FIGURE 1 Microbial Density and Diversity at Various Sites Within the Gastrointestinal Tract
David J. Barry,1,2 PhD, ND, DC, Anja Lindblad,3 ND, Claudia Jiménez-ten Hoevel,4 PhD, and Matthew B. Cooke,5 PhD
ABSTRACT
The gut microbiota is a pivotal determinant of human health, influencing both local and systemic physiological processes. Understanding its composition and function is crucial for exploring its impact on diseases, including cancer. Dysbiosis—or imbalances in the gut microbiota linked to negative health outcomes—is increasingly implicated in the pathogenesis of various cancers through mechanisms such as chronic inflammation, immune modulation, and metabolic interactions. The gut microbiome plays a fundamental role in maintaining host health by influencing gut integrity, metabolism, and immune function, with accumulating evidence suggesting a direct impact on cancer development and also cancer drug metabolism, modulating both treatment efficacy and toxicity. This manuscript explores the interactions between the gut microbiome and cancer, focusing on its role in tumorigenesis and its influence on the efficacy of cancer treatments. We review the underlying mechanisms by which specific bacterial species promote tumour development and discuss the microbiome’s role in modulating chemotherapy, immunotherapy and radiotherapy outcomes. The complex interplay between the gut microbiome and cancer therapy continues to reveal new avenues for improving treatment outcomes, and as microbiome science becomes increasingly integrated into oncology, future research should focus on identifying specific microbial signatures predictive of treatment response, developing targeted microbiome-modulating interventions, and incorporating microbiome profiling into clinical trial design.
Key Words Gut microbiota, dysbiosis, microbial metabolites, host-microbiome-drug interactions
The term “microbiota” refers to the overall microbial taxa associated with humans1 and therefore, “gut microbiota” refers to the large range of microorganisms inhabiting the gastrointestinal tract (GIT).2 Each host shares a unique, generally symbiotic relationship with its microbiota.3 These microbial communities, which can act as health-promoting microorganisms, innocuous commensals, or opportunistic pathogens,2 reside within the various epithelial surfaces of the human body (skin, airways, urogenital tract, oral and nasal cavities). It is well established that the majority of human microbiota reside in the GIT, particularly in the large intestine,4,5 and that both microbial density and diversity within the GIT increase from the proximal to the distal gut.6 Figure 1 illustrates the microbial density and diversity throughout the human GIT.
FIGURE 1 Microbial Density and Diversity at Various Sites Within the Gastrointestinal Tract
The human gut microbiota is a complex and diverse community consisting of an estimated 1013 to 1014 microorganisms.7,8 Bacteria are the predominant microbes, which also include viruses, fungi, protozoa, and archaea. This dynamic ecosystem is home to more than 1000 distinct bacterial phylotypes dominated by up to 10 bacterial phyla.9,10 It has been reported that 90% of the total gut microbial population is often constituted by two phyla, Bacteroidetes and Firmicutes.7,11 The other major phyla are often Actinobacteria, Proteobacteria and Verrucomicrobia.7,11,12 Facultative anaerobic and anaerobic microorganisms populate the healthy adult gut. Gram-negative rods (belonging to genera Bacteroides, Fusobacterium and Enterococcus) and anaerobic Gram-positive bacteria (including Lactobacilli and Streptococci) are present in abundance, while Bifidobacterium species may account for up to 25%13,14 (see Table 1).
TABLE 1 Major Bacterial Phyla of the Human Gut Microbiota and Their General Actions
The gut microbiota undergoes continuous adaptive remodelling, supporting a bidirectional, mutually beneficial symbiosis with the host. There is significant variation in microbial diversity within populations,15,16 and composition is influenced by factors such as genetics, age, medication use, nutritional status, and physical activity.17 A balanced gut microbiota supports various physiological processes, including regulating metabolism and maintaining intestinal homeostasis. The GIT also acts as a major immune organ, containing up to 80% of the body’s immune cells and helping to maintain systemic immune balance despite constant exposure to exogenous antigens.1
However, altered microbial balance can disturb communications between host and microbiota. The term “dysbiosis” refers to a perturbation [of the microbiota], marking a detrimental shift in its composition and/or function. Some researchers use the term “pathobiosis” to describe this disturbed microbial state. Petersen and Round define dysbiosis as “any change to the composition of resident commensal communities relative to the community found in healthy individuals.”19 However, such definitions tend to be broad and non-specific, which can create ambiguity about the role of dysbiosis in disease or may lead to inappropriate correlations between illness and microbial profiles. At present, our understanding of the mechanisms underlying these associations remains limited, making it difficult to determine whether dysbiosis is a cause or consequence of disease.20
Dysbiosis has been linked to inflammatory bowel disease, irritable bowel syndrome, and colorectal cancer (CRC).21,22 Growing evidence illustrates that the influence of GIT microbiota extends beyond the gastrointestinal system, affecting neurological, musculoskeletal and cardiovascular disorders. Microbiome imbalances have been implicated in obesity, diabetes, Alzheimer’s and Parkinson’s diseases, depression, rheumatoid arthritis and sarcopenia. 23–26 An overgrowth of pathogenic populations can disrupt various metabolic and nutrient signalling pathways and promote chronic inflammation and DNA damage, processes that have been linked to carcinogenesis.27
Often incorrectly used interchangeably with “microbiota,” the term “microbiome” refers to the collective genomes of the microorganisms residing in a specific habitat28 and the metabolic capabilities they provide.29 Collectively, the genes in the microbiome outnumber those in the human genome by at least 150-fold. The gut microbiome alone is estimated to contain 3.3 million non-redundant genes11 compared with the approximately 22,000 in the human genome.30 This vast genetic reservoir supports a wide array of metabolic and biochemical functions, significantly contributing to host physiology, with a metabolic capacity comparable to that of the liver.15
The gut microbiome performs a range of essential functions that impact overall health and disease susceptibility. It is involved in immune system conditioning, drug metabolism and protection against epithelial cell injury.31,32
Gut bacteria assist in the digestion of complex carbohydrates, producing short-chain fatty acids (SCFAs) such as butyrate, acetate, and propionate from fermentation of dietary fibres, which provide energy to colonocytes and exert anti-inflammatory effects. Microbial metabolism influences the biosynthesis and absorption of essential nutrients, including vitamin K and B vitamins (e.g., pyridoxine, cobalamin, folate, biotin). Gut microbial enzymes modify bile acids, impacting lipid digestion, cholesterol homeostasis and systemic metabolic pathways.
The microbiome plays a critical role in the establishment and maintenance of immune tolerance, modulating the equilibrium between pro-inflammatory and anti-inflammatory responses. Intestinal microbiota are instrumental in educating the immune system to discriminate between pathogenic organisms and commensal microbes. Gut microbes influence adaptive immune responses, promoting the differentiation of CD4+ and CD8+ T cells.33 Commensal bacteria, including Lactobacillus, support immune homeostasis by inducing and activating regulatory T cells, while Clostridium species increase production of interleukin (IL)-17 through proliferation of intestinal T helper (TH)17 cells.34 Specific bacterial taxa, including Bacteroides fragilis and Faecalibacterium prausnitzii, produce immunomodulatory metabolites, such as SCFAs, indoles, and polysaccharides, that modulate immune signalling cascades and attenuate inflammatory processes, while Bifidobacterium species stimulate B cells to release secretory immunoglobulin A (IgA).35
The gut microbiome reinforces intestinal barrier function by promoting mucus secretion and enhancing the integrity of tight junctions between epithelial cells. Specific commensal bacteria, such as Akkermansia muciniphila, stimulate goblet cell activity and mucus layer production, thereby fortifying the mucosal barrier. 36 Additionally, beneficial microbes confer protection against pathogenic invasion by excluding harmful organisms through nutrient competition and occupation of epithelial binding sites.37 Microbiota-derived metabolites—including SCFAs and antimicrobial peptides such as P-glycoprotein (P-gp)—further enhance epithelial cohesion and barrier integrity. SCFAs modulate the expression and function of tight junction proteins, including claudins and zonula occludens, which enhance barrier function, while P-gp modulates the movement of xenobiotics and bacterial toxins across the intestinal mucosa.38,39 Compromised intestinal barrier integrity can facilitate the translocation of microbial components and metabolites, such as lipopolysaccharide (LPS) and trimethylamine (TMA), into the systemic circulation. LPS, a glycolipid endotoxin derived from the outer membrane of many gram-negative pathogenic bacteria, exerts potent proinflammatory effects and further disrupts epithelial barrier function.40 TMA, a metabolite generated by gut microbiota from dietary choline, is subsequently oxidized in the liver to form trimethylamine-N-oxide (TMAO), a compound strongly implicated in the pathogenesis of cardiometabolic disorders and CRC.6,41
The microbiome is increasingly recognized as a key modulator in the pathophysiology of numerous human diseases, including cancer. Emerging evidence highlights its significant influence on the efficacy of cancer therapies, with studies indicating that modulation of the gut microbiome can alter therapeutic responses across various treatment modalities.42 Microbial-derived metabolites have been shown to influence tumour microenvironments, affecting gene expression, cell cycle regulation and apoptosis.43 By altering drug metabolism, the gut microbiome can modulate the bioavailability and efficacy of chemotherapeutic and immunotherapeutic agents, leading to enhanced immune responses and mitigation of treatment toxicities.44 A better understanding of an individual’s microbiome could lead to more tailored and effective cancer treatments, which are increasingly explored in the emerging fields of personalized medicine and pharmacomicrobiomics.45,46
Several recent papers have described relationships between altered gut microbial composition and various malignancies, including gastrointestinal and hematological cancers.47,48 Accumulating evidence indicates that the gut microbiome can modulate host immune responses, influencing outcomes across a spectrum of oncologic treatments, including chemotherapy, immunotherapy, and radiotherapy,49 and the gut microbiome has been proposed as a potential biomarker in cancer therapy.50,51 This narrative review summarizes current literature examining the relationship between the gut microbiome and its role in cancer development and therapeutic response. Relevant studies were identified through non-systematic searches of PubMed, Scopus, and Google Scholar using keywords such as “gut microbiome,” “cancer,” “gut microbial metabolites,” and “host-microbiome drug interactions.” Priority was given to peer-reviewed review articles and original research published in the past 5 to 10 years, although earlier foundational studies were included where appropriate. Articles were selected based on relevance and contribution to key themes, without formal inclusion or exclusion criteria or a systematic protocol. This manuscript aims to examine how the human gut microbiome contributes to cancer pathogenesis and explores how various microbial-derived metabolites interact with cancer treatments, influencing drug metabolism, therapeutic response, and resistance.
