Unveiling the microbial orchestra: exploring the role of microbiota in cancer development and treatment

Abstract

The human microbiota comprises a diverse microbial ecosystem that significantly impacts health and disease. Among its components, the gut microbiota plays a crucial role in regulating metabolic, immunologic, and inflammatory responses. Dysbiosis, an imbalance in microbial composition, has been linked to carcinogenesis through mechanisms such as chronic inflammation, metabolic disturbances, epigenetic modifications, and immune system dysregulation. Additionally, dysbiosis influences the efficacy and toxicity of cancer therapies. Given these associations, there is growing interest in leveraging the microbiota as a biomarker for cancer detection and outcome prediction. Notably, distinct microbial signatures have been identified across various cancer types, suggesting their potential as diagnostic markers. Furthermore, modulation of the microbiota presents a promising avenue for improving cancer treatment outcomes through strategies such as antibiotics, prebiotics, probiotics, fecal microbiota transplantation, dietary interventions, small-molecule inhibitors, and phage therapy. To explore these relationships, we conducted a comprehensive literature review using Web of Science, Scopus, PubMed, MEDLINE, Embase, and Google Scholar as our primary online databases, focusing on indexed peer-reviewed articles up to the present year. This review aims to elucidate the role of dysbiosis in cancer development, examine the molecular mechanisms involved, and assess the impact of microbiota on cancer therapies. Additionally, we highlight microbiota-based therapeutic strategies and discuss their potential applications in cancer management. A deeper understanding of the intricate interplay between the microbiota and cancer may pave the way for novel approaches to cancer prevention, early detection, and treatment optimization.

Graphical abstract

Introduction

The prized connection between the human microbiota and cancer has become one of the most popular and captivating topics of discussion in the field of biomedical sciences due to its ability to gain deeper insights into disease development, further evolution, and potential treatment strategies [1, 2]. Consisting of numerous microorganisms living mainly in the gastrointestinal tract, the human microbiota plays a critical role in controlling various aspects of human physiology, such as metabolism, immune responses, and inflammation [3]. This mutualistic association, known as eubiosis, highlights the fundamental role of the microbiota in maintaining the well-being and stability of the host [4]. Nevertheless, several diseases, including cancer, correlate with shifts in the microbial structure and its activities, known as dysbiosis [5]. Cancer, a complex human body disease affecting all ages and genders, is one of the worst diseases in the world [6, 7]. Although genetics and environmental conditions remain the primary initiators of cancer and tumour development, current research has delineated the functions of the microbiota in the carcinogenesis process and tiers of therapy [8, 9]. In fact, changes in the balance of harmful microbes in mixed microbial systems can cause or encourage cancer-causing processes like inflammation, changes in DNA methylation, problems with metabolism, and the immune system losing its focus [10]. Furthermore, microbial signalling with the host immune system and tumour microenvironment strongly influences cancer and treatment responses [11]. Consequently, providing an account of the mechanisms that govern microbiota-cancer interactions has emerged as a critical research direction, mainly because it reveals novel approaches for cancer prevention, detection, and therapy. As an application of microbiota, microbial biomarkers—the presence of some microbes in an abnormal way—are now being looked at as a way to find objective signs of when cancer starts or how bad it is [12]. Furthermore, it holds promise in revealing more about the role of microbiota in cancer treatment response and in patients'therapeutic resistance, allowing for the optimal customization of the therapeutic management plan [13]. The intersection of Microbiota research and oncology opens up a new area in the study and treatment of cancer [14]. This includes clinical trials that aim to change the microbiota to find new ways to treat cancer and the use of Microbiota data in the care of cancer patients [15].

Composition of the human microbiota: an overview

The human body hosts a complex and diverse community of microorganisms, including bacteria, viruses, fungi, and archaea, collectively referred to as the human microbiota [16]. This microbiota plays a pivotal role in maintaining physiological homeostasis and modulating various bodily functions, including immune response, metabolism, and protection against pathogens [16]. The composition of the microbiota varies across different locations in the body, with each site harboring a distinct microbial community adapted to its specific environmental conditions [16, 17]. The balance of these microbial communities is essential for health and disease, and disruptions to this balance, known as dysbiosis, have been implicated in various diseases, including cancer. In this context, understanding the normal microbial balance (eubiosis) in different body sites is crucial for understanding the impact of dysbiosis on human health.

Gastrointestinal tract (GIT) microbiota

The gastrointestinal tract is home to the most diverse and dense microbial community in the human body. The composition of the microbiota along the GIT varies depending on the region (stomach, small intestine, and large intestine) and is influenced by dietary habits, age, health status, and antibiotic use [18].

