INTRODUCTION
Microbes appeared on Earth around 4 billion years ago, marking a critical point in the planet's history as it signifies the beginnings of life due to their role in oxygen production. It is well known that nowadays, microorganisms are ubiquitous, inhabiting diverse environments, including the human organism. In the continuing narrative of cancer treatment, a burgeoning field is emerging, shedding light on a potent ally inherent within our body: The gut microbiome. The article entitled "Bringing gut microbiota into the spotlight of clinical research and medical practice", authored by Davoutis et al[1] establishes a foundational comprehension of the crucial role the gut microbiota assumes in both clinical research and medical practice. The current editorial endeavors to further explore the insights provided by the article, elucidating how the gut microbiome possesses significant potential in reshaping cancer treatment outcomes and revolutionizing oncology practice.
GUT MICROBIOME: A HIDDEN PLAYER IN CANCER PATHOGENESIS
The symbiotic relationship between higher organisms and their commensal gut microbiota plays a crucial role in governing various aspects of human health, including but not limited to nutrition regulation, metabolic processes, homeostasis maintenance, developmental stages, and the functionality of both innate and adaptive immune responses[2-4]. Furthermore, this interaction exerts influence over inflammatory processes, albeit to a lesser degree, and contributes to the modulation of morphogenesis[4]. These multifaceted roles underscore the intricate interplay between the gut microbiome and human physiology.
Dysbiosis, an imbalance in the gut microbial community, has emerged as a hallmark of cancer pathogenesis, impacting tumor initiation, progression, and response to therapy[5]. Through intricate interactions with the host immune system and systemic physiology, the gut microbiome influences key hallmarks of cancer, including inflammation, immune evasion, and angiogenesis[6]. The article by Davoutis et al[1], underscores the significance of unraveling the complex interplay between the gut microbiome and cancer biology, shedding light on novel therapeutic avenues for combating malignancies.
Recent studies have highlighted the role of specific bacterial species in promoting or inhibiting tumor growth[7]. For instance, certain members of the Firmicutes phylum, such as Faecalibacterium and Clostridiales, have been associated with anti-tumorigenic effects, while others, like Fusobacterium spp. and Bacteroides fragilis, have been implicated in promoting tumor development[8,9].
MICROBIOME-MEDIATED EFFECTS ON CANCER THERAPY
One of the most compelling aspects highlighted in the article is the microbiome's influence on cancer therapy outcomes. By modulating the tumor microenvironment and systemic immune responses, the gut microbiome exerts profound effects on the efficacy and toxicity of conventional treatments such as chemotherapy and radiation therapy[7,10,11]. Moreover, emerging evidence suggests that the gut microbiome plays a pivotal role in shaping responses to cutting-edge immunotherapies, including immune checkpoint inhibitors and adoptive cell therapies[12]. Understanding the mechanisms underlying these microbiome-mediated effects is crucial for optimizing treatment strategies and personalizing cancer care.
Recent preclinical and clinical studies have provided compelling evidence supporting the role of the gut microbiome in modulating responses to immunotherapy. Routy et al[12], found that the gut microbiome composition predicts the response to PD-1 blockade in patients with advanced solid tumors, suggesting that microbiome-based biomarkers could guide patient selection and treatment strategies in the era of precision oncology. Similarly, Gopalakrishnan et al[13], demonstrated that the gut microbiome influences the efficacy of immune checkpoint inhibitors in melanoma patients, with specific bacterial taxa associated with enhanced anti-tumor immune responses and improved clinical outcomes.
It is noteworthy to mention that gut microbiome influences not only the efficacy of immunotherapy but also the efficacy and toxicity of other treatments, such as chemotherapy[14]. Recent research has elucidated how specific gut microbial communities can influence the effectiveness of chemotherapy drugs and mitigate their side effects[14,15]. Certain bacteria can metabolize chemotherapy agents, affecting their bioavailability and performance, while others can modulate inflammation and intestinal permeability, reducing the risk of gastrointestinal side effects[14]. More specifically, the elimination of intestinal bacteria through previous antibiotic therapy diminishes both myeloid and Th17 responses, subsequently lowering the effectiveness of oxaliplatin and cyclophosphamide[7,14]. Furthermore, the influence of microbiota on the efficacy of 5-fluorouracil (5-FU) may occur via the bacterial processing of vitamins and ribonucleotides, while the suppression of bacterial deoxyribonucleotide metabolism could potentially augment the effectiveness of 5-FU[16]. Additionally, a notable prevalence of Fusobacterium nucleatum (F. nucleatum) correlates with resistance to oxaliplatin and 5-FU. This phenomenon operates through a mechanistic pathway where F. nucleatum triggers the TLR4/MYD88-dependent pathway, thereby instigating innate immunity. This activation results in the depletion of microRNA segments, prompting a transition in cancer cell behavior from apoptosis to autophagy, consequently fostering the emergence of chemoresistance. Consequently, the targeting of F. nucleatum to diminish autophagy levels in colorectal cancer (CRC) cells holds promise for enhancing the chemosensitivity of CRC[11].