Dysbiosis has been increasingly recognized as a contributing factor in cancer development and progression, either through direct cellular interactions or the secretion of bioactive metabolites.43 This disruption in gut microbial homeostasis can result in an inflammatory environment, immune dysfunction and metabolic alterations, which may contribute to tumorigenesis. A reduction in beneficial bacteria (Lactobacillus, Bifidobacterium) and increased levels of pathogenic bacteria (Fusobacterium nucleatum, Escherichia coli) have been associated with immune evasion and tumour growth.52 Dysbiosis can promote chronic, systemic, low-grade inflammation by increasing the production of pro-inflammatory cytokines IL-6, IL-1β, and tumour necrosis factor (TNF)-α.35 Helicobacter pylori infection is a well-documented cause of gastric cancer, promoting tumorigenesis through chronic inflammation and activation of oncogenic pathways like β-catenin signalling.53 An overabundance of Enterococcus faecalis, E. coli, B. fragilis and Campylobacter has been implicated in developing CRC.54,55 These bacteria drive tumorigenesis by inducing inflammation56 and through the production of genotoxins— toxic compounds that cause DNA damage and disrupt DNA repair mechanisms—including colibactin and cytolethal distending toxin (CDT).52 Further, F. nucleatum enhances colorectal carcinogenesis progression through the actions of FadA and Fap2, adhesins that promote proliferation and immune evasion.57
Bioactive metabolites, generated from dietary components and microbial metabolic pathways, can influence cancer development and progression by affecting inflammation, immune response, and cellular signalling. Several important classes of microbial metabolites have been identified as key players in tumorigenesis, acting either as tumour-promoting or tumour-suppressing agents.
SCFAs are produced by microbial fermentation of non-digestible dietary fibre by gut bacteria and exert significant effects on cancer biology. The most abundant SCFAs, butyrate, acetate and propionate, constitute approximately 90% of the SCFAs produced by the microbiome.58 Butyrate, produced by bacteria such as F. prausnitzii, Roseburia intestinalis, and Agathobacter rectale, serves as a primary energy source for colonic epithelial cells.59 Butyrate supports mucosal integrity, preventing microbial translocation and systemic inflammation.60 At low concentrations, butyrate has been shown to inhibit histone deacetylases (HDACs), leading to increased apoptosis and reduced proliferation of cancer cells, particularly in CRC.61,62 Animal models have demonstrated that SCFAs enhance regulatory T-cell (Treg) differentiation and promote an anti-inflammatory microenvironment, which can attenuate tumour progression.63 In clinical trials, patients with advanced colorectal adenoma were found to have reductions of the main butyrate-generating taxa (Clostridia, Firmicutes, Eubacterium) and reduced fecal butyrate.64 A 2015 systematic review by Borges-Canha et al. reported that decreased butyrate and a microbial profile with reduced representation of butyrate producers were associated with colorectal carcinogenesis. 65 Table 2 provides a summary of the mechanisms of gut microbiota-derived metabolites.
TABLE 2 Cancer-related mechanisms, actions and effects of gut microbiota-derived metabolites
The gut microbiome modifies primary bile acids into secondary bile acids, which can have pro-carcinogenic effects.92 Colonic bacteria within the phylum Firmicutes have demonstrated 7-dehydroxylation activity, capable of metabolizing cholic and chenodeoxycholic acids into deoxycholic acid (DCA) and lithocholic acid (LCA).93 DCA and LCA have been linked to oxidative stress and DNA damage in colon epithelial cells, contributing to colorectal carcinogenesis.94 These metabolites activate nuclear receptors like the farnesoid X receptor (FXR) and pregnane X receptor (PXR), influencing bile acid homeostasis and inflammation pathways associated with cancer.95 Elevated DCA levels have been associated with the progression of CRC.94
Polyamines, such as putrescine, spermidine, and spermine, are synthesized through the decarboxylation of the amino acids, ornithine, arginine, and lysine. Depending on their circulating levels, polyamines can either promote normal cellular differentiation and intestinal mucosal integrity or contribute to tumorigenesis. 96 Elevated polyamine levels, which are linked with dysbiosis, have been associated with increased proliferation of cancer cells, reduced apoptosis and disruption of epithelial barrier integrity. Polyamines have induced oxidative stress, resulting in DNA damage and CRC in animal models.97 Spermidine reduces the concentration of IL-18 in the colon and has been implicated in modulating chromatin structure and gene expression, affecting pathways involved in cancer progression.96 Spermine has been associated with increased expression of catenin, involved in tumour cell proliferation.98
Ingested tryptophan (TRP) that is not absorbed in the small intestine is metabolized by colonic bacteria into several bioactive indole derivatives, which have dual roles in tumorigenesis (tumour-suppressing and pro-carcinogenic effects). Clostridium and Ruminococcus have been shown to degrade TRP to tryptamine by the action of tryptophan dehydrogenase, and indole-3-acetic acid (IAA) is synthesized by species within Bifidobacteria, Bacteroides and Eubacteria.99 Tryptophanase, expressed by certain Bacteroides and Lactobacillus species, generates indole-3-propionic acid (IPA), which has been shown to enhance gut epithelial integrity.100 IAA, IPA, indole-3-aldehyde (I3A), indole-3-lactic acid (ILA) and indoxyl-3-sulfate serve as ligands for the activation of aryl hydrocarbon receptor (AhR), expressed on the surface of neutrophils, macrophages, dendritic cells and TH17 cells.101 These metabolites mediate anti-inflammatory actions through AhR signalling, resulting in increased production of IL-22 and inhibition of LPS-induced IL-6 expression.102,103 The tumour-suppressing actions of indole-3-carbinol (I3C) through accelerated apoptosis are well characterized.104 Conversely, kynurenine, a tryptophan metabolite produced through the indoleamine 2,3-dioxygenase (IDO) pathway, has been linked to T-cell inhibition in the tumour microenvironment (TME), promoting cancer cell evasion from immune surveillance.101 High expression of IDO and tryptophan 2,3-dioxygenase (TDO) in the TME can result in local tryptophan deficiency, immune suppression and tumour expansion and is associated with poor prognosis in patients with gastric adenoma.105,106 Indeed, the use of IDO and TDO inhibitors to block tryptophan metabolism is currently being investigated in clinical trials.107
The gut microbiome shapes the metabolic fate of exogenous compounds. Gut microbes can modify therapeutic compounds directly as they pass through the GIT or influence their processing within the enterohepatic circulation,108 influencing the pharmacokinetics of various cancer therapies. These modifications may lead to bioactivation or inactivation depending on the activity of enzymes expressed by resident microbes.109 Further, the microbiome regulates host gene expression in both the liver and intestine, including those involved in detoxification pathways such as cytochrome P450 enzymes and multidrug resistance proteins.110 The gut microbiome also affects drug absorption, distribution and elimination. It exerts these effects by modulating intestinal permeability, altering the expression of drug transporters and directly binding to the compounds.111 Bacterial-derived metabolites, including SCFAs, bile acids, and polyamines, influence the expression of P-gp and other efflux transporters in the gut epithelium, affecting drug bioavailability.112
Inter-individual differences in drug response pose a significant challenge in cancer treatment. Accumulating evidence suggests that variability in gut microbiome characteristics influences drug response profiles.113 Recent research on gut microbial co-metabolism indicates substantial within-species variation in bacterial capacity to metabolize drugs,114 potentially explaining the wide variability in drug–microbiome interactions observed between individuals during treatment. Pharmacomicrobiomics is an emerging field that attempts to clarify the complex host–microbiome–drug interactions (HMDIs). It explores the molecular mechanisms that drive individual differences in clinical outcomes resulting from microbiota-mediated drug metabolism, while also examining how pharmaceutical agents, in turn, affect the composition and function of the microbiome.45,115 It is well established that the microbiome exerts regulatory control over the biotransformation, bioavailability, absorption and distribution of a wide range of pharmaceuticals.116,117
Substantial pre-clinical and human evidence confirms the GIT microbial environment can influence the bioavailability, efficacy, and toxicity of cancer therapeutic agents. Enteric bacterial metabolism can either inactivate these drugs or alter their absorption, resulting in lower plasma concentrations and reduced therapeutic efficacy. Several well-characterized HMDIs provide insight into how the gut microbiome can influence cancer treatment outcomes.