Stomach

Due to its acidic environment (low pH), the microbial load in the stomach is relatively low. However, Helicobacter pylori is a prominent bacterium found in the gastric mucosa, and its presence can lead to gastric diseases such as ulcers and cancer. Despite the acidity, other bacteria such as Lactobacillus and Streptococcus are also found here, though in smaller numbers [19, 20].

Small intestine

The small intestine has a slightly higher pH and a more varied microbial population compared to the stomach. The microbiota here is characterized by the presence of Lactobacilli, Bifidobacteria, and Enterococci, among others. These microorganisms play essential roles in nutrient absorption, digestion, and the synthesis of certain vitamins. However, the bacterial load remains relatively low compared to the large intestine to prevent interference with digestion and absorption [21–23].

Large intestine (colon)

The colon is the most densely populated region of the human microbiota, containing trillions of microorganisms. The microbiota here is dominated by Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, which play critical roles in fermentation of non-digestible carbohydrates, production of short-chain fatty acids (SCFAs) like butyrate, and the regulation of immune function. This complex ecosystem is essential for maintaining gut health, modulating inflammation, and protecting against harmful pathogens [16, 24].

Skin microbiota

The skin is an external barrier and has a unique microbiota that varies by body site, with distinct microbial communities residing in sebaceous (oily), dry, and moist regions. Skin microbiota includes a variety of bacteria, fungi, and viruses that help prevent pathogenic colonization and maintain skin health [16].

Sebaceous areas (e.g., face, scalp)

These areas are rich in lipids, supporting the growth of Propionibacterium acnes and Staphylococcus epidermidis. These microorganisms play roles in preventing infections and modulating immune responses. Disruption of this balance is associated with conditions like acne [25, 26].

Dry areas (e.g., forearms, legs)

The microbiota here is less diverse and dominated by Corynebacteria, Betaproteobacteria, and Firmicutes. These microbes are adapted to low moisture environments and help maintain skin barrier function [16, 27].

Moist areas (e.g., armpits, groin)

Moist areas host a more diverse microbiota, with high populations of Staphylococcus, Corynebacterium, and Malassezia fungi. These areas are more prone to overgrowth of harmful pathogens if the microbiota balance is disturbed, leading to infections such as folliculitis or dermatitis [28, 29].

Vaginal microbiota

The vaginal microbiota is primarily dominated by Lactobacillus species, which produce lactic acid, maintaining an acidic pH that inhibits the growth of pathogens [30]. The diversity and composition of the vaginal microbiota vary during different life stages, such as puberty, menstruation, pregnancy, and menopause, as well as depending on hormonal fluctuations [31].

Healthy vaginal microbiota (Eubiosis)

A healthy vaginal microbiota is primarily composed of Lactobacillus species (e.g., Lactobacillus crispatus, Lactobacillus iners) [32]. These bacteria help maintain an acidic environment, preventing the overgrowth of harmful microorganisms, including Gardnerella vaginalis, Candida albicans, and other pathogens [33].

Dysbiosis in the vaginal microbiota

Dysbiosis in the vaginal microbiota, characterized by a reduction in Lactobacillus and overgrowth of anaerobic bacteria, has been associated with conditions such as bacterial vaginosis, yeast infections, and an increased risk of sexually transmitted infections [34]. Furthermore, dysbiosis in the vaginal microbiota has been linked to preterm birth, pelvic inflammatory disease, and an increased susceptibility to HIV [35].

Respiratory tract microbiota

The respiratory tract, including the nasal cavity, pharynx, and lungs, harbors a diverse community of microbes, although their composition is less dense compared to the gut or skin. The composition of the respiratory microbiota varies with age, environmental exposures, and disease state [36].

Nasal cavity

The nasal microbiota is mainly composed of Staphylococcus, Corynebacterium, Propionibacterium, and Streptococcus. These microorganisms help protect against pathogenic colonization and contribute to the maintenance of respiratory tract immunity [37, 38].

Lower respiratory tract

The lungs, previously thought to be sterile, have been found to host a low-density microbiota, with microbes such as Prevotella, Veillonella, and Fusobacterium species present in healthy individuals [39, 40]. Dysbiosis in the lung microbiota has been associated with respiratory conditions like asthma, chronic obstructive pulmonary disease (COPD), and pneumonia [41, 42].

Urinary tract microbiota

The urinary tract microbiota, particularly in females, plays a significant role in maintaining urinary tract health. The microbiota of the urinary tract is influenced by factors such as age, hygiene, sexual activity, and the use of antibiotics [16, 43].

Healthy urinary tract microbiota

In a healthy state, the urinary microbiota consists mainly of Lactobacillus, Corynebacterium, and Staphylococcus species, which help prevent urinary tract infections (UTIs) by inhibiting the growth of uropathogens [16].

