathways [21]. Alexander et al., proposed the TIMER mechanism (Translocation, Immunomodulation, Metabolism, Enzymatic degradation, Reduced diversity and ecological variation), explaining the key processes by which the intestinal microbiota affects the efficacy of the chemotherapeutic agents [22]. A chronological summarization of studies dealing with the impact of the microbiome on various chemotherapeutic agents is provided in Table 1.

Table 1: The relationship between gut/intratumoral microbiome and chemotherapy. The table summarizes the major findings from preclinical and clinical studies.

Model

Type of Chemotherapy

Malignancy

Major findings

Study [Ref.]

mouse feces

cisplatin/

oxaliplatin

colon cancer

lymphoma

melanoma

The effect of antitumor agents was significantly reduced in case of tumor-bearing mice treated with antibiotics. The production of ROS by oxaliplatin was not induced in antibiotic-treated animals, disturbing the efficacy of oxaliplatin-induced DNA damage and apoptosis. The expression of proinflammatory genes was downregulated in the absence of gut microbiota.

Iida et al. 2013

[23]

mouse feces

cyclophosphamide doxorubicin

melanoma

sarcoma

The gut barrier of murine models was disrupted after cyclophosphamide treatment, leading to a higher permeability for commensal bacteria such as Lactobacillus johnsonii, Lactobacillus murinus, Enterococcus hirae, and microbiota changes within the small intestine. Antibiotic administration inhibited the effect of cyclophosphamide to cure cancer.

Viaud et al. 2013

[24]

mouse tumor

samples

gemcitabine and

bevacizumab

pancreatic cancer

Mouse model treated with chemotherapy agents revealed the beneficial effect of Salmonella typhimurium A1-R, documented by significantly decreased tumor growth compared to control samples.

Hiroshima et al. 2014

[25]

mouse tumor

samples

gemcitabine

breast carcinoma

Antitumor effect of gemcitabine was decreased in mice with Mycoplasma hyorhinis-infected murine mammary tumors in comparison with animals bearing unaffected breast tumors.

Vande et al. 2014

[26]

mouse tumor

samples

cisplatin

lung cancer

Cisplatin-treated mice receiving antibiotic cocktail reported larger tumors and reduced survival. Both parameters were improved after orogastric administration of Lactobacillus acidophilus to lung tumor-bearing mice on cisplatin treatment.

Gui et al. 2015

[27]

mouse tumor

samples

gemcitabine

CB1954

colorectal carcinoma

According to the results, intratumoral-injected Escherichia coli decreased the efficacy of gemcitabine and increased the toxicity of CB1954 in a mouse model with colorectal carcinoma.

Lehouritis et al. 2015

[28]

mouse feces

intestinal mucosa

cyclophosphamide

melanoma

sarcoma

Both Enterococcus hirae and Barnesiella intestinihominis have played an important role in antitumor effect of alkylating agents. The reduced effect of chemotherapy with cyclophosphamide in antibiotic-treated mice was compensated by oral gavage of Enterococcus hirae which led to a restoration of antitumor activity. On the other hand, Escherichia coli, Lactobacillus johnsonii, or Lactobacilli isolates failed to restore the efficacy of therapy.

Daillere et al. 2016

[29]

human/mouse intratumoral samples

gemcitabine

colon cancer

PDAC

 

The presence of Mycoplasma hyorhinis contributed to gemcitabine resistance in the colorectal cancer murine model. Microbiome analysis of tumor samples from PDAC patients revealed that the abundance of Gammaproteobacteria was correlating with the resistance to therapy.

Geller et al. 2017

[30]

human/mouse colorectal tissue

samples

oxaliplatin

5-FU

colorectal carcinoma

Patient samples showed an association between a higher amount of Fusobacterium nucleatum and the promotion of chemoresistance and reduced survival without recurrence. Similarly, the presence of Fusobacterium nucleatum eliminated the effect of oxaliplatin in a murine model treated with different doses of oxaliplatin.

Yu et. al 2017

[31]

human feces

chemotherapeutic cocktail containing

5-FU and oxaliplatin

colorectal cancer

A comprehensive analysis of microbial composition in colorectal carcinoma patients treated with chemotherapy revealed the abundance of Firmicutes and Bacteroidetes phyla. In particular, Fusobacterium, Oscillospira, and Prevotella were presented. Bacterial species Bacteroides plebeius, Veillonella dispar, and Prevotella copri were observed only in fecal samples from patients treated with a conventional chemotherapeutic cocktail.

Deng et al. 2018

[32]

mouse feces

gemcitabine

pancreatic cancer

Decreased levels of Firmicutes and Bacteroidetes and a higher abundance of Proteobacteria and Verrucomicrobia were observed in fecal samples from gemcitabine-receiving mice. At the species level, the amounts of Akkermansia muciniphila and Escherichia coli were significantly increased while the presence of Bacteroides acidifaciens was decreased compared to control samples.