Irinotecan (CPT-11) is a widely used prodrug chemotherapeutic for CRC. Hepatic carboxylation converts CPT-11 into its active form, SN-38, which is later inactivated by glucuronidation in the liver.118 However, gut bacteria such as E. coli and Clostridium species express β-glucuronidases, which can deconjugate SN-38, leading to its reactivation in the intestine.119 This process results in severe gastrointestinal toxicity, including diarrhea, which can limit treatment efficacy.118 It is widely accepted that administration of cytotoxic agents results in changes to the gut microbiome.120 However, chemotherapy can disrupt niche-specific competitive inhibition, permitting pathobionts to flourish, which in turn may contribute to drug-induced toxicity. For example, a 2017 study of tumour-bearing rats reported that increased abundances of pathobiont species Fusobacteria and Proteobacteria were detected following irinotecan administration.121
Gemcitabine (2’,2’-difluorodeoxycytidine) is an antimetabolite used in the treatment of various solid tumours, including breast, lung, and ovarian cancers, which interferes with DNA replication, thereby halting the growth of rapidly dividing cancer cells.122 Gammaproteobacteria were shown to metabolize gemcitabine into an inactive form (2’,2’-difluorodeoxyuridine) through expression of cytidine deaminase, leading to treatment resistance.122,123
Methotrexate (MTX), an antimetabolite chemotherapy agent, is subject to microbial metabolism in the gut. MTX inhibits mammalian dihydrofolate reductase (DHFR) and has been shown to modify human GIT microbiota, which may elucidate differences in treatment responders and non-responders.124 Genes expressed by Firmicutes and Bacteroidetes metabolize MTX, reducing its bioavailability, and may contribute to drug resistance.125 Therefore, differences in GIT microbiome profiles may impact host therapeutic response outcomes.126
Cyclophosphamide (CTX), an alkylating agent used in various cancer therapies, is influenced by the immunomodulatory effects of gut microbiota. Gram-positive bacteria, including Lactobacillus and Enterococcus species, stimulate CTX-induced immune responses in the TME, indirectly promoting the activation of Th1 and Th17 cells and enhancing anti-tumour immunity.127 Barnesiella intestinihominis, a gram-negative bacterium, stimulates the accumulation of tumour-specific cytotoxic CD8+ and CD4+ T cells and enhances the infiltration of interferon (IFN)–γ–producing T cells into the TME following CTX treatment.128
The gut microbiome shapes innate and adaptive immune responses, influencing immune homeostasis, regulating chronic inflammation and suppressing tumour growth. The interaction between the microbiota and the host immune system is complex, involving immune cell modulation, cytokine signalling pathways and various receptors, including pattern recognition receptors such as the Toll-like receptor (TLR) superfamily.
Bacterial taxa, including A. muciniphila, B. fragilis, E. coli, and Lachnospiraceae and Bifidobacterium species, exhibit anti-inflammatory properties and are associated with immune cell activation.129 The gut microbiome modulates T-cell differentiation, influencing the balance between pro-inflammatory Th1/Th17 responses and anti-inflammatory Treg cells. B. fragilis produces polysaccharide A, which induces Treg differentiation and suppresses excessive inflammation. Segmented filamentous bacteria (SFB) promote Th17 responses, which can be beneficial for mucosal defense. Commensal bacteria, including E. coli, Bifidobacteria and SFB, stimulate B cell activation, leading to the production of IgA, which reinforces mucosal immunity by neutralizing pathogens and maintaining epithelial integrity.130 Commensal bacteria interact with host immune cells through TLRs, which helps maintain immune surveillance and inflammatory balance. Bifidobacteria and Lactobacilli promote the maturation of dendritic cells, enhancing antigen presentation and immune tolerance.131 Akkermansia and Bifidobacteria stimulate dendritic cells, leading to improved antigen presentation and activation of cytotoxic T cells.132
Other microbes, including F. nucleatum and Bacteroides vulgatus, are associated with cancer progression, in part, by driving chronic inflammation and facilitating immune evasion.57 While some Bacteroides species are beneficial, B. fragilis has been linked to immunotherapy resistance due to its role in suppressing immune responses and inducing regulatory T cells.133 Further, B. fragilis augments phagocytosis, polarizing macrophages to an M1 state.134 Enterococcus faecalis drives nuclear factor (NF)-κB pro-inflammatory pathways,135 while Peptostreptococcus anaerobius has been shown to induce reactive oxygen species (ROS) formation and stimulate cell proliferation through activation of the PI3K-Akt pathway.136,137
Microbial metabolites such as SCFAs influence macrophage polarization, shifting them from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype through histone acetylation, which promotes tissue repair and reduces inflammation.138 SCFAs, particularly butyrate, produced by F. prausnitzii and Ruminococcus, reinforce Treg activity while simultaneously enhancing cytotoxic T lymphocyte infiltration into tumours.139 Butyrate has been shown to inhibit the release of IL-6 and IL-12, modulate immune tolerance of colonic macrophages to commensal organisms,62 and induce apoptosis in cancer cells, enhancing the efficacy of gemcitabine.14
The gut microbiome also significantly influences the response to immune checkpoint inhibitors (ICIs), which target lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligand (PD-L1). Perhaps unsurprisingly, an inverse correlation has been reported between antibiotic treatment and positive ICI outcomes in observational studies.141–143 The abundance levels of specific bacterial species have been associated with enhanced efficacy of ICIs by promoting immune activation and improving therapy response rates.144–146 Higher microbial diversity has been linked to improved responses to anti-PD-1 therapy in patients with lung and renal carcinoma; in particular, non-responders to PD-1 blockade were found to have low levels of A. muciniphila.143 A. muciniphila enhances gut epithelial integrity, promotes immune system activation and inhibits inflammation. 147 Higher abundances of Bifidobacteria have been reported in patients responding to ICIs, which appear to promote dendritic cell activation and augment anti-tumour immune responses, although the specific mechanisms underlying these immunomodulating effects are still unknown.148–150 Profiling of gut microbiota in melanoma patients receiving combined immune checkpoint blockade targeting PD-1 and CTLA-4 demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with adverse events.151
Various factors, particularly immunological modulation, critically influence tumour progression and therapeutic response to ionizing radiation. Radiotherapy has been shown to induce immunogenic cell death, facilitating antigen release and enhancing the recruitment and infiltration of effector lymphocytes into the TME. Radiation therapy is a cornerstone of cancer treatment; however, its efficacy and side effects can be influenced by the gut microbiome. Radiation therapy, particularly for abdominal and pelvic cancers, can cause significant gastrointestinal side effects, including mucositis, diarrhea, and dysbiosis.152 Radiation exposure often leads to dysbiosis, characterized by a relative decrease in the richness of favourable microorganisms, e.g., Lactobacilli and Bifidobacteria, and an increase in the richness of opportunistic pathogens, e.g., Fusobacteria and Clostridium difficile. Dysbiosis following radiation exposure may exacerbate radiation enteropathy, resulting from impaired epithelial integrity, bacterial translocation and systemic inflammation.153 Mounting evidence suggests microbiome-mediated interactions impact both radiation sensitivity and toxicity, impacting treatment outcomes. Certain bacterial species can enhance tumour response to radiation therapy by modulating immune activity, oxidative stress and antioxidant responses, and augmenting DNA repair pathways.
A. muciniphila has been linked with improved responses to radiation due to its role in promoting anti-tumour immunity. Previous studies have demonstrated a positive correlation between relative abundances of A. muciniphila and clinical responses to radiotherapy.128 SCFAs and other bacterial metabolites promote the expansion of regulatory Tregs, reducing the effectiveness of radiation-induced immune responses.155 Chronic inflammation induced by pathogenic bacteria may activate NF-κB and signal transducer and activator of transcription (STAT)3 pathways, which promote tumour survival and resistance to radiation.156
Some bacterial metabolites can impact DNA repair pathways, making tumour cells more susceptible to radiation-induced damage. SCFAs, particularly acetate and butyrate, influence epigenetic modifications that upregulate DNA repair genes.157 Conversely, certain bacteria can enhance the DNA repair capabilities of tumour cells, leading to increased radiation resistance.158 B fragilis, for example, has been demonstrated to stimulate host cellular stress responses,159 which may enhance the ability of cancer cells to repair radiation-induced DNA damage.