Dysbiosis and UTIs

Disruption of the urinary microbiota, such as a reduction in Lactobacillus species, can lead to the overgrowth of uropathogens like Escherichia coli, resulting in UTIs. This imbalance has also been associated with conditions such as interstitial cystitis and pelvic pain syndrome [44, 45].

The composition of the human microbiota is highly dynamic and varies across different body sites, including the gastrointestinal tract, skin, vaginal, respiratory, and urinary tracts. Eubiosis in these regions ensures proper physiological functioning and protection from pathogens, while dysbiosis can result in adverse health outcomes, including cancer. A better understanding of the role of microbiota in maintaining health and its contribution to cancer pathogenesis could lead to new therapeutic strategies, such as microbiome modulation, for preventing or treating cancer.

This review comprehensively examines the intricate relationship between the gut microbiota and cancer, focusing on its role in carcinogenesis, prognosis, and therapeutic interventions. By analyzing current evidence on microbial dysbiosis, molecular mechanisms, and therapeutic modulation, we aim to elucidate how microbiota influences cancer development, progression, and treatment responses. Additionally, we highlight emerging microbiota-based strategies for cancer prevention, diagnosis, and therapy, offering insights into their potential clinical applications.

Methodology

To achieve the aim of this research, this study adopted a thorough narrative review of articles that explained the involvement of the human gut microbiota in cancer development, prognosis, and therapy. The study encompassed in vitro, animal, and clinical models, as well as in vitro, animal, and clinical examination studies. We identified the study's articles from electronic databases such as PubMed, Medline, Embase, Web of Science, Scopus, and Google Scholar, using keywords like human microbiota, cancer, dysbiosis, carcinogenesis, biomarkers, therapy response, and microbiota-targeted interventions. We included high-quality, relevant, and recent literature. Criteria included publication type, language, date range, study design, relevance, data source, microbiota scope, therapeutic strategies, and exclusion criteria. The review focused on peer-reviewed articles, systematic reviews, meta-analyses, and clinical studies published within the last 10 years. The review excluded non-English articles, non-peer-reviewed sources, older studies, non-relevant focus, limited data, and duplicate publications. We made sure to adhere to the appropriate ethical considerations, including the citation of relevant references.

Overview of the human microbiota and its significance in health

The term “human microbiota” refers to the trillions of microorganisms, including bacteria, viruses, and fungi, that make up the human body [23]. The human body contains these microbes in various areas, with many settling in the digestive system, a collection known as gut flora [46]. The gut microbiota is a set of microorganisms that reside in a person’s digestive tract and is important for most physiological functions that affect an individual’s well-being, such as metabolism, immune response, inflammation, and nutrient absorption [47]. People refer to it as a “vital organ” due to its bidirectional connections with every other organ via neural, endocrine, and immunologic interfaces [48]. According to scientific evidence, a healthy state of the gut microbes, known as eubiosis, is critical for the regulation of microbial diseases as well as human health in general [49]. The composition of the microbiota can be affected by diet, age, geographical location, systemic diseases, and drug use [50]. The entire microbial community, or microbiota, inhabiting the gastrointestinal tract interacts with the host to influence its metabolic homeostasis, immune system, and defence mechanisms [51]. In addition, the composition of the gastro intestinal track (GI) Microbiota plays a significant role starting at birth and continuing through the life cycle, with influences on digestion, and even the nervous system [52]. Dysbiosis refers to an imbalance in the composition of organisms residing in the intestines, and it has been associated with different diseases. Knowledge of the gut microbiota's components and roles is critical for promoting health and preventing diseases caused by microbial community imbalance disruptions [23]. Summarily, microbiota-targeted therapeutic strategies, including probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT)., and phage therapy and other related concepts have been summarized in Table 1 below.

Table 1.

Microbiota-targeted therapeutic strategies: mechanisms, applications, and challenges