Panebianco et al. 2018

[33]

human/mouse feces

variety of cytotoxic

targeted chemotherapy immunotherapy

different types of

solid tumors and

hematological malignancies

An abundance of Bacteroides ovatus, Bacteroides xylanisolvens, Prevotella copri, and Alistipes spp. in responder samples correlated with an enhanced response to the therapy. On the contrary, Clostridium symbiosum and Ruminococcus gnavus were enriched in feces from non-responders. Oral administration of Bacteroides ovatus/xylanisolvens into antibiotic pre-treated mice showed a positive impact on reduced tumor growth.

Heshiki et al. 2020

[34]

human feces

neoadjuvant chemotherapy

rectal cancer

Differences in microbiota composition have revealed that non-responder samples were enriched in bacteria belonging to the Clostridiales order while patients grouped into responders were characterized by a higher abundance of Shuttleworthia.

Shi et al. 2020

[35]

A pilot study concerning the association between the gut microbiome and therapeutic responses to neoadjuvant chemoradiotherapy (nCRT) revealed different relative abundances of several bacteria taxa before and after nCRT in rectal cancer patients. Similarly, differences in microbiota composition between responders and non-responders have been identified, showing Shuttleworthia enrichment in responders while microbiota of non-responders was characterized by a higher abundance of Clostridiales [35]. Recently, metagenomic analysis of samples from eight different cancer types described the baseline gut microbiome signatures predicting treatment outcome of cytotoxic or targeted chemotherapy, immunotherapy, or a combination of anti-cancer treatments. Based on microbial differences between responders and non-responders, a positive correlation between Bacteroides ovatus/xylanisolvens and treatment efficacy was identified by machine learning and proved by oral gavage in mice bearing lung cancer [34].

3.1 Platinum-based derivates

The antineoplastic mechanism of platinum-based chemotherapeutics (oxaliplatin and cisplatin) involves the formation of intra-stranded DNA adducts, inhibiting DNA replication, and activating mitochondrial signaling pathways that cause cell death [36]. Iida et al. reported that a group of antibiotic-treated and germ-free (GF) mice did not respond correctly to platinum derivatives, showing insufficient production of reactive oxygen species related to anti-cancer effects of selected drugs [23]. Moreover, the genes responsible for monocyte activation and differentiation were inhibited after antibiotic administration. After oxaliplatin treatment, the proinflammatory genes were reduced in GF animals, suggesting the importance of inflammation for anticancer treatment [23]. In colorectal cancer (CRC) patients, Fusobacterium nucleatum was shown to play the role in chemoresistance to oxaliplatin through the activation of the innate immune system. According to the results, induced autophagy, mediated via microRNA (miR-4802 and miR-18a*) downregulation led to „in vitro“ oxaliplatin resistance [31].

3.2 Cyclophophamide

The relationship between microbiota composition and therapeutic efficacy in cyclophosphamide (CTX)-treated murine model has been monitored [24]. Stimulation of anti-tumor immune responses through a variety of immunological pathways, supporting Th1 and Th17 cells to control cancer growth, represents the main mechanism of CTX antineoplastic effects [22][37]. As shown by Viaud et al., the alkylating agent CTX significantly altered the microbiota composition of the small intestine leading to the reduction in the abundance of bacterial species from Firmicutes phylum (Roseburia, Coprococcus, Clostridium cluster XIVa, unclassified Lachnospiraaceae) as well as lactobacilli and enterococci in mice bearing subcutaneous melanomas and sarcomas [24]. Additionally, the microbial barrier of the small intestine was more permeable to gram-positive bacteria (Lactobacillus johnsonii, Lactobacillus murinus, Enterococcus hirae) leading to their translocation from the gut into the lymphoid organs. Translocated bacteria induced the generation of pathogenic T helper 17 cells and immune response against the tumor. Importantly, antibiotic-treated mice bearing tumors were resistant to cyclophosphamide action [24]. Daillere et al. confirmed the key bacterial species involved in the immunomodulatory effects of CTX, showing the gram-negative microorganism Barnesiella intestinihominis plays an anticancer immunomodulatory role in the colon. Interestingly, CTX-mediated antitumor effects were restored by oral administration of Enterococcus hirae. This finding highlights the importance of reconstituting the optimal microbiota diversity by genera Enterococcus and Barnesiella, to optimize responses to alkylating agents [29].

3.3 Gemcitabine

Gemcitabine is a nucleoside analog used to treat metastatic pancreatic, breast, ovarian, or lung cancer [38]. A modification in the structure of chemotherapeutical drugs including gemcitabine, fludarabine, cladribine, and CB1954 by bacteria was confirmed using high-performance liquid chromatography and mass spectrometry [28]. Moreover, murine colon cancer model CT26 revealed the chemoresistance to gemcitabine and increased cytotoxicity of CB1954 after intratumoral administration of E. coli, documenting the ability of bacteria to metabolize chemotherapeutics while affecting their activity and local concentration [28][39].