ROS generated during radiotherapy serve as key mediators of oxidative stress, inducing extensive molecular and cellular damage within tumour cells. The gut microbiome can modulate cellular antioxidant defenses, enhancing radiation-induced tumour cell death and reducing radiation sensitivity. The antioxidant capacity of several Lactobacilli strains has been described, which includes producing ROS-scavenging metabolites and regulating antioxidant enzyme activity and signalling pathways.160,161 In murine models, L. casei increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity, while L. plantarum could attenuate oxidative stress induced by D-galactose.162,163 Early in-vitro studies demonstrated L. acidophilus is capable of protecting against lipid peroxidation, and L. fermentum species were shown to have SOD activity.164,165 Further, some bacteria affect host iron regulation, impacting the Fenton reaction and decreasing the generation of cytotoxic free radicals.16 Interestingly, most pathogenic GIT bacteria possess enhanced systems for acquiring free iron, enabling them to outcompete commensal microbiota. Iron deficiency anemia is a common clinical manifestation of CRC patients, necessitating iron supplementation. However, the route of iron administration may contribute to a pro-carcinogenic microbial profile.167 Oral supplementation can increase the amount of iron directly available to gut microbes, leading to the proliferation of oncogenic species.168 This microbial shift is less likely following intravenous administration, which doesn’t increase luminal iron.169
The gut microbiome is central in regulating metabolic, immune, and inflammatory processes. Gaining deeper insight into host–microbiome–drug relationships may lead to innovative microbiome-targeted strategies that enhance oncologic treatment efficacy. Emerging evidence supports the utility of microbial signatures as predictive biomarkers for treatment response, representing a promising frontier in precision oncology. As the field advances, the integration of microbiome-informed diagnostics and therapeutics into clinical workflows may enable more effective, personalized treatment paradigms tailored to individual microbiota profiles. By leveraging microbiome insights, clinicians can refine therapeutic approaches, enhance patient outcomes, and minimize treatment-related complications, moving toward a more precise and individualized approach to oncology care.
The gut microbiome is a critical modulator of host physiology, exerting both local and systemic effects by preserving intestinal epithelial barrier integrity, regulating host metabolic homeostasis, and modulating innate and adaptive immune responses. Dysregulation of the gut microbiome is increasingly implicated in the initiation and progression of various malignancies, mediated through mechanisms including chronic inflammation, disruption of immune homeostasis, and alterations in microbial metabolic activity. The human microbiome may directly contribute to oncogenesis by modulating anti-tumour immune surveillance and shaping host responses to treatment. Microbial-mediated drug resistance is an ongoing concern in cancer therapy. The current review described several bidirectional interactions between the gut microbiome and cancer, highlighting the microbiota’s capacity to influence the pharmacokinetics of anticancer therapies, thereby affecting treatment efficacy and toxicity profiles. Gut microbial enzymes may directly modify drugs as they pass through the intestinal tract before they reach their target or indirectly by affecting detoxification pathways within the enterohepatic circulation, impacting drug clearance mechanisms. A better understanding of HMDIs could lead to enhanced treatment outcomes by enabling the development of personalized microbiome-targeted therapies, such as identifying microbial biomarkers that predict drug efficacy or toxicity, engineering probiotics to modulate specific immune pathways, and tailoring antibiotic or dietary interventions to preserve beneficial microbial communities during treatment.
1Clinical Gerontology, National Ageing Research Institute, Melbourne, VIC, Australia
2Department of Biomedical, Health and Exercise Sciences, School of Health Sciences, Swinburne University of Technology, Hawthorn, VIC, Australia
3Lifeplus International, Batesville, AR, USA
4Functional Nutrition, Oxidation and Cardiovascular Diseases Group (NFOC-Salut), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain
5Sport, Performance and Nutrition Research Group, School of Allied Health, Human Services and Sport, La Trobe University, Bundoora, VIC, Australia
Not applicable
We have read and understood the CAND Journal’s policy on conflicts of interest and declare that we have none.
This research did not receive any funding.
1. Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human microbiome. Nutr Rev. 2012;70(Suppl 1):S38–S44. https://doi.org/10.1111/j.1753-4887.2012.00493.x
Crossref PubMed PMC
2. Guarner F, Malagelada JR. Gut flora in health and disease. Lancet. 2003;361(9356):512–519. https://doi.org/10.1016/S0140-6736(03)12489-0
Crossref PubMed
3. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124(4):837–848. https://doi.org/10.1016/j.cell.2006.02.017
Crossref PubMed
4. Lloyd-Price J, Mahurkar A, Rahnavard G, et al. Strains, functions and dynamics in the expanded Human Microbiome Project. Nature. 2017;550(7674):61–66. https://doi.org/10.1038/nature23889
Crossref PubMed PMC
5. O’Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep. 2006;7(7):688–693. https://doi.org/10.1038/sj.embor.7400731
Crossref
6. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev. 2010;90(3):859–904. https://doi.org/10.1152/physrev.00045.2009
Crossref PubMed
7. Human Microbiome Project C. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486(7402):207–214. https://doi.org/10.1038/nature11234
Crossref PubMed PMC
8. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449(7164):804–810. https://doi.org/10.1038/nature06244
Crossref PubMed PMC
9. Flint HJ, Scott KP, Louis P, Duncan SH. The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol. 2012;9(10):577–589. https://doi.org/10.1038/nrgastro.2012.156
Crossref PubMed
10. Rajilić-Stojanović M, Heilig HG, Molenaar D, et al. Development and application of the human intestinal tract chip, a phylogenetic microarray: analysis of universally conserved phylotypes in the abundant microbiota of young and elderly adults. Environ Microbiol. 2009;11(7):1736–1751. https://doi.org/10.1111/j.1462-2920.2009.01900.x
Crossref
11. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65. https://doi.org/10.1038/nature08821
Crossref PubMed PMC
12. Claesson MJ, Cusack S, O’Sullivan O, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A. 2011;108(Suppl 1):4586–4591. https://doi.org/10.1073/pnas.1000097107
Crossref PMC
13. Ghoddusi H, Tamime A. Biology of Bifidobacteria. In: Batt CA, Tortorello ML, eds. Encyclopedia of Food Microbiology. Elsevier, Ltd.; 2014:639–645.
Crossref
14. de Melo Pereira GV, de Oliveira Coelho B, Magalhães Júnior AI, Thomaz-Soccol V, Soccol CR. How to select a probiotic? A review and update of methods and criteria. Biotechnol Adv. 2018;36(8):2060–2076. https://doi.org/10.1016/j.biotechadv.2018.09.003
Crossref PubMed
15. Gill SR, Pop M, Deboy RT, et al. Metagenomic analysis of the human distal gut microbiome. Science. 2006;312(5778):1355–1359. https://doi.org/10.1126/science.1124234
Crossref PubMed PMC
16. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science. 2005;308(5728):1635–1638. https://doi.org/10.1126/science.1110591
Crossref PubMed PMC
17. Peterson J, Garges S, Giovanni M, et al. The NIH Human Microbiome Project. Genome Res. 2009;19(12):2317–2323. https://doi.org/10.1101/gr.096651.109
Crossref PubMed PMC
18. Wiertsema SP, van Bergenhenegouwen J, Garssen J, Knippels LMJ. The interplay between the gut microbiome and the immune system in the context of infectious diseases throughout life and the role of nutrition in optimizing treatment strategies. Nutrients. 2021;13(3):886. https://doi.org/10.3390/nu13030886
Crossref PubMed PMC
19. Petersen C, Round JL. Defining dysbiosis and its influence on host immunity and disease. Cell Microbiol. 2014;16(7):1024–1033. https://doi.org/10.1111/cmi.12308
Crossref PubMed PMC
20. Bäckhed F, Fraser CM, Ringel Y, et al. Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications. Cell Host Microbe. 2012;12(5):611–622. https://doi.org/10.1016/j.chom.2012.10.012
Crossref PubMed
21. DeGruttola AK, Low D, Mizoguchi A, Mizoguchi E. Current understanding of dysbiosis in disease in human and animal models. Inflamm Bowel Dis. 2016;22(5):1137–1150. https://doi.org/10.1097/MIB.0000000000000750
Crossref PubMed PMC
22. Lavelle A, Sokol H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2020;17(4):223–237. https://doi.org/10.1038/s41575-019-0258-z
Crossref PubMed
23. Madhogaria B, Bhowmik P, Kundu A. Correlation between human gut microbiome and diseases. Infect Med (Beijing). 2022;1(3):180–191. https://doi.org/10.1016/j.imj.2022.08.004
Crossref PubMed PMC
24. Korf JM, Ganesh BP, McCullough LD. Gut dysbiosis and age-related neurological diseases in females. Neurobiol Dis. 2022;168:105695. https://doi.org/10.1016/j.nbd.2022.105695
Crossref PubMed PMC
25. Cryan JF, O’Riordan KJ, Sandhu K, Peterson V, Dinan TG. The gut microbiome in neurological disorders. Lancet Neurol. 2020;19(2):179–194. https://doi.org/10.1016/S1474-4422(19)30356-4
Crossref
26. Barry DJ, Wu SSX, Cooke MB. The relationship between gut microbiota, muscle mass and physical function in older individuals: a systematic review. Nutrients. 2024;17(1):81. https://doi.org/10.3390/nu17010081
Crossref
27. Le Ngoc K, Pham TTH, Nguyen TK, Huong PT. Pharmacomicrobiomics in precision cancer therapy: bench to bedside. Front Immunol. 2024;15:1428420. https://doi.org/10.3389/fimmu.2024.1428420