Strategy	Definition	Mechanism of action	Therapeutic applications	Applications in cancer patients	Advantages	Limitations/challenges	References
Probiotics	Live beneficial microorganisms that confer health benefits when administered in adequate amounts	Compete with pathogenic bacteria, enhance gut barrier function, modulate immune responses, and produce antimicrobial compounds	Used in treating gastrointestinal disorders (IBS, IBD, diarrhea), metabolic diseases, and neurodegenerative conditions	May improve cancer patients'gut microbiota, reduce chemotherapy-induced diarrhea, and enhance immune responses to immunotherapy	Restore gut microbiota balance, reduce inflammation, and enhance gut health	Strain specificity, viability issues during storage and passage through the gut, and risk of infections in immunocompromised individuals	[80, 81]
Prebiotics	Non-digestible dietary fibers that selectively stimulate the growth of beneficial gut microbes	Enhance beneficial microbiota growth (e.g., Bifidobacteria, Lactobacilli) by providing substrates for fermentation, producing short-chain fatty acids (SCFAs)	Used in metabolic syndrome, diabetes, cardiovascular diseases, and inflammatory bowel disease (IBD)	Support gut microbiota composition in cancer patients, improve SCFA production, and potentially reduce inflammation linked to tumor progression	Improve gut microbiota composition, promote SCFA production, and support immune function	Potential bloating and gas production, inter-individual variability in response	[81, 82]
Synbiotics	A combination of probiotics and prebiotics that work synergistically to enhance gut microbiota composition and function	Enhance the survival of probiotics by providing a specific substrate for their growth, leading to improved colonization and metabolic activity	Applied in gastrointestinal health, obesity management, and immune system modulation	May help in cancer patients by improving gut health, reducing inflammation, and supporting overall well-being during treatment	Synergistic effect, improved colonization and efficacy of probiotics, better gut health benefits	Requires strain-substrate compatibility, production cost, and regulatory challenges	[83, 84]
Fecal Microbiota Transplantation (FMT)	Transfer of fecal microbiota from a healthy donor to a recipient to restore gut microbiota composition	Replenishes gut microbiota diversity, restores metabolic and immune functions, and eliminates harmful pathogens	Primarily used for Clostridioides difficile infections (CDI), inflammatory bowel disease (IBD), and metabolic disorders	Investigated for improving gut microbiota diversity in cancer patients undergoing chemotherapy or immunotherapy	Highly effective in refractory CDI, restores a natural microbiota ecosystem	Donor screening challenges, risk of pathogen transmission, ethical and regulatory concerns	[85, 86]
Phage Therapy	Use of bacteriophages (viruses that infect bacteria) to selectively target and eliminate pathogenic bacteria	Lyses pathogenic bacteria without affecting beneficial microbiota, reducing antibiotic resistance and promoting gut microbiota balance	Investigated for treating antibiotic-resistant infections, gut dysbiosis, and inflammatory conditions	Potential application in cancer patients to reduce infections, modulate gut microbiota, and decrease inflammation	High specificity, reduced collateral damage to microbiota, potential alternative to antibiotics	Bacterial resistance to phages, regulatory hurdles, stability and delivery challenges	[87–89]
Postbiotics	Metabolites or cell components from probiotics that exert beneficial effects without requiring live microorganisms	Modulate immune responses, produce SCFAs, regulate gut barrier function, and exert antimicrobial activity	Potential applications in immune modulation, metabolic disorders, and gut health	May enhance anti-cancer immunity and reduce inflammation in cancer patients	More stable than probiotics, easier to formulate, and free from viability concerns	Research is still emerging, and effectiveness varies by strain-derived metabolites	[90–93]
Next-Generation Microbiota-Based Therapies	Includes engineered probiotics, microbial consortia, and Microbiota-modulating drugs for targeted therapeutic effects	Designed to modify specific metabolic pathways, enhance gut-brain axis signaling, and optimize host-microbiota interactions	Potential applications in neurological diseases, metabolic syndromes, and precision medicine approaches	Can be used for precision cancer treatment by modulating gut microbiota to enhance therapy response	Precision-targeted therapies with high efficacy potential	High development cost, regulatory and safety challenges, personalized medicine integration issues	[94–96]

Mechanisms of microbiota dysbiosis contributing to cancer initiation

Microbiota dysbiosis disrupts the complexity and functionality of microbial communities within a human body, leading to multiple effects on cancer initiation [53]. Researchers have identified several key mechanisms through which the microbiota can influence cancer as summarized in Fig. 1, and explained below:

Fig. 1.

Mechanisms of microbiota dysbiosis (created in BioRender.com). PRC2—Polycomb Repressive Complex 2, RNAPII—RNA Polymerase II, Me—Methyl group, SAM—S-Adenosylmethionine

1. Inflammation: The microbiota has the ability to influence and induce genome instability, which can lead to cancer, tumour-promoting inflammation, and immunosuppression [54]. It also regulates and controls host immunity, as well as immune cell motion. For instance, researchers have linked certain bacterial species to gut inflammation, thereby increasing the risk of developing colorectal cancer [55]. It also plays an important role in healthy immune system development and regulation, which could potentially aid in cancer detection and immune responses against tumours. Some of the effects that pathogenic bacteria are known to have include disruption of the epithelial layer, which produces inflammation [56]. Dysbiosis can cause an immune reaction, which leads to chronic inflammation. Helicobacter pylori bacteria, for example, can cause an inflammatory state in the stomach's lining tissues and, consequently, are associated with gastric cancer [57]. Zhao et al. [58]reported the immunological mechanisms of inflammatory diseases caused by gut microbiota dysbiosis.

