Who would have thought not long ago that the gut microbiota would have a bearing on the clinical course of cancer or patient response to cancer therapy? Evidence has emerged to link the seemingly disparate processes of microbial signaling from the gut, immune and metabolic cascades, and the host response to cancer therapy. Indeed, the gut microbiome may become a prognostic readout, part of the investigative assessment and staging of patients in advance of initiating cancer treatment.
The microbiome refers to the collective genomes of bacteria, viruses, and fungi resident within and on the body. It is linked with the host response and, in turn, with sensitivity to chemotherapeutic agents. Previously, the relationship between microbes and cancer was recognized as a cause-and-effect relationship (1), with 17% of cancers worldwide causally linked with microorganisms (2) such as Helicobacter pylori (3) Epstein–Barr virus, hepatitis B and C, human papillomavirus, and HIV type 1 (4). The relationship between microbes and cancer is now known to be more subtle and complex, but full of therapeutic potential.
The microbiome varies with diet, lifestyle, and environmental factors (5). A change in microbiota has been implicated in cancer initiation (6) and progression at both an epithelial level and in the tumor microenvironment (7,8) through host immune system modulation (9). Microbiome manipulation to increase the efficacy and decrease the toxicity of cancer therapy may become an integral part of future cancer treatment regimens. Here, we present an overview of emerging evidence for the role of the microbiome in cancer therapy.
MICROBIAL MODIFICATION OF CHEMOTHERAPEUTIC AGENTS
Several striking discoveries have alerted oncologists to the influence of the microbiome on a patient's response to chemotherapy at both gut and tumor levels (8,10). Drugs and other xenobiotics can be transformed into metabolites by the gut microbiota, often by enzymatic alteration (11), altering the bioavailability and chemical structure of the substance and its effect on host physiology (12). This may have significant clinical implications in cancer treatment. However, large human studies are yet to be completed.
The following examples illustrate the complexity of relationships between the microbiome, the immune system, and the action of chemotherapeutic agents. First, Parabacteroides distasonis is a Gram-negative Bacteroidetes present in the normal distal human gut that is reported to mediate anti-inflammatory effects and T-cell regulation in the colon (13). Outgrowth of P. distasonis can occasionally occur in antibiotic-treated mice, which was noted to lead to decreased efficacy of doxorubicin (10). Subsequent inoculation of antibiotic-sterilized mice with P. distasonis produced the same drug failure (10). Second, some tumors are resistant to treatment with cisplatin, oxaliplatin, and cyclophosphamide in the absence of microbes such as in germ-free or antibiotic-treated mice (8,10). Finally, in murine models, cyclophosphamide induces translocation of Lactobacillus jonsonii (10) and Enterococcus hirae (14) from the gut into lymphoid organs, stimulating “pathogenic” T helper 17 (pTH17) cells and memory TH1 immune response. Barnesiella intestinihominis also accumulates in the colon during cyclophosphamide treatment, upregulating IFN-γ-producing cells in tumors (14). Transfer of pTH17 cells into germ-free mice partially restores drug efficacy (10). The presence of TH1 cells specific to E. hirae and B. intestinihominis is associated with longer progression-free survival in patients with lung and ovarian cancer (14).
MICROBIAL MODIFICATION OF RESPONSE TO IMMUNOTHERAPY
In certain cancers such as melanoma, renal cell carcinoma, and some lymphomas, cancer tissue develops immune resistance by upregulating production of immune checkpoint molecules such as programmed cell death 1 (PD-1) ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (15). This inhibits apoptosis of tumor cells and promotes peripheral T effector cell ineffectiveness (16). A series of monoclonal antibodies have been developed that are directed against T-cell ligands and that function therapeutically to enhance adaptive immune cell function against tumor cells (17). Examples of these immunotherapies include ipilimumab, an antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (18), pembrolizumab and nivolumab, which block PD-1 (19), and atezolizumab, a PD-L1-targeted monoclonal antibody (19), all of which are licensed to treat an expanding range of malignancies. Treatment is often complicated by immune-mediated side effects such as enterocolitis (20) that have microbiome linkages. Currently, 20%–30% of treated patients benefit from these therapies (21).