Crossref PubMed PMC
28. Liu X. Microbiome. Yale J Bill Med. 2016;89(3):275–276.
29. Lederberg J. Infectious history. Science. 2000;288(5464):287–293. https://doi.org/10.1126/science.288.5464.287
Crossref PubMed
30. Consortium IHGS. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931–945. https://doi.org/10.1038/nature03001
Crossref
31. Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science. 2001;292(5519):1115–1118. https://doi.org/10.1126/science.1058709
Crossref PubMed
32. Macpherson AJ, Gatto D, Sainsbury E, Harriman GR, Hengartner H, Zinkernagel RM. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science. 2000;288(5474):2222–2226. https://doi.org/10.1126/science.288.5474.2222
Crossref PubMed
33. Kim KS. Regulation of T cell repertoires by commensal microbiota. Front Cell Infect Microbiol. 2022;12:1004339. https://doi.org/10.3389/fcimb.2022.1004339
Crossref PubMed PMC
34. Song B, Li P, Yan S, et al. Effects of dietary astragalus polysaccharide supplementation on the Th17/Treg balance and the gut microbiota of broiler chickens challenged with necrotic enteritis. Front Immunol. 2022;13:781934. https://doi.org/10.3389/fimmu.2022.781934
35. Zhao M, Chu J, Feng S, et al. Immunological mechanisms of inflammatory diseases caused by gut microbiota dysbiosis: a review. Biomed Pharmacother. 2023;164:114985. https://doi.org/10.1016/j.biopha.2023.114985
Crossref PubMed
36. Mo C, Lou X, Xue J, et al. The influence of Akkermansia muciniphila on intestinal barrier function. Gut Pathog. 2024;16(1):41. https://doi.org/10.1186/s13099-024-00635-7
Crossref PubMed PMC
37. Woelfel S, Silva MS, Stecher B. Intestinal colonization resistance in the context of environmental, host, and microbial determinants. Cell Host Microbe. 2024;32(6):820–836. https://doi.org/10.1016/j.chom.2024.05.002
Crossref PubMed
38. Schreiber F, Balas I, Robinson MJ, Bakdash G. Border control: the role of the microbiome in regulating epithelial barrier function. Cells. 2024;13(6):477. https://doi.org/10.3390/cells13060477
Crossref PubMed PMC
39. Ahmed J, II, Abdul Hamid AA, Abd Halim KB, Che Has AT. P-glycoprotein: new insights into structure, physiological function, regulation and alterations in disease. Heliyon. 2022;8(6):e09777. https://doi.org/10.1016/j.heliyon.2022.e09777
Crossref
40. Farhana A, Khan Y. Biochemistry, lipopolysaccharides. National Library of Medicine, National Center for Biotechnology Information; 2023. https://www.ncbi.nlm.nih.gov/books/NBK554414/
41. Thomas AM, Manghi P, Asnicar F, et al. Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation. Nat Med. 2019;25(4):667–678. https://doi.org/10.1038/s41591-019-0405-7
Crossref PubMed PMC
42. Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell. 2018;33(4):570–580. https://doi.org/10.1016/j.ccell.2018.03.015
Crossref PubMed PMC
43. Perez Escriva P, Correia Tavares Bernardino C, Letellier E. De-coding the complex role of microbial metabolites in cancer. Cell Rep. 2025;44(3):115358. https://doi.org/10.1016/j.celrep.2025.115358
Crossref PubMed
44. Torres-Carrillo N, Martinez-Lopez E, Torres-Carrillo NM, et al. Pharmacomicrobiomics and drug-infection interactions: the impact of commensal, symbiotic and pathogenic microorganisms on a host response to drug therapy. Int J Mol Sci. 2023;24(23):17100. https://doi.org/10.3390/ijms242317100
Crossref PubMed PMC
45. Doestzada M, Vila AV, Zhernakova A, et al. Pharmacomicrobiomics: a novel route towards personalized medicine? Protein Cell. 2018;9(5):432–445. https://doi.org/10.1007/s13238-018-0547-2
Crossref PubMed PMC
46. Arga KY, Attia H, Aziz RK. Pharmacomicrobiomics-guided precision oncology: a new frontier of P4 (predictive, personalized, preventive, and participatory) medicine and microbiome-based therapeutics. OMICS. 2024;28(1):5–7. https://doi.org/10.1089/omi.2023.0254
Crossref PubMed
47. Dumitru IG, Todor SB, Ichim C, Helgiu C, Helgiu A. A literature review on the impact of the gut microbiome on cancer treatment efficacy, disease evolution and toxicity: the implications for hematological malignancies. J Clin Med. 2025;14(9):2982. https://doi.org/10.3390/jcm14092982
Crossref PubMed PMC
48. Meng C, Bai C, Brown TD, Hood LE, Tian Q. Human gut microbiota and gastrointestinal cancer. Genomics Proteomics Bioinformatics. 2018;16(1):33–49. https://doi.org/10.1016/j.gpb.2017.06.002
Crossref PubMed PMC
49. Clayton TA, Lindon JC, Cloarec O, et al. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature. 2006;440(7087):1073–1077. https://doi.org/10.1038/nature04648
Crossref PubMed
50. Zhang M, Liu J, Xia Q. Role of gut microbiome in cancer immunotherapy: from predictive biomarker to therapeutic target. Exp Hematol Oncol. 2023;12(1):84. https://doi.org/10.1186/s40164-023-00442-x
Crossref PubMed PMC
51. Han EJ, Ahn JS, Choi YJ, Kim DH, Choi JS, Chung HJ. Exploring the gut microbiome: a potential biomarker for cancer diagnosis, prognosis, and therapy. Biochim Biophys Acta Rev Cancer. 2025;1880(1):189251. https://doi.org/10.1016/j.bbcan.2024.189251
Crossref
52. Ahmad A, Mahmood N, Raza MA, et al. Gut microbiota and their derivatives in the progression of colorectal cancer: mechanisms of action, genome and epigenome contributions. Heliyon. 2024;10(8):e29495. https://doi.org/10.1016/j.heliyon.2024.e29495
Crossref PubMed PMC
53. Polk DB, Peek RM, Jr. Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer. 2010;10(6):403–14. https://doi.org/10.1038/nrc2857
Crossref PubMed PMC
54. Ternes D, Karta J, Tsenkova M, Wilmes P, Haan S, Letellier E. Microbiome in colorectal cancer: how to get from meta-omics to mechanism? Trends Microbiol. 2020;28(5):401–423. https://doi.org/10.1016/j.tim.2020.01.001
Crossref PubMed
55. Arthur JC, Perez-Chanona E, Muhlbauer M, et al. Intestinal inflammation targets cancer-inducing activity of the microbiota. Science. 2012;338(6103):120–123. https://doi.org/10.1126/science.1224820
Crossref PubMed PMC
56. Gagniere J, Raisch J, Veziant J, et al. Gut microbiota imbalance and colorectal cancer. World J Gastroenterol. 2016;22(2):501–518. https://doi.org/10.3748/wjg.v22.i2.501
Crossref PubMed PMC
57. Lopez LR, Bleich RM, Arthur JC. Microbiota effects on carcinogenesis: initiation, promotion, and progression. Annu Rev Med. 2021;72:243–261. https://doi.org/10.1146/annurev-med-080719-091604
Crossref
58. Rios-Covian D, Ruas-Madiedo P, Margolles A, Gueimonde M, de Los Reyes-Gavilan CG, Salazar N. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol. 2016;7:185. https://doi.org/10.3389/fmicb.2016.00185
Crossref PubMed PMC
59. Hodgkinson K, El Abbar F, Dobranowski P, et al. Butyrate’s role in human health and the current progress towards its clinical application to treat gastrointestinal disease. Clin Nutr. 2023;42(2):61–75. https://doi.org/10.1016/j.clnu.2022.10.024
Crossref
60. O’Keefe SJ. Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol. 2016;13(12):691–706. https://doi.org/10.1038/nrgastro.2016.165
Crossref
61. Buda A, Qualtrough D, Jepson MA, Martines D, Paraskeva C, Pignatelli M. Butyrate downregulates alpha2beta1 integrin: a possible role in the induction of apoptosis in colorectal cancer cell lines. Gut. 2003;52(5):729–734. https://doi.org/10.1136/gut.52.5.729
Crossref PubMed PMC
62. Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2014;111(6):2247–2252. https://doi.org/10.1073/pnas.1322269111
Crossref PubMed PMC
63. Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504(7480):446–450. https://doi.org/10.1038/nature12721
Crossref PubMed
64. Chen HM, Yu YN, Wang JL, et al. Decreased dietary fiber intake and structural alteration of gut microbiota in patients with advanced colorectal adenoma. Am J Clin Nutr. 2013;97(5):1044–1052. https://doi.org/10.3945/ajcn.112.046607
Crossref PubMed
65. Borges-Canha M, Portela-Cidade JP, Dinis-Ribeiro M, Leite-Moreira AF, Pimentel-Nunes P. Role of colonic microbiota in colorectal carcinogenesis: a systematic review. Rev Esp Enferm Dig. 2015;107(11):659–671. https://doi.org/10.17235/reed.2015.3830/2015