2. Epigenetic modulation: Several selective organisms within the gut preemptively regulate DNA methylation, DNA repair, and DNA damage, which are critical to cancer development, particularly with regards to the regulation of cell growth and cell signaling [59]. For example, some genotypes of Escherichia coli release colibactin, a genotoxin that causes DNA double-strand breaks [60]. The Epigenetic modulation by gut microbuiota has previously been established by Tian et al. [61], Kim et al. [62], and Pepke et al. [63]. Furthermore, dysbiotic microbiota may increase reactive oxygen and reactive nitrogen species levels, which promote DNA oxidative modification [64].

3. Metabolic dysregulation: Dysbiosis can lead to altered metabolism and carcinogenic conditions. Pathogenic bacteria can alter bile acids into secondary forms that are toxic to the gastrointestinal tract, especially in cases of colorectal cancer as earlier reported [65]. According to a Korean study, cholecystectomy, or the removal of the gall bladder, raises the risk of cancer in the colon, liver, pancreas, biliary system, throat, and oral cavity, among other gastrointestinal sites [66]. Once more, changes in the microbiota result in the formation of toxic compounds such as nitrosamines, which are as dangerous as they are carcinogenic [67].

4. Dysbiosis: Alterations in the environment or the host can trigger these changes, influencing the onset and progression of diseases such as cancer. Abuse of antibiotics can also contribute to the development of cancer and exacerbate its aggressiveness, as they eradicate all bacteria within the body, including those that are beneficial to health, promote the growth of harmful bacteria, and eliminate all bacteria without preserving the harmless ones [68]. Volkova and colleagues established that early-life exposure to the antibiotic penicillin has a negative impact on the expression of amygdala genes, the frontal brain, and the gut flora [69]. Researchers have established a connection between the gut microbiota and cancer in distant organs like the breast, liver, pancreas, and lung [70–73]. Researchers have isolated bacteria not only from the gut, but also from both normal and malignant breast tissues [74]. A microbial imbalance affects hormones that are associated with cancer risk [75]. The enterohepatic circulation involves oestrogens, and reports also suggest a role for bacteria in the gastrointestinal tract. Dysbiosis can also elevate circulating oestrogen levels, for instance, a factor linked to breast and endometrial cancers [76].

5. Metabolism and carcinogenesis: The microbiota plays a role in the breakdown of numerous nutrients and could therefore directly affect the production of carcinogenic metabolites. For instance, certain bacteria have the ability to ferment dietary fibres into short-chain fatty acids (SCFAs,) which are known to possess anti-inflammatory and anti-cancer properties [77]. Other microbial metabolites, such as secondary bile acids and trimethylamine N-oxide (TMAO), are known to promote carcinogenic activity in the gut and other related organisms [78]. Alteration of the microbiota favours the formation of toxic compounds, precursors of nitrosamines that are toxic and carcinogenic [79].

Microbiota as biomarkers in cancer diagnosis

Biomarkers are quantifiable variables used to assess a specific biological state or status [97]. In cancer diagnosis, biomarkers can be substances found in the body, such as those produced by the tumour or changes that occur due to the tumour’s presence [98]. Microbiota as biomarkers for cancer diagnosis is a relatively new approach that aims to gain information about the specific microbial ecosystem in a human body to determine the presence of cancer or even its type [99]. Numerous studies have established a correlation between certain bacterial profiles and various cancer types, including colorectal cancer (CRC), gastric cancer (GC), hepatocellular carcinoma (HCC), pancreatic cancer (PC), and esophageal cancer (EC) [100, 101]. For example, in CRC, colibactin-producing Escherichia coli (CoPEC) adheres strongly to the colonic mucosa, and these bacteria actively contribute to CRC development in preclinical models [99]. As a novel predictive biomarker and therapeutic aim to enhance CRC prognosis and treatment, CoPEC may open a new perspective [102]. Prevotella intermedia, Porphyromonic asaccharolytica, Peptostreptococcus anaerobitis, Parvimonas micra, Dialister pneumosintes, and Anaerococcus vaginalis are some other possible biomarkers for CRC [103]. The identification of the oral Microbiota is another approach that appears to be less invasive and holds potential for diagnosing CRC [104]. Finally, researchers have proposed oral microbiota as biomarkers for CRC diagnosis, but further research is necessary to establish their diagnostic efficiency. Researchers have also attempted to understand the lung microbiota from a lung cancer perspective [105]. Depending on the local environment, researchers have identified some bacterial species as strongly associated with lung cancer, such as the Streptococcus genus in the respiratory tract [106]. Researchers in PC have detected 16S rRNA-known biomarkers in both faecal and saliva samples [107], and the integration of Microbiota data with serum CA19-9 enhances the diagnostic precision [108]. However, the results obtained vary between studies, indicating the need for further validation of the findings. Some studies involving cervical cancer have focused on changes in the composition of the vaginal microbiota. Studies have shown that while Gardnerella vaginalis and Atopobium vaginae, which are normally anaerobic bacteria, are more abundant in cervical cancer and its precursors [109], Lactobacillus species are less prevalent in cervical cancer cases compared to normal women [110]. A study by Wu et al. [111] shows a correlation between changes in reproductive-age women from HPV infection to cervical cancer and the composition of their cervical microbiota, with higher diversity and less Lactobacillus resulting in a more severe pathological state. Variations in the oral microbiota may orchestrate head and neck cancers, according to Benjamin and colleagues [112]. Particularly, studies have highlighted the presence of Porphyromonas gingivalis and Treponema denticola in higher concentrations in any of these cancers [113]. Despite the immense potential of the Microbiota as a cancer biomarker, it is still premature for clinical application. There is a need to engage in larger, prospective, multicentric studies that use uniform sampling and analytical approaches to ascertain the role of the Microbiota as an early cancer marker.