HARNESSING THE MICROBIOME TO ENHANCE IMMUNOTHERAPY
Immunotherapy has emerged as a game-changer in cancer treatment, offering durable responses and improved survival outcomes across a spectrum of malignancies. However, response rates to immunotherapy remain variable, underscoring the need to identify predictive biomarkers and strategies to enhance treatment efficacy[17]. Sivan et al[18] showed how the gut microbiome serves as a key determinant of immunotherapy response, with specific microbial signatures associated with favorable or adverse outcomes. The concept of modulating the gut microbiome as a therapeutic approach in cancer aligns with the increasing focus on microbiome-based interventions, including fecal microbiota transplantation, probiotics, selective antibiotics, or bacteriophages[19,20]. Furthermore, dietary habits, physical activity, and other lifestyle factors shape the composition and function of the gut microbiome, influencing an individual's susceptibility to cancer development and response to treatment[21,22]. These interventions aim to restore a healthy equilibrium in the gut microbiome. Leveraging microbiome-targeted interventions, such as fecal microbiota transplantation and microbial modulators, seems promising not only for enhancing the efficacy of immunotherapy but also on overcoming resistance mechanisms.
Recent preclinical studies have provided compelling evidence supporting the potential of microbiome-based interventions to enhance the efficacy of immunotherapy. For example, the administration of certain microbial metabolites, such as short chain fatty acids, has been shown to potentiate the anti-tumor effects of immune checkpoint blockade by modulating the activity of tumor-infiltrating immune cells and promoting the generation of memory T cells[18,23,24]. Moreover, researchers demonstrated that the efficacy of anti-PD-1 therapy in melanoma-bearing mice is dependent on the composition of the gut microbiome, with specific bacterial species, such as Bacteroidales and Burkholderiales, promoting anti-tumor immune responses and tumor regression[17].
TRANSLATING MICROBIOME RESEARCH INTO CLINICAL PRACTICE
Despite the growing body of evidence implicating the gut microbiome in cancer pathogenesis and treatment, several challenges hinder its translation into clinical practice. Standardization of methodologies for microbiome profiling, validation of microbial biomarkers, and integration of microbiome-targeted interventions into existing treatment paradigms represent critical areas of focus[25]. Moreover, the importance of multidisciplinary collaboration between oncologists, microbiologists, and computational biologists to harness the full potential of microbiome-based therapies and realize tangible benefits for cancer patients is also highlighted in the literature. Emerging research is focusing on the development of microbiome-based biomarkers for predicting cancer prognosis, treatment response, and therapeutic toxicity. Microbial signatures in blood, stool, or tumor tissue hold promise as non-invasive biomarkers for guiding treatment decisions and monitoring disease progression[12,26].
CONCLUSION
In navigating the intricate landscape of cancer treatment, the gut microbiome emerges as a beacon of hope, offering novel insights and therapeutic strategies to enhance patient outcomes. Through this path and by leveraging the microbiome's influence to tilt the scales in favor of the patient, we can unveil new avenues for personalized cancer therapy.
Ethical issues surrounding the use of microbiome-based interventions in cancer care, including patient consent, privacy concerns, and equitable access to emerging therapies, demand attention[27,28]. Regulatory hurdles in evaluating the safety and efficacy of microbiome-targeted interventions underscore the necessity of interdisciplinary collaboration and regulatory oversight to advance research. Expanding on these insights, it is imperative to stress the importance of further research to fully comprehend the complex interplay between the gut microbiome and cancer treatment outcomes. This entails investigating specific microbial signatures associated with treatment response and resistance, as well as elucidating the mechanisms through which the microbiome influences cancer progression and therapy efficacy. Additionally, efforts should be directed towards establishing standardized protocols for microbiome analysis and intervention implementation in clinical settings, ensuring reproducibility and consistency across studies. The article by Davoutis et al[1] serves as a catalyst for deeper exploration, and as the field of microbiome-guided oncology evolves, there is a pressing need for ongoing education and awareness among healthcare professionals and the public regarding the potential benefits and limitations of microbiome-based interventions in cancer care. This involves fostering dialogue around ethical considerations, promoting transparency in research practices, and dispelling misconceptions or unrealistic expectations surrounding microbiome therapies.
In summary, while the gut microbiome presents significant promise as a therapeutic target in cancer treatment, its integration into clinical practice demands careful consideration of ethical, regulatory, and scientific challenges. The article by Davoutis et al[1] lays the groundwork for further investigation in this domain, encouraging collaboration and innovation to unlock the full potential of microbiome-guided oncology in enhancing patient care and outcomes.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Medicine, research and experimental
Country of origin: Cyprus
Peer-review report’s classification
Scientific Quality: Grade B
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Chen K S-Editor: Liu H L-Editor: Filipodia P-Editor: Xu ZH