Crossref PubMed
66. Ha HC, Sirisoma NS, Kuppusamy P, Zweier JL, Woster PM, Casero RA, Jr. The natural polyamine spermine functions directly as a free radical scavenger. Proc Natl Acad Sci U S A. 1998;95(19):11140–11145. https://doi.org/10.1073/pnas.95.19.11140
Crossref PubMed PMC
67. Gao XN, Gao EJ, Zhu MC. Synthesis, crystal structure, DNA binding, and cytotoxicity of a Zn(II) complex constructed from phenylacetic acid. J Structur Chem. 2019;60(7):1180–1188. https://doi.org/10.1134/S0022476619070217
Crossref
68. Rupasinghe HPV, Parmar I, Neir SV. Biotransformation of cranberry proanthocyanidins to probiotic metabolites by Lactobacillus rhamnosus enhances their anticancer activity in HepG2 cells in vitro. Oxid Med Cell Longev. 2019;2019:4750795. https://doi.org/10.1155/2019/4750795
Crossref PubMed PMC
69. Joachim L, Gottert S, Sax A, et al. The microbial metabolite desaminotyrosine enhances T-cell priming and cancer immunotherapy with immune checkpoint inhibitors. EBioMedicine. 2023;97:104834. https://doi.org/10.1016/j.ebiom.2023.104834
Crossref PubMed PMC
70. Guo C, Xie S, Chi Z, et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity. 2016;45(4):802–816. https://doi.org/10.1016/j.immuni.2016.09.008
Crossref PubMed
71. Cheng K, Raufman JP. Bile acid-induced proliferation of a human colon cancer cell line is mediated by transactivation of epidermal growth factor receptors. Biochem Pharmacol. 2005;70(7):1035–1047. https://doi.org/10.1016/j.bcp.2005.07.023
Crossref PubMed
72. Miko E, Vida A, Kovacs T, et al. Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness. Biochim Biophys Acta Bioenerg. 2018;1859(9):958–974. https://doi.org/10.1016/j.bbabio.2018.04.002
Crossref PubMed
73. Behary J, Amorim N, Jiang XT, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun. 2021;12(1):187. https://doi.org/10.1038/s41467-020-20422-7
Crossref PubMed PMC
74. Luu M, Riester Z, Baldrich A, et al. Microbial short-chain fatty acids modulate CD8(+) T cell responses and improve adoptive immunotherapy for cancer. Nat Commun. 2021;12(1):4077. https://doi.org/10.1038/s41467-021-24331-1
Crossref PubMed PMC
75. He Y, Fu L, Li Y, et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8(+) T cell immunity. Cell Metab. 2021;33(5):988–1000.e7. https://doi.org/10.1016/j.cmet.2021.03.002
Crossref PubMed
76. Kang X, Liu C, Ding Y, et al. Roseburia intestinalis generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8(+) T cells. Gut. 2023;72(11):2112–2122. https://doi.org/10.1136/gutjnl-2023-330291
Crossref PubMed PMC
77. Zhu X, Li K, Liu G, et al. Microbial metabolite butyrate promotes anti-PD-1 antitumor efficacy by modulating T cell receptor signaling of cytotoxic CD8 T cell. Gut Microbes. 2023;15(2):2249143. https://doi.org/10.1080/19490976.2023.2249143
Crossref PubMed PMC
78. Coutzac C, Jouniaux JM, Paci A, et al. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat Commun. 2020;11(1):2168. https://doi.org/10.1038/s41467-020-16079-x
Crossref PubMed PMC
79. Ternes D, Tsenkova M, Pozdeev VI, et al. The gut microbial metabolite formate exacerbates colorectal cancer progression. Nat Metab. 2022;4(4):458–475. https://doi.org/10.1038/s42255-022-00558-0
Crossref PubMed PMC
80. Gao G, Shen S, Zhang T, et al. Lacticaseibacillus rhamnosus Probio-M9 enhanced the antitumor response to anti-PD-1 therapy by modulating intestinal metabolites. EBioMedicine. 2023;91:104533. https://doi.org/10.1016/j.ebiom.2023.104533
Crossref PubMed PMC
81. Jiang SS, Xie YL, Xiao XY, et al. Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer. Cell Host Microbe. 2023;31(5):781–797 e9. https://doi.org/10.1016/j.chom.2023.04.010
Crossref PubMed
82. Hezaveh K, Shinde RS, Klotgen A, et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity. 2022;55(2):324–340.e8. https://doi.org/10.1016/j.immuni.2022.01.006
Crossref PubMed PMC
83. Bender MJ, McPherson AC, Phelps CM, et al. Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. Cell. 2023;186(9):1846–1862.e26. https://doi.org/10.1016/j.cell.2023.03.011
Crossref PubMed PMC
84. Liu D, Liang CH, Huang B, et al. Tryptophan metabolism acts as a new anti-ferroptotic pathway to mediate tumor growth. Adv Sci (Weinh). 2023;10(6):e2204006. https://doi.org/10.1002/advs.202204006
Crossref PubMed PMC
85. Mohseni AH, Taghinezhad-S S, Beatty PL, Finn OJ. Abstract 644: gut microbiota-derived metabolites as regulators of immunity in pre-cancer. Cancer Res. 2023;83(7 Suppl):644. https://doi.org/10.1158/1538-7445.AM2023-644
Crossref
86. Megna BW, Carney PR, Nukaya M, Geiger P, Kennedy GD. Indole-3-carbinol induces tumor cell death: function follows form. J Surg Res. 2016;204(1):47–54. https://doi.org/10.1016/j.jss.2016.04.021
Crossref PubMed PMC
87. Tintelnot J, Xu Y, Lesker TR, et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature. 2023;615(7950):168–174. https://doi.org/10.1038/s41586-023-05728-y
Crossref PubMed PMC
88. Fong W, Li Q, Ji F, et al. Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis. Gut. 2023;72(12):2272–2285. https://doi.org/10.1136/gutjnl-2023-329543
Crossref PubMed PMC
89. Zhang Q, Zhao Q, Li T, et al. Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8(+) T cell immunity. Cell Metab. 2023;35(6):943–960.e9. https://doi.org/10.1016/j.cmet.2023.04.015
Crossref PubMed
90. Sugimura Y, Kanda A, Sawada K, et al. Association between gut microbiota and body composition in Japanese general population: a focus on gut microbiota and skeletal muscle. Int J Environ Res Public Health. 2022;19(12)7464. https://doi.org/10.3390/ijerph19127464
Crossref PubMed PMC
91. Han JX, Tao ZH, Wang JL, et al. Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer. Nat Microbiol. 2023;8(5):919–933. https://doi.org/10.1038/s41564-023-01363-5
Crossref PubMed
92. Kiriyama Y, Nochi H. Physiological role of bile acids modified by the gut microbiome. Microorganisms. 2021;10(1):68. https://doi.org/10.3390/microorganisms10010068
Crossref
93. Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47(2):241–259. https://doi.org/10.1194/jlr.R500013-JLR200
Crossref
94. Zeng H, Umar S, Rust B, Lazarova D, Bordonaro M. Secondary bile acids and short chain fatty acids in the colon: a focus on colonic microbiome, cell proliferation, inflammation, and cancer. Int J Mol Sci. 2019;20(5):1214. https://doi.org/10.3390/ijms20051214
Crossref PubMed PMC
95. Mancin L, Wu GD, Paoli A. Gut microbiota-bile acid-skeletal muscle axis. Trends Microbiol. 2023;31(3):254–269. https://doi.org/10.1016/j.tim.2022.10.003
Crossref
96. Holbert CE, Cullen MT, Casero RA, Jr., Stewart TM. Polyamines in cancer: integrating organismal metabolism and antitumour immunity. Nat Rev Cancer. 2022;22(8):467–480. https://doi.org/10.1038/s41568-022-00473-2
Crossref PubMed PMC
97. Goodwin AC, Destefano Shields CE, Wu S, et al. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc Natl Acad Sci U S A. 2011;108(37):15354–15359. https://doi.org/10.1073/pnas.1010203108
Crossref PubMed PMC
98. Wang C, Ruan P, Zhao Y, et al. Spermidine/spermine N1-acetyltransferase regulates cell growth and metastasis via AKT/beta-catenin signaling pathways in hepatocellular and colorectal carcinoma cells. Oncotarget. 2017;8(1):1092–1109. https://doi.org/10.18632/oncotarget.13582
Crossref PMC
99. Williams BB, Van Benschoten AH, Cimermancic P, et al. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe. 2014;16(4):495–503. https://doi.org/10.1016/j.chom.2014.09.001
Crossref PubMed PMC
100. Rothhammer V, Mascanfroni ID, Bunse L, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016;22(6):586–597. https://doi.org/10.1038/nm.4106
Crossref PubMed PMC
101. Gupta SK, Vyavahare S, Duchesne Blanes IL, Berger F, Isales C, Fulzele S. Microbiota-derived tryptophan metabolism: impacts on health, aging, and disease. Exp Gerontol. 2023;183:112319. https://doi.org/10.1016/j.exger.2023.112319
Crossref PubMed