Microbiota and cancer therapy response

Researchers have identified the human Microbiota, most commonly the gut, as having high relevance in regulating the efficacy of cancer treatment. These studies have found different ways that the microbiota can influence cancer therapy outcomes by acting on factors such as immunity response, drug pharmacokinetics, and tumour microenvironment [114]. Some key findings and concepts are as follows and presented in Table 2:

Table 2.

Role of gut microbiota in modulating cancer therapy response: mechanisms and therapeutic implications

S/no.	Key aspect	Description	Microbial influence	Mechanism of action	Therapeutic impact	Potential interventions	References
1	Immune Modulation	Gut microbiota affects immune response in cancer therapy	Bifidobacterium, Akkermansia	Stimulates dendritic cell maturation and T-cell infiltration	Enhances immunotherapy response	Probiotic supplementation, microbiota-targeted therapies	[114–117]
2	Chemotherapy Efficacy	Microbiota influences chemotherapy drug metabolism	Microbial enzymes, metabolites short-chain fatty acids (SCFAs)	Modifies pharmacokinetics and pharmacodynamics of drugs	Can enhance or reduce drug potency	Personalized Microbiota modulation, prebiotics	[118–120]
3	Drug resistance	Dysbiosis contributes to resistance to cancer therapies	Altered microbiota composition	Affects drug metabolism and immune modulation	Reduces effectiveness of chemotherapy, immune checkpoint inhibitors	Fecal microbiota transplantation (FMT), Microbiota restoration	[121–123]
4	Tumour microenvironment	Microbial metabolites impact inflammation and tumour progression	SCFAs, butyrate	Regulates immune function and inflammation in tumours	Can promote or inhibit tumour growth	Probiotic and metabolite-based therapies	[124, 125]
5	Histone modification	Microbiota influences epigenetic regulation in cancer	Butyrate-producing bacteria	Interacts with histone deacetylase, modifies gene expression	Potential role in cancer prevention and therapy	Epigenetic drugs targeting microbiota interactions	[126]
6	Fecal microbiota transplantation (FMT)	Restoration of healthy microbiota to improve treatment response	Diverse gut microbiota	Balances immune response and improves drug efficacy	Enhances response in patients non-responsive to immunotherapy	Clinical trials, personalized microbiota transplants	[123]
7	Inflammation control	Gut microbiota regulates inflammation affecting cancer therapy	Anti-inflammatory SCFAs	Reduces pro-inflammatory cytokine levels	Creates a favorable immune environment for therapy	Diet-based microbiota modulation, anti-inflammatory probiotics	[124, 125]
8	Future directions	Advancing microbiota-based therapies in oncology	Personalized microbiota interventions	Precision medicine approach for cancer treatment	Increased therapy success, reduced resistance	Microbiota sequencing, AI-driven microbiota analysis	[114, 126]

Immune modulation

The composition of the communities of microbes that dwell in the gut may also promote or inhibit tumour immunity, thereby modulating the effectiveness of immunotherapy, chemotherapy, radiation therapy, and cancer surgery [115]. Some forms of bacteria, such as Bifidobacterium and Akkermansia, have an important role to play in the enhancement of immunotherapy [116]. Some of these commensal bacteria can also increase the body's immune responses by stimulating dendritic cell maturation and increasing T-cell infiltration in tumours [117].