The microbiome influences the efficacy of immunotherapy (22). Proliferation of tumor-specific cytotoxic T cells in mice is enhanced by translocation of the gut microbiota into mesenteric lymph nodes, which occurs with reduced efficacy in antibiotic-treated mice (23). Similarly, antibiotic-treated or germ-free mice treated with CpG-oligonucleotide immunotherapy had reduced cytokine production and decreased tumor necrosis, suggesting that an intact microbiota was required to control myeloid-derived cellular functions in the tumor microenvironment (8).
No single microbe has yet been identified as universally important for immunotherapy efficacy or prevention of side effects. In patients treated with anti-PD-1 immunotherapy, treatment responders had an abundance of Bifidobacterium longum, Enterococcus faecium, and Collinsella aerofaciens (24). In mice treated with CpG-oligonucleotide, Ruminococcus and Alistipes enhanced the response to immunotherapy, while a Lactobacillus-predominant microbiota impaired the response (8). In murine studies, T-cell responses specific to Bacteroides species were associated with the efficacy of CTLA-4 blockade (25). Tumors in germ-free or antibiotic-treated mice did not respond adequately to CTLA-4 immunotherapy. Reintroduction of Bacteroides fragilis or Bacteroides thetaiotaomicron led to restored efficacy of immunotherapy in these mice. Supplementary feeding with B. fragilis and Burkholderia cepacia also reduced rates of immune-mediated colitis (25). Similarly, in patients treated with ipilimumab, the increased abundance of members of the Bacteroidetes phylum correlated with the resistance to colitis (26,27). Conversely, in a small study of ipilimumab-treated patients, the Faecalibacterium genus and other Firmicutes were associated with a longer progression-free survival and overall survival, but patients had a higher occurrence rate of colitis (27).
External environmental and lifestyle factors that alter an individual's microbiome, such as diet, antibiotic exposure, and socioeconomic development (5), should be considered when interpreting findings of immunotherapy studies. In experimental mice with melanoma, animals from 2 separate breeding facilities had different microbiotas, which resulted in differences in spontaneous tumor immunity and melanoma growth (28). Differences were eliminated by cohousing or fecal microbiota transplant (FMT) between mice. In the same study, the Bifidobacterium genus was associated with antitumor effects by enhanced CD8+ T-cell priming and accumulation in the tumor microenvironment. Moreover, administration of a bifidobacterium probiotic improved tumor control to the same extent as PD-L1 checkpoint immunotherapy with combination therapy almost completely halting melanoma growth (28). A correlation between an abundance of Akkermansia muciniphila and clinical response in non-small cell lung cancer and renal cell carcinoma was reported in a cohort of patients receiving PD-1/PD-L1 immunotherapy (29). Oral supplementation of A. muciniphila in mice treated by FMT from nonresponsive patients restored efficacy of PD-1 immunotherapy (29). Immunotherapy-responsive melanoma patients in a separate cohort had a higher abundance of Ruminococcaceae and Clostridiales bacteria (30). Increased microbiota alpha diversity (intraindividual diversity of microbes) correlated with improved clinical response in both groups (29,30).
MICROBIOME AND TOXICITY OF CHEMOTHERAPEUTICS
Chemotherapy toxicity requires dose reduction or dose delays and adversely affects clinical outcome. Gastrointestinal toxicity causes mucositis, increasing the risk of bacteremia, mycethemia, sepsis, and overall mortality (31). The incidence of a blood infection is 21% post-stem cell transplant, with a total attributable mortality of 3.3% (32).
Traditionally, mucositis was thought to lead to bacterial translocation and sepsis through mucosal damage and ulceration (33). Some chemotherapeutic agents such as cisplatin and oxaliplatin are directly toxic to intestinal mucosal cells (31). It is now known that the microbiota also contributes to mucosal inflammation by altering intestinal permeability and manipulation of immune effector molecules (34). In mice treated with doxorubicin, jejunal apoptosis was noted in both germ-free and control mice (35). However, statistically significant changes in crypt depth, and number and expansion of Paneth and goblet cells occurred, but only in the mice with an intact microbiota (35).