102. Zhang HL, Zhang AH, Miao JH, et al. Targeting regulation of tryptophan metabolism for colorectal cancer therapy: a systematic review. RSC Adv. 2019;9(6):3072–3080. https://doi.org/10.1039/c8ra08520j
Crossref PubMed PMC
103. Walter K, Grosskopf H, Karkossa I, von Bergen M, Schubert K. Proteomic characterization of the cellular effects of AhR activation by microbial tryptophan catabolites in endotoxin-activated human macrophages. Int J Environ Res Public Health. 2021;18(19):10336. https://doi.org/10.3390/ijerph181910336
Crossref PubMed PMC
104. Liu Y, Pei Z, Pan T, Wang H, Chen W, Lu W. Indole metabolites and colorectal cancer: gut microbial tryptophan metabolism, host gut microbiome biomarkers, and potential intervention mechanisms. Microbiol Res. 2023;272:127392. https://doi.org/10.1016/j.micres.2023.127392
Crossref PubMed
105. Liu H, Shen Z, Wang Z, et al. Increased expression of IDO associates with poor postoperative clinical outcome of patients with gastric adenocarcinoma. Sci Rep. 2016;6:21319. https://doi.org/10.1038/srep21319
Crossref PubMed PMC
106. Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34(3):137–143. https://doi.org/10.1016/j.it.2012.10.001
Crossref PMC
107. Nayak-Kapoor A, Hao Z, Sadek R, et al. Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. J Immunother Cancer. 2018;6(1):61. https://doi.org/10.1186/s40425-018-0351-9
Crossref PubMed PMC
108. Bilotta AJ, Cong Y. Gut microbiota metabolite regulation of host defenses at mucosal surfaces: implication in precision medicine. Precis Clin Med. 2019;2(2):110–119. https://doi.org/10.1093/pcmedi/pbz008
Crossref PubMed PMC
109. Le Bastard Q, Al-Ghalith GA, Gregoire M, et al. Systematic review: human gut dysbiosis induced by non-antibiotic prescription medications. Aliment Pharmacol Ther. 2018;47(3):332–345. https://doi.org/10.1111/apt.14451
Crossref
110. Mruk-Mazurkiewicz H, Kulaszynska M, Jakubczyk K, et al. Clinical relevance of gut microbiota alterations under the influence of selected drugs-updated review. Biomedicines. 2023;11(3):952. https://doi.org/10.3390/biomedicines11030952
Crossref PubMed PMC
111. Musso G, Gambino R, Cassader M. Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med. 2011;62:361–380. https://doi.org/10.1146/annurev-med-012510-175505
Crossref PubMed
112. Foley SE, Tuohy C, Dunford M, et al. Gut microbiota regulation of P-glycoprotein in the intestinal epithelium in maintenance of homeostasis. Microbiome. 2021;9(1):183. https://doi.org/10.1186/s40168-021-01137-3
Crossref PubMed PMC
113. Savage N. The complex relationship between drugs and the microbiome. Nature. 2020;577(7792):S10–S11. https://doi.org/10.1038/d41586-020-00196-0
Crossref PubMed
114. Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 2019;570(7762):462–467. https://doi.org/10.1038/s41586-019-1291-3
Crossref PubMed PMC
115. Wang S, Ju D, Zeng X. Mechanisms and clinical implications of human gut microbiota-drug interactions in the precision medicine era. Biomedicines. 2024;12(1):194. https://doi.org/10.3390/biomedicines12010194
Crossref PubMed PMC
116. Wilson ID, Nicholson JK. Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res. 2017;179:204–222. https://doi.org/10.1016/j.trsl.2016.08.002
Crossref
117. Enright EF, Gahan CG, Joyce SA, Griffin BT. The impact of the gut microbiota on drug metabolism and clinical outcome. Yale J Biol Med. 2016;89(3):375–382.
PubMed PMC
118. Mahdy MS, Azmy AF, Dishisha T, et al. Irinotecan-gut microbiota interactions and the capability of probiotics to mitigate Irinotecan-associated toxicity. BMC Microbiol. 2023;23(1):53. https://doi.org/10.1186/s12866-023-02791-3
Crossref PubMed PMC
119. Yue B, Gao R, Wang Z, Dou W. Microbiota-host-irinotecan axis: a new insight toward irinotecan chemotherapy. Front Cell Infect Microbiol. 2021;11:710945. https://doi.org/10.3389/fcimb.2021.710945
Crossref PubMed PMC
120. Montassier E, Gastinne T, Vangay P, et al. Chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment Pharmacol Ther. 2015;42(5):515–528. https://doi.org/10.1111/apt.13302
Crossref PubMed
121. Forsgard RA, Marrachelli VG, Korpela K, et al. Chemotherapy-induced gastrointestinal toxicity is associated with changes in serum and urine metabolome and fecal microbiota in male Sprague-Dawley rats. Cancer Chemother Pharmacol. 2017;80(2):317–332. https://doi.org/10.1007/s00280-017-3364-z
Crossref PubMed PMC
122. Geller LT, Barzily-Rokni M, Danino T, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017;357(6356):1156–1160. https://doi.org/10.1126/science.aah5043
Crossref PubMed PMC
123. Mendes I, Vale N. Overcoming microbiome-acquired gemcitabine resistance in pancreatic ductal adenocarcinoma. Biomedicines. 2024;12(1):227. https://doi.org/10.3390/biomedicines12010227
Crossref PubMed PMC
124. Nayak RR, Alexander M, Deshpande I, et al. Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation. Cell Host Microbe. 2021;29(3):362–377.e11. https://doi.org/10.1016/j.chom.2020.12.008
Crossref PubMed PMC
125. Han M, Zhang N, Mao Y, et al. The potential of gut microbiota metabolic capability to detect drug response in rheumatoid arthritis patients. Front Microbiol. 2022;13:839015. https://doi.org/10.3389/fmicb.2022.839015
Crossref PubMed PMC
126. Fan J, Jiang T, He D. Advances in the implications of the gut microbiota on the treatment efficacy of disease-modifying anti-rheumatic drugs in rheumatoid arthritis. Front Immunol. 2023;14:1189036. https://doi.org/10.3389/fimmu.2023.1189036
Crossref PubMed PMC
127. Viaud S, Saccheri F, Mignot G, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971–976. https://doi.org/10.1126/science.1240537
Crossref PubMed PMC
128. Daillere R, Vetizou M, Waldschmitt N, et al. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity. 2016;45(4):931–943. https://doi.org/10.1016/j.immuni.2016.09.009
Crossref PubMed
129. Li Z, Xiong W, Liang Z, et al. Critical role of the gut microbiota in immune responses and cancer immunotherapy. J Hematol Oncol. 2024;17(1):33. https://doi.org/10.1186/s13045-024-01541-w
Crossref PubMed PMC
130. Lundell AC, Bjornsson V, Ljung A, et al. Infant B cell memory differentiation and early gut bacterial colonization. J Immunol. 2012;188(9):4315–4322. https://doi.org/10.4049/jimmunol.1103223
Crossref PubMed
131. Saito S, Okuno A, Peng Z, Cao DY, Tsuji NM. Probiotic lactic acid bacteria promote anti-tumor immunity through enhanced major histocompatibility complex class I-restricted antigen presentation machinery in dendritic cells. Front Immunol. 2024;15:1335975. https://doi.org/10.3389/fimmu.2024.1335975
Crossref PubMed PMC
132. Shvets Y, Khranovska N, Senchylo N, et al. Microbiota substances modulate dendritic cells activity: a critical view. Heliyon. 2024;10(5):e27125. https://doi.org/10.1016/j.heliyon.2024.e27125
Crossref PubMed PMC
133. Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A. 2010;107(27):12204–12209. https://doi.org/10.1073/pnas.0909122107
Crossref PubMed PMC
134. Deng H, Li Z, Tan Y, et al. A novel strain of Bacteroides fragilis enhances phagocytosis and polarises M1 macrophages. Sci Rep. 2016;6:29401. https://doi.org/10.1038/srep29401
Crossref PubMed PMC
135. Strickertsson JA, Desler C, Martin-Bertelsen T, et al. Enterococcus faecalis infection causes inflammation, intracellular oxphos-independent ROS production, and DNA damage in human gastric cancer cells. PLoS One. 2013;8(4):e63147. https://doi.org/10.1371/journal.pone.0063147
Crossref PubMed PMC
136. Long X, Wong CC, Tong L, et al. Peptostreptococcus anaerobius promotes colorectal carcinogenesis and modulates tumour immunity. Nat Microbiol. 2019;4(12):2319–2330. https://doi.org/10.1038/s41564-019-0541-3
Crossref PubMed
137. Tsoi H, Chu ESH, Zhang X, et al. Peptostreptococcus anaerobius induces intracellular cholesterol biosynthesis in colon cells to induce proliferation and causes dysplasia in mice. Gastroenterology. 2017;152(6):1419–1433.e5. https://doi.org/10.1053/j.gastro.2017.01.009