Chemotherapy

The microbiota influences the effectiveness of cancer treatments through the metabolism process. Microbial metabolites, such as short-chain fatty acids, can influence the immune response against cancer cells as well as the efficacy of cancer therapy [118]. Microbial enzymes also influence the pharmacokinetics of chemotherapeutic agents used in cancer treatments [119]. The microbiota has the ability to affect the pharmacokinetics and pharmacodynamics of oral chemotherapy drugs, thus determining their potency [120]. Zhao et al. [121] in their study revealed a link between gut microbiota dysbiosis and resistance to cancer therapies like chemotherapy and immune checkpoint inhibitors. Research shows that restoring a healthy gut microbiota effectively addresses issues of treatment failure [122]. Faecal microbiota transplantation has evidenced a positive potential for enhancing prognoses for patients who are non-responsive to immunotherapy [123].

Inflammation and metabolites

The products of the microbiota, such as metabolites and inflammatory factors, can influence the tumour environment and, thus, the progress and treatment of cancer [124]. For instance, gut bacteria synthesize short-chain fatty acids, which have anti-inflammatory properties and can regulate immune function in the tumour microenvironment [125]. Some pro-biotic microbial metabolites, such as butyrate, interact with histone deacetylase and may control gene expression in a way that helps treat and prevent cancer [126].

Microbiota-targeted therapeutic strategies

The consideration of developing a microbiota-therapeutic approach has hit the limelight because of the profound involvement of the microbiota in physiology and pathophysiology, including cancer development and response to treatment. Such strategies include antibiotic therapy, use of probiotics and prebiotics, foetal microbiota transplantation, diet intervention, small molecule-borne inhibitors, and bacteriophage therapy [127–129]. Antibiotics can neutralise or inactivate dangerous bacteria and also control the immune response. Probiotics introduce friendly bacteria that can replace the undesirable ones and help to strengthen the body’s ability to fight cancer. Lactobacillus and Bifidobacterium are two major types of probiotics that have demonstrated positive results in experimental cancer therapy by inhibiting tumour growth and fortifying immunity [130].

Prebiotics are substances present in food that the human body does not digest, yet they stimulate the growth of beneficial bacteria in the stomach, aiding in coping with chemotherapy side effects and preserving stomach function [131]. Inulin and fructooligosaccharides are popular prebiotics that improve gut bacteria such as Bifidobacteria and Lactobacilli [132]. Faecal microbiota transplantation accelerates the improvement of the disrupted microbiota balance and increases treatment effectiveness [123]. A changing diet can affect the community of microorganisms in the gut and increase the population of beneficial microbes. For instance, high-fibre diets promote the growth of beneficial bacteria in the intestines, which produce short-chain fatty acids (SCFAs), such as butyrate, which play a significant role in promoting anti-inflammatory and anti-cancer effects [133]. Small-molecule inhibitors interfere with dangerous bacterial processes and decrease toxic byproducts. For example, taurine metabolism inhibitors affect bacterial taurine metabolism in order to minimise its immunosuppressive activity during chemotherapy [134]. Phage therapy targets and eliminates only the pathogenic bacteria helping to prevent dysbiosis, while the bacteria aiding digestion remain intact [121]. However, because the human Microbiota is diverse and unique in each patient, these strategies must be patient-specific.

Immunotherapy and radiotherapy influence on microbiota

Recent research suggests that the microbiota plays a crucial role in the efficacy and side effects of cancer treatments. Immunotherapy, including immune checkpoint inhibitors, can be influenced by the gut microbiota, which plays a crucial role in shaping the immune response [135]. Firmicutes and Bacteroidetes, which are specific microbial populations, have been associated with improved outcomes in patients undergoing immune checkpoint inhibitors [136]. The microbiota also influences the development of immune-related adverse events (irAEs), such as colitis or dermatitis [137]. Microbial metabolites, such as short-chain fatty acids (SCFAs), can modulate immune cells and enhance immune responses, improving systemic inflammation or influencing the tumor microenvironment [138].

Radiotherapy can profoundly alter the microbiota, particularly in the gut, due to radiation-induced damage to both normal and cancerous cells [135]. Dysbiosis, particularly in abdominal or pelvic cancer treatments, can lead to gastrointestinal symptoms such as diarrhea, mucositis, and colitis [139]. A healthy microbiota can enhance the anti-tumor effects of radiation by supporting immune responses, while dysbiosis can diminish immune activation, potentially reducing the therapeutic efficacy of radiotherapy. Specific microbes, such as those producing metabolites like butyrate, can counteract radiation-induced immune suppression and improve recovery, potentially alleviating side effects [135, 140].

Limitations of microbiota-based therapies

Microbiota-based therapies, including probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), and Microbiota-targeted drugs, have gained significant attention for their potential in treating various health conditions. However, several challenges and limitations hinder their widespread application. These limitations can be classified into biological, technical, clinical, regulatory, ethical, and economic concerns [121, 135, 141–144].