Geller et al. found that Gamaproteobacteria expressing a long form of cytidine deaminase (CDD) can convert the active form of gemcitabine (2´2´-difluorodeoxycytidine) into its inactive form (2´2´-difluorodeoxyuridine) in colon cancer models [30]. Since pancreatic ductal adenocarcinoma (PDAC) responds poorly to treatment with traditional chemotherapeutic agents due to the phenomenon of intrinsic or acquired drug resistance [40], a better understanding of drug resistance mechanisms is needed. The presence of pancreatic intra-tumor Gammaproteobacteria (Enterobacteriaceae and Pseudomonadaceae families) has been detected in human PDAC samples, pointing at their potential role in treatment efficacy [30]. Moreover, antibiotic treatment with ciprofloxacin has been shown to overcome gemcitabine resistance [30][41]. The resistance to gemcitabine may also be associated with the presence of Mycoplasma hyorhinis and its ability to encode CDD and disrupt the cytostatic activity of chemotherapeutic agent [26]. Elevated levels of oral pathogens Agregatibacter actinomycetemcomitans and Porphyromonas gingivalis, which may affect resistance to chemotherapy by expressing CDD, have also been observed in patients with pancreatic cancer [42]. This observation suggests the ability of bacteria from other tissues to affect the resistance to and efficacy of chemotherapy [43].

In 2018, Panebianco et al. noted a reduction in tumor volume (approximately 35%) at the end of gemcitabine therapy along with the changes in bacterial composition in applied mouse models. Gemcitabine treatment significantly reduced the proportion of the two dominant phyla - Firmicutes (Lachnospiraceae, Ruminococcaceae, Erysipelatoclostridium) and Bacteroidetes (Bacteroidales, Alistipes) from 39 to 17% and from 38 to 17%, respectively. In contrast, the bacterial composition shifted in favor of two phyla which are generally minor constituents of the intestinal microbiota - Proteobacteria (Escherichia coli, Aeromonas hydrophila) and Verrucomicrobia (Akkermansia muciniphila) from 15 to 32% and from 5 to 33%, respectively [33]. Ganesh et al. reported that Akkermansia muciniphila exacerbated intestinal inflammation due to its mucolytic activity [44], which could have a negative effect on gemcitabine-treated mice. According to the previous findings, the overgrowth of proteobacteria was associated with intestinal inflammation and the decrease of bacteria from the phyla Firmicutes and Bacteroidetes was associated with intestinal pathology [45][46][47]. Moreover, gemcitabine-treated mice reported an increased incidence of the infectious organism Peptoclostridium difficile compared to untreated animals [33]. As reported in previous studies, overgrowth of Peptoclostridium difficile with Enterobacteriaceae is a common consequence of chemotherapy [48][49]. Interestingly, a mouse model of pancreatic cancer treated with gemcitabine and bevacizumab suggested a clinical potential for Salmonella typhimurium since its positive effect on changes in tumor size leading to tumor shrinkage [25].

3.4 Fluoropyrimidine analogs and anthracyclines

The enrichment of Fusobacterium nucleatum, a well-known pathogenic bacterium [50][51], was observed in stool samples from colorectal adenoma and carcinoma patients compared to healthy controls [52]. Mima et al. showed that relative abundance of Fusobacterium nucleatum was associated with worse clinical outcomes in CRC patients [53]. In addition, the relationship between Fusobacterium nucleatum together with certain bacterial taxa including the genus Sutterella and species Veillonella dispar, and the resistance to a chemotherapeutic cocktail containing tegafur (a prodrug of 5-fluorouracil, 5-FU) and oxaliplatin was detected in CRC patients [32]. More recently, in addition, Fusobacterium was reported to be responsible for chemoresistance to 5-FU and oxaliplatin in patients with CRC via activation of the innate immune system [31]. F. nucleatum plays an important role in the colon cancer microenvironment since interaction with the immune cells leads to an increase in tumor-associated neutrophils, dendritic cells, and pro-cancer M2 macrophages, and inhibition of the cytotoxicity of T and NK cells represses the host immune responses [54].

According to the findings, a few bacterial species play a role in the metabolism of anthracyclines, and the ability of Streptomyces WAC04685 and Raoultella planticola to inactivate doxorubicin by deglycosylation mechanism has been described [55][56].

Conclusions and future directions

Mounting evidence from preclinical and clinical studies highlights the crucial role of microbiota not only in cancer initiation and progression but also in the efficacy of anticancer therapies, mainly chemo- and immunotherapy. Still, limited data are available and the microbiome is very likely to have a more significant impact on treatment than expected. The identification of specific bacterial taxa which represent microbial biomarkers linked with enhanced responses to cancer treatment is the key for the development of microbial-based and microbial-targeted therapies. Comprehensive research aiming at a deep understanding represents a big challenge and can bring benefits for non-responding patients. In the era of precision medicine, evaluation of patients´ gut dysbiosis followed by microbiota modulation-related approaches may provide an emerging trend for optimizing the responses to anticancer therapies and improving outcomes for cancer patients.

The research was funded by the Slovak Research and Development Agency (APVV), grant number APVV-19-0411 and APVV-20-0158, and by the Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences (VEGA), contract No. 1/0327/19 and 2/0069/22. 

This entry is adapted from the peer-reviewed paper 10.3390/ijms23010488

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