Crossref PubMed
138. Duan H, Wang L, Huangfu M, Li H. The impact of microbiota-derived short-chain fatty acids on macrophage activities in disease: mechanisms and therapeutic potentials. Biomed Pharmacother. 2023;165:115276. https://doi.org/10.1016/j.biopha.2023.115276
Crossref PubMed
139. Rangan P, Mondino A. Microbial short-chain fatty acids: a strategy to tune adoptive T cell therapy. J Immunother Cancer. 2022;10(7):e004147. https://doi.org/10.1136/jitc-2021-004147
Crossref PubMed PMC
140. Panebianco C, Villani A, Pisati F, et al. Butyrate, a postbiotic of intestinal bacteria, affects pancreatic cancer and gemcitabine response in in vitro and in vivo models. Biomed Pharmacother. 2022;151:113163. https://doi.org/10.1016/j.biopha.2022.113163
Crossref PubMed
141. Matson V, Chervin CS, Gajewski TF. Cancer and the microbiome-influence of the commensal microbiota on cancer, immune responses, and immunotherapy. Gastroenterology. 2021;160(2):600–613. https://doi.org/10.1053/j.gastro.2020.11.041
Crossref
142. Wilson BE, Routy B, Nagrial A, Chin VT. The effect of antibiotics on clinical outcomes in immune-checkpoint blockade: a systematic review and meta-analysis of observational studies. Cancer Immunol Immunother. 2020;69(3):343–354. https://doi.org/10.1007/s00262-019-02453-2
Crossref
143. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–97. https://doi.org/10.1126/science.aan3706
Crossref
144. Yousefi Y, Baines KJ, Maleki Vareki S. Microbiome bacterial influencers of host immunity and response to immunotherapy. Cell Rep Med. 2024;5(4):101487. https://doi.org/10.1016/j.xcrm.2024.101487
Crossref PubMed PMC
145. Zhou CB, Zhou YL, Fang JY. Gut microbiota in cancer immune response and immunotherapy. Trends Cancer. 2021;7(7):647–660. https://doi.org/10.1016/j.trecan.2021.01.010
Crossref PubMed
146. Fessler J, Matson V, Gajewski TF. Exploring the emerging role of the microbiome in cancer immunotherapy. J Immunother Cancer. 17 2019;7(1):108. https://doi.org/10.1186/s40425-019-0574-4
Crossref PubMed PMC
147. Ouyang J, Lin J, Isnard S, et al. The bacterium Akkermansia muciniphila: a sentinel for gut permeability and its relevance to HIV-related inflammation. Front Immunol. 2020;11:645. https://doi.org/10.3389/fimmu.2020.00645
Crossref PubMed PMC
148. Pickard JM, Zeng MY, Caruso R, Nunez G. Gut microbiota: role in pathogen colonization, immune responses, and inflammatory disease. Immunol Rev. 2017;279(1):70–89. https://doi.org/10.1111/imr.12567
Crossref PubMed PMC
149. Mager LF, Burkhard R, Pett N, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science. 2020;369(6510):1481–1489. https://doi.org/10.1126/science.abc3421
Crossref PubMed
150. Arboleya S, Watkins C, Stanton C, Ross RP. Gut bifidobacteria populations in human health and aging. Front Microbiol. 2016;7:1204. https://doi.org/10.3389/fmicb.2016.01204
Crossref PubMed PMC
151. Andrews MC, Duong CPM, Gopalakrishnan V, et al. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat Med. 2021;27(8):1432–1441. https://doi.org/10.1038/s41591-021-01406-6
Crossref PubMed PMC
152. Oh B, Eade T, Lamoury G, et al. The gut microbiome and gastrointestinal toxicities in pelvic radiation therapy: a clinical review. Cancers (Basel). 2021;13(10): 2353. https://doi.org/10.3390/cancers13102353
Crossref PubMed PMC
153. Reis Ferreira M, Andreyev HJN, Mohammed K, et al. Microbiota- and radiotherapy-induced gastrointestinal side-effects (MARS) study: a large pilot study of the microbiome in acute and late-radiation enteropathy. Clin Cancer Res. 2019;25(21):6487–6500. https://doi.org/10.1158/1078-0432.CCR-19-0960
Crossref PubMed
154. Zhao X, Zhao J, Li D, et al. Akkermansia muciniphila: a potential target and pending issues for oncotherapy. Pharmacol Res. 2023;196:106916. https://doi.org/10.1016/j.phrs.2023.106916
Crossref PubMed
155. Shiao SL, Kershaw KM, Limon JJ, et al. Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy. Cancer Cell. 2021;39(9):1202–1213.e6. https://doi.org/10.1016/j.ccell.2021.07.002
Crossref PubMed PMC
156. Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther. 2023;8(1):198. https://doi.org/10.1038/s41392-023-01460-1
Crossref PubMed PMC
157. Kopczynska J, Kowalczyk M. The potential of short-chain fatty acid epigenetic regulation in chronic low-grade inflammation and obesity. Front Immunol. 2024;15:1380476. https://doi.org/10.3389/fimmu.2024.1380476
Crossref PubMed PMC
158. Lu L, Li F, Gao Y, Kang S, Li J, Guo J. Microbiome in radiotherapy: an emerging approach to enhance treatment efficacy and reduce tissue injury. Mol Med. 2024;30(1):105. https://doi.org/10.1186/s10020-024-00873-0
Crossref PubMed PMC
159. Sun J, Chen F, Wu G. Potential effects of gut microbiota on host cancers: focus on immunity, DNA damage, cellular pathways, and anticancer therapy. ISME J. 2023;17(10):1535–1551. https://doi.org/10.1038/s41396-023-01483-0
Crossref PubMed PMC
160. Wang Y, Wu Y, Wang Y, et al. Antioxidant properties of probiotic bacteria. Nutrients. 2017;9(5):521. https://doi.org/10.3390/nu9050521
Crossref PubMed PMC
161. Amaretti A, di Nunzio M, Pompei A, Raimondi S, Rossi M, Bordoni A. Antioxidant properties of potentially probiotic bacteria: in vitro and in vivo activities. Appl Microbiol Biotechnol. 2013;97(2):809–817. https://doi.org/10.1007/s00253-012-4241-7
Crossref
162. Zhao J, Tian F, Yan S, Zhai Q, Zhang H, Chen W. Lactobacillus plantarum CCFM10 alleviating oxidative stress and restoring the gut microbiota in d-galactose-induced aging mice. Food Funct. 2018;9(2):917–924. https://doi.org/10.1039/c7fo01574g
Crossref PubMed
163. Wang Y, Li Y, Xie J, et al. Protective effects of probiotic Lactobacillus casei Zhang against endotoxin- and d-galactosamine-induced liver injury in rats via anti-oxidative and anti-inflammatory capacities. Int Immunopharmacol. 2013;15(1):30–37. https://doi.org/10.1016/j.intimp.2012.10.026
Crossref
164. Lin MY, Chang FJ. Antioxidative effect of intestinal bacteria Bifidobacterium longum ATCC 15708 and Lactobacillus acidophilus ATCC 4356. Dig Dis Sci. 2000;45(8):1617–1622. https://doi.org/10.1023/a:1005577330695
Crossref PubMed
165. Kullisaar T, Zilmer M, Mikelsaar M, et al. Two antioxidative lactobacilli strains as promising probiotics. Int J Food Microbiol. 2002;72(3):215–224. https://doi.org/10.1016/s0168-1605(01)00674-2
Crossref PubMed
166. Frawley ER, Fang FC. The ins and outs of bacterial iron metabolism. Mol Microbiol. 2014;93(4):609–616. https://doi.org/10.1111/mmi.12709
Crossref PubMed PMC
167. Phipps O, Al-Hassi HO, Quraishi MN, Kumar A, Brookes MJ. Influence of iron on the gut microbiota in colorectal cancer. Nutrients. 2020;12(9):2512. https://doi.org/10.3390/nu12092512
Crossref PubMed PMC
168. Phipps O, Al-Hassi HO, Quraishi MN, et al. Oral and intravenous iron therapy differentially alter the on- and off-tumor microbiota in anemic colorectal cancer patients. Cancers (Basel). 2021;13(6):1341. https://doi.org/10.3390/cancers13061341
Crossref PubMed PMC
169. Al-Hassi HO, Ng O, Evstatiev R, et al. Intravenous iron is non-inferior to oral iron regarding cell growth and iron metabolism in colorectal cancer associated with iron-deficiency anaemia. Sci Rep. 2021;11(1):13699. https://doi.org/10.1038/s41598-021-93155-2
Crossref PubMed PMC
Correspondence to: David J. Barry, Royal Melbourne Hospital – Royal Park, Building 8, 34-54 Poplar Road, Parkville VIC 3052, Australia. E-mail: d.barry@nari.edu.au
To cite: Barry DJ, Lindblad A, Jiménez-ten Hoevel C, Cooke MB. Considerations of gut microbiome and cancer—part 1: exploring its role in tumorigenesis and treatment response. CAND Journal. 2025;32(4):11-22. https://doi.org/10.54434/candj.209
Received: 8 April 2025; Accepted: 9 July 2025; Published: 11 December 2025
© 2025 Canadian Association of Naturopathic Doctors. For permissions, please contact candj@cand.ca.
CAND Journal | Volume 32, No. 4, December 2025