Biological limitations

The human gut microbiota is extremely personalized, shaped by genetics, nutrition, environment, age, and lifestyle choices. A treatment that is beneficial for one person may not be helpful for another owing to variations in microbial diversity and functioning. Research on Microbiota functionality remains inadequate, and the roles of various bacterial strains and their metabolites in illness prevention or therapy are not well understood. The native gut microbiota has inherent resilience; however, given probiotics may lack long-term persistence, hence limiting their effectiveness. Horizontal gene transfer among bacteria, particularly involving antibiotic resistance genes, may provide health hazards, and the introduction of novel microbial strains might unintentionally exacerbate antibiotic resistance.

Technical limitations

Isolating and characterizing essential microbial strains within gut microbiota is difficult owing to the uncultivable conditions present in laboratory settings. Despite advancements in metagenomic sequencing for identification, culture continues to be a hurdle. Standardization challenges persist, and the heterogeneity among commercial probiotic strains hinders their effectiveness. Challenges related to stability and storage exist, since probiotics and microbiota-derived products may deteriorate with time. The intricacy of microbial relationships complicates result predictions, because modifying one species might adversely affect the total Microbiota equilibrium.

Clinical limitations

The effectiveness of probiotics and fecal microbiota therapy (FMT) is a topic of debate due to several factors. These include inconsistent clinical outcomes, short-term efficacy, difficulty in targeted delivery, adverse effects in vulnerable populations, and limited long-term safety data. Studies often fail to replicate results due to variations in design, dosage, and patient populations. Probiotics often do not permanently colonize the gut, necessitating repeated dosing. Targeted delivery is also challenging, with encapsulation and formulation strategies being explored but still imperfect. Adverse effects in vulnerable populations include infections from live microbial therapies, bacteremia and fungemia in critically ill patients, and limited long-term safety data.

Regulatory limitations

Microbiota-based products face several challenges, including a lack of clear classification, inconsistent approval processes due to different guidelines from regulatory bodies like the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency), and inconsistencies in microbial strain composition and viability due to variability in manufacturing processes. Additionally, many commercial probiotics lack scientific validation and quality assurance. Clinical trial design is complex due to individual Microbiota differences and ethical concerns arise from using fecal microbiota transplantation as a standard treatment without full regulatory approval.

Ethical and safety limitations

Fecal microbiota transplantation (FMT) raises ethical concerns due to rigorous donor screening, potential transmission of pathogens or undesirable traits, and unexplored long-term risks. Dysbiosis, a microbial imbalance, can result from FMT, potentially leading to new health issues and autoimmune or inflammatory diseases. Biocontainment and biosafety issues arise from the potential uncontrolled spread of engineered bacteria or genetically modified microbes in the environment. The impact of microbial interventions on ecosystems and human health is still uncertain. Informed consent challenges arise from patients not fully understanding potential risks and the ethical implications of modifying the gut Microbiota for non-medical purposes.

Economic and logistical limitations

Microbiota-based therapies hold great promise for treating various diseases, but significant challenges remain. High production costs, limited accessibility in low-resource settings, and logistical challenges in storage and transportation pose challenges. The rise of commercially marketed probiotics has led to exaggerated claims and consumer confusion, and many supplements lack clinical evidence. Personalized approaches are needed, as Microbiota profiling may require individualized treatment plans, increasing costs and complexity. Generalized probiotic formulations may not be effective for all patients. Overcoming these limitations will require advanced research, improved clinical trial designs, standardized regulatory guidelines, and more affordable therapeutic approaches. Until then, the integration of microbiota-based therapies into mainstream medicine will remain limited.

Conclusion

The intricate relationship between microbiota and cancer presents promising avenues for both understanding carcinogenesis and developing innovative therapeutic strategies. Beyond summarizing existing knowledge, future research should focus on delineating the precise microbial signatures associated with different cancer types, standardizing microbiota-based biomarkers for early diagnosis, and exploring personalized Microbiota interventions to enhance cancer therapy outcomes. Integrating microbiota-targeted therapies into clinical practice will require rigorous validation through large-scale clinical trials, improved regulatory frameworks, and the development of precise, patient-specific therapeutic approaches. Additionally, understanding how diet, probiotics, prebiotics, and fecal microbiota transplantation can be tailored to improve immunotherapy and chemotherapy responses remains a crucial area for exploration. Advancing this field will not only refine cancer treatment but also pave the way for preventive strategies that leverage the Microbiota’s role in maintaining immune homeostasis and reducing cancer risk.

Author contributions

Authors contributions: Conceptualization: EUA, DEU, OPCU, Writing of original draft,: EUA, BNA, Validation: DEU, FOE, C A, Reviewing and editing: All authors.

Funding

This article did not receive any funding.

Data availability

Data used are within the manuscript.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All Authors read and approved the manuscript for publication.

Patient consent

Not applicable.

Competing interests

The authors declare no competing interests.