Mucositis is a common side effect of irinotecan chemotherapy used for treating colorectal cancer. The exact pathogenesis of irinotecan-induced mucositis is ill-defined but may involve interleukin-1/Toll-like receptor family members involved in epithelial cell apoptosis (36). A functional change in microbiota may also contribute to mucositis as supplementation with fiber in rats induced microbial production of butyrate, which decreased irinotecan-induced mucositis (37). Intravenous irinotecan prodrug is metabolized in the liver to its active drug form (7-ethyl-10-hydroxycamptothecin (SN-38)) (Figure 1). SN-38 is inactivated by the liver by glucuronidation to SN-38G and excreted into the small intestine. Here, it is reactivated by bacterial β-glucuronidases expressed by the host microbiota, which convert SN-38G to SN-38, the bioactive form of irinotecan, thereby causing toxicity, mucosal damage, and diarrhea (38). In murine models, selective disruption of bacterial β-glucuronidases diminishes this damage (39), without altering serum pharmacokinetics of irinotecan or its metabolites (40). However, a randomized controlled trial evaluating cotreatment of irinotecan with neomycin, which is known to decrease β-glucuronidase-producing bacteria, showed limited efficacy in reducing diarrhea (41).
MICROBIOTA DIVERSITY AND CANCER OUTCOMES
A change in gut microbiota may arise from the cancer state (42) or from its treatment with chemoradiotherapy and/or intercurrent antimicrobial therapy (43). Microbiota α-diversity is an independent risk factor for survival post-hematopoietic stem cell transplant (HSCT) (44) with a lower diversity also being linked to a higher infection risk (45) and greater side effects of treatment (46). Similarly, in patients treated with PD-1 immunotherapy, greater richness of the microbiota correlated with improved clinical response to treatment (29,30).
Chemotherapy may disturb microbial metabolism, resulting in a reduced capacity for energy metabolism, xenobiotic degradation, and metabolism of nucleotides, cofactors, and vitamins (47). Certain chemotherapeutic drugs such as 5-flurorouracil also seem to exhibit antibacterial effects on the gut microbes in vitro (48). Chemotherapy also reduces α-diversity (49). Irinotecan decreases fecal microbiota diversity in rat models independent of other factors (50). Baseline stool microbiota diversity is significantly lower in patients who develop infections during induction chemotherapy (51) with microbial diversity decreasing throughout the treatment process, leading to potential colonization of pathogens (52). There may be temporal instability of microbial diversity during chemotherapy treatment with increased variability at different time points seen in patients with acute myeloid leukemia, correlating with adverse clinical outcomes (53). The impact on microbial diversity and treatment outcomes in oncology needs more detailed exploration taking into account the potentially confounding effects of antibiotic administration, diet, exercise, and host polymorphisms (54).
Hematopoietic stem cell transplant is used primarily to treat hematologic and lymphoid cancers (55). It alters gut microbiota causing decreasing diversity as treatment progresses (56), with a microbial recovery period of up to 100 days post-transplant (57). Patients with a pre-HSCT high diversity microbiota had an overall 3-year survival of 67% vs 36% in the low-diversity group. In prechemotherapy fecal samples, low diversity and decreased taxa were associated with a higher level of bacteremia post-stem cell transplant (45).
Major complications of HSCT such as graft-versus-host disease (GVHD), mucositis, and infections and relapse are linked to loss of microbiota diversity. In GVHD, donor-derived T cells are recognized as foreign by the host immune system, leading to an autoimmune-like attack on organs such as the liver, lungs, thymus, and gut (58). There is loss of microbial diversity in both murine models and humans who develop GVHD (46). Paneth cells targeted in GVHD decrease the expression of α-defensins, which, in mice, led to reduced microbiota diversity and outgrowth of pathogenic bacteria causing sepsis (59). Eliminating Lactobacillales in mice prior to HSCT aggravated GVHD, whereas reintroduction of Lactobacillus as the predominant genus protected against and alleviated GVHD (46).
ANTIMICROBIALS AND CANCER THERAPY
Antibiotics can be lifesaving in severe neutropenic sepsis, but also can significantly affect microbial diversity, efficacy of treatment, future infection risk, and ultimately survival in patients with cancer.
Antimicrobial therapy rapidly and sometimes persistently alters the taxonomic, genomic, and functional capacity of the gut microbiota (60,61). The combination of microbiota disruption and impairment of host immunity may enhance the infection risk in immunosuppressed patients (56). Broad-spectrum antibiotic treatment (carbapenem) during induction chemotherapy significantly lowers α-diversity, making patients vulnerable to infection within the 90-day neutrophil recovery period (51). In contrast, a large randomized controlled trial showed that rates of fever and infections were lower in neutropenic patients prophylactically treated with a fluoroquinolone (62), suggesting that specific antibiotics may be of benefit.
There is intriguing evidence to suggest that antimicrobial therapy may also alter the clinical course of cancer, appearing to influence cancer development, progression, and response to treatment. Prechemotherapy analysis of tumor gene expression in antibiotic-treated mice inoculated with tumors demonstrated upregulation of genes in relation to cancer development and metabolism and downregulation of genes related to immune therapy, inflammation, and phagocytosis (8). Patients with chronic lymphocytic leukemia cotreated with cisplatin, cyclophosphamide, and antibiotics were found to have a shorter progression-free survival and overall survival independent of other factors (63). Mice with lung cancer treated with cisplatin and broad-spectrum antibiotics also had a significant reduction in survival rate (64).
Antibiotics are also an independent risk factor for resistance to anti-PD-1/PD-L1 immune checkpoint inhibitors, with overall survival and progression-free survival significantly lower in patients with antibiotic exposure (29). Fecal microbiota transplant from treatment-responsive patients to germ-free or antibiotic-treated mice restored the efficacy of treatment (29).
Treatment with antibiotics during HSCT is thought to be the main modifier of microbiota during the transplant process (58). Gut “decontamination” with antibiotics was used for 3 decades, but there is now controversy regarding antibiotic use (65). A large retrospective study demonstrated an overall lower median survival and higher risk of acute severe GVHD in patients receiving antibiotics for gut decontamination (66). In patients post-HSCT, treating neutropenic sepsis with piperacillin–tazobactam and imipenem–cilastatin antibiotics was associated with an increased GVHD-related 5-year mortality (67). Studies in murine models found that imipenem–cilastatin treatment caused compromise of the intestinal barrier due to loss of protective mucous (67).
Patients with cancer are often treated with broad-spectrum antibiotics, usually empirically, as an adjunct to cancer therapy (43). This has contributed to antimicrobial resistance after chemotherapy, with 27% of infection-causing pathogens being resistant to standard antibiotic regimens in the United States (68). The increase in prevalence of carbapenem-resistant Enterobacteriaceae (CRE) and carbapenemase-producing Enterobacteriaceae as a consequence of overuse of antibiotics is a major public health concern, particularly in immunocompromised patients such as cancer patients (69), due to limited antimicrobial effectiveness in treatment (70). The main risk of intestinal colonization with CRE or carbapenemase-producing Enterobacteriaceae is transition from a carrier state to systemic infection (Figure 2) (71). In an intensive care unit cohort, CRE colonization independently increased 90-day mortality (71). Carriage of multidrug-resistant organisms is increasing in patients with cancer (72), highlighting an indirect way that antimicrobial therapy could alter clinical course in cancer patients by limiting treatment options in the event of sepsis. Fecal microbiota transplant may represent a treatment strategy for decolonization of drug-resistant bacteria in this patient cohort in the future, as post-FMT for recurrent C. difficile infection fecal diversity of recipients increases and resembles the composition of the donor (73). With such important negative outcomes from overtreatment with antibiotics evident, more targeted, personalized antimicrobial strategies will need to be used in the cancer population.
MICROBIOME AS A BIOMARKER OF RISK OF GASTROINTESTINAL CANCER
Microbiome assessment may become a key method of cancer risk prediction in the future. H. pylori in the stomach is an established risk factor for the development of gastric carcinoma (3,74). Similarly, evidence supports microbiome analysis to predict risk of other gastrointestinal cancers. The microbiota profiles in patients with colorectal cancer are distinctly different from healthy controls (75,76) and individuals with polyps (75). These compositional differences often consist of an abundance of oral bacteria on the lesion and throughout the colon (75,77), with similar networks of oral-based bacteria found on the gut mucosa and oral mucosa (77). Combining standard fecal immunochemical testing with microbiota analysis improves the detection of colonic lesions (78). A classification model of an oral swab combined with a fecal microbiota sample has a specificity of 96% with a sensitivity of 76% for detection of colorectal cancer and 88% for polyp detection (77). The association of a microbial change linked with a known risk factor for cancer (polyps) raises the intriguing potential of using the microbiota to identify a subset of patients at increased risk of cancer long before the usual age of conventional screening and at a time when microbiota manipulation could possibly be used as a preventive strategy.
MANIPULATION OF FECAL MICROBIOTA AS AN ADJUNCT TO CANCER TREATMENT
The emerging evidence for the role of the microbiota in influencing the risk, clinical course, and treatment of several cancers raises the prospect of manipulation of the microbiota as a preventive or therapeutic adjunct. Manipulation of the microbiota may involve supplements with single organisms (probiotics or live biotherapeutics), alone or in combination, the use of dietary modifiers of microbial composition, or whole microbial transplantation (Figure 3). A systematic review of probiotic use in pelvic and abdominal cancer patients with chemotherapy-induced diarrhea concluded that probiotics are generally safe and are potentially effective in reducing treatment-related diarrhea (79). Lactobacillus casei or Lactobacillus acidophilus and Bifidobacterium bifidum probiotics downregulated inflammatory cascades and ameliorated clinically significant diarrhea in mice with 5-fluorouracil-induced mucositis (80). Mice cotreated with L. acidophilus and cisplatin also had improved survival rates (64). Similarly, mice supplemented with Lactobacillus rhamnosus before and after HSCT were found to have higher overall survival and decreased acute GVHD vs controls (81). A recent small pilot study of 4 FMTs post-HSCT with steroid refractory GVHD is promising with 75% of patients showing resolution of GVHD (61). Preliminary work in mouse models has also shown promising results in increasing the efficacy of immunotherapy in poor responders or germ-free mice via microbiota manipulation by oral supplementation (25) or FMT from human drug responders (24,29,30). While preliminary studies in the area are encouraging (82), most studies are in murine models and may not accurately reflect the human microbiome or physiological responses. Robust, adequately powered clinical trials in patients with cancer are required to evaluate the efficacy and best method of microbiome manipulation as an adjunct to chemotherapeutic treatment, with some relevant trials currently ongoing (83–85).
The microbiota is now an important consideration in oncology. Microbial signaling from the gut acts at various levels to influence the clinical course of established tumors, bioavailability, efficacy, and toxicity of therapeutic strategies and in some instances modifies the risk of cancer development. While most studies have been preclinical, translation of microbiome science to human cancer prevention and treatment is emerging. As microbial diversity influences many aspects of cancer treatment, attention needs to switch from empirical antimicrobial usage to maintenance of a diverse microbiota. Microbiota manipulation by transplantation, live biotherapeutics, and other strategies promises to become an integral part of cancer treatment.
CONFLICTS OF INTEREST
Guarantor of the article: Clodagh Murphy, MD.
Specific author contributions: All authors contributed to the content of this manuscript.
Financial support: The authors are funded in part by Science Foundation Ireland (APC/SFI/12/RC/2273) in the form of a research center, APC Microbiome Ireland.
Potential competing interests: F.S. is a cofounder, shareholder in Atlantia Food Clinical Trials, 4D Pharma Cork, Alimentary Health. He is the director of APC Microbiome Ireland, a research center funded in part by Science Foundation Ireland (APC/SFI/12/RC/2273) and which has recently been in receipt of research grants from AbbVie, Alimentary Health, Cremo, Danone, Janssen, FrieslandCampina, General Mills, Kerry, Mead Johnson, Nutricia, 4D Pharma and Second Genome, and Sigmoid Pharma. P.W.O.T. is a cofounder of 4D Pharma Cork.
We thank all investigators who have made significant contributions to this field including those whose work we are unable to cite due to space limitations, which we regret.
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