Cancer is a serious public health concern with ~20,000,000 new cases diagnosed and 10,000,000 cases of cancer-related mortality reported worldwide in 2020. According to a World Health Organization (WHO) report, the incidence of cancer is increasing, where it has been predicted that there may be ~28.4 million diagnosed cases worldwide by 2040 (1). Several factors have been reported to contribute to carcinogenesis, although excessive uncontrolled cell division caused by irregular cell signaling is common across most if not all cancer types (2). Hanahan and Weinberg (3) previously proposed six hallmarks of cancer. Specifically, these six hallmarks are resistance to inhibitory growth signals, persistence of proliferative signaling, evasion of cell death, initiation of angiogenesis, invasion and metastasis (3). Subsequently, Hanahan and Weinberg (4) added two more details to this six-hallmark concept in 2011, including dysregulation of cell metabolism and circumvention of immune destruction to the critical characteristics of cancer. A decade later, Hanahan (5) then expanded the hallmarks of cancer to include the importance of non-mutational epigenetic reprogramming, phenotype plasticity and the host-microbiome as recent insights in cancer studies emerged. Among these integrative concepts of cancer, the present review aimed to discuss the association between the microbiome and cancer development, in addition to between the microbiome and malignant progression.

The human body contains trillions of symbiotic microbiomes, including a community of bacteria, viruses, fungi and protozoa, which is collectively known as the human microbiota (6,7). Although the skin, oral cavity, respiratory tract and other body parts all harbor microbiomes, the majority of the microbiome population is predominantly contained within the gastrointestinal tract (8). Specifically, the host-associated microbial community within the gastrointestinal system is called the gut microbiome (1). They have been documented to influence various physiological and pathophysiological processes in the body (9). For example, the metabolites produced by an imbalanced microbiota can result in the pathogenesis of certain neurological conditions. Furthermore, physiological energy homeostasis has been reported to be regulated by microbiota, and microbiota-generated butyrate provides energy to colonocytes and prevents autophagy in the colon (9). In addition, microbiota also disrupt physiological homeostasis, host metabolism and contribute to the immune dysregulation (9).

Over the past decade, high-throughput sequencing and multi-omics methods have contributed to the understanding of gut microbiome diversity, elucidating its functional potential (10). Explorative research in the possible relationship between the gut microbiota and various diseases has revealed that alterations in the microbiome profile of the human gut are associated with a number of diseases, including obesity, cancer, diabetes and neurodegenerative diseases (11). However, the causative role mediated by these microbiomes in various disease conditions remains to be fully characterized. This altered population of microbiota has been documented to be great influencers of the host physiology, in processes including digestion, metabolism, cognition and immunity, though additional as yet unrevealed functions are highly likely (12). Several microbiome studies have previously found that other established factors in cancer, including obesity, inflammation and genotoxicity, are either directly or indirectly associated with the interaction between the human microbiota and the human system and metabolism (13,14).

Obesity is becoming a major global issue and already affects millions of individuals. A person is considered obese when their body mass index (BMI) is >30 kg/m². By this metric, ~650,000,000 adults >18 years old are estimated to be clinically obese worldwide, as reported by the WHO (15). Obesity has been reported to associate the incidence of numerous ailments, including type 2 diabetes, hypertension, cardiovascular disease, osteoarthritis, kidney failure, liver inflammation and cancer. In particular, chronic inflammation and altered phenotype due to obesity are the main driving factors in disease progression (16,17).

Previous studies have reported links between cancer and obesity, specifically in terms of the associated mortality rate. Obesity is an important contributing factor to the development of various types of cancer. According to a previous report, ~20% of cancer cases are associated with obesity (18). In addition, obesity enhances colorectal cancer-associated mortality by 14 and 20% in men and women, respectively (19). According to the International Agency for Research on Cancer, obesity is associated with 13 different types of cancer, including breast, colorectal, endometrial, gall bladder, kidney, gastric cardia, ovarian, liver, pancreatic and thyroid cancer, and adenocarcinoma, meningioma and multiple myeloma (20). However, obesity is not the only isolated factor associated with cancer. Age, family history, resident environment, body fat, alcohol, smoking, sex hormone levels, insulin and nutrient levels have all been observed to contribute to cancer development (21).

The excessive deposition of nutrients into the white adipose tissue causes inflammation in obese individuals. Adipocytes in this specialized type of tissue normally functions to store triglycerides as a long-term source of energy in the form of cytoplasmic lipid droplets. White adipose tissues can also secrete various adipokines, including cytokines, hormones and growth factors, which have a role in obesity-associated disease conditions (22,23). These cytokines and growth factors can activate a number of signaling pathways, including NF-κB, JNK and protein kinase R pathways. Low-grade inflammation is induced upon the stimulation of these signaling pathways, which causes the release of common inflammatory cytokines, including IL-1, IL-6 and TNF-α (24). Hyperplasia and hypertrophy of adipocytes can also aggravate this low-grade inflammatory response by increasing the production of free fatty acids, tissue remodeling and changing the profile of adipokine production (25). Furthermore, overproduction of unfolded proteins and subsequent activation of metabolic pathways by endoplasmic stress in obese individuals can activate inflammatory responses (26). Although white adipocyte tissues serve as the primary area for inflammatory pathway activation, other tissues, such as the liver, brain and pancreas, are also associated with obesity-induced inflammation (27). Due to the reported involvement of adipokines in cancer cell growth, the role of leptin and adiponectin in cancer have been widely studied (28,29). It has been reported that low levels of adiponectin may have a permissive role in triggering the neoplastic growth of ERα-positive breast cancer cells through the MAPK-activating signaling pathway (30). Obesity-associated insulin-like growth factor I and insulin resistance are also involved in the stimulation of several types of cancer, according to data produced from previous in vitro and in vivo analyses (31,32).

According to a previous meta-analysis, malignant melanoma, colon, gallbladder, pancreatic and renal cancer are significantly more common in obese men (33). In obese women, esophageal adenocarcinoma, leukemia, endometrial, colon, gallbladder, pancreatic, postmenopausal breast and renal cancer tended to be more common (Fig. 1). Obese female patients with breast cancer have been reported to show more aggressive characteristics of tumor formation and metastasis (34). In addition, the severity of breast cancer in patients is greatly influenced by age, where women with advancing age are more likely to gain weight and develop obesity. A particularly high risk of breast cancer has been reported in menopausal women between 50 and 60 years old, with weight gain also proposed to be a contributing factor (35). Primary liver cancer is the sixth most common type of cancer globally (36). Several factors have been documented to impact the development of liver cancer. Being overweight is one of the main factors that is associated with the mortality rate of patients with liver cancer and hepatitis viral infection (37,38). Another previous cohort study reported a 17 and 89% liver cancer risk in overweight and obese individuals, respectively, compared with the expected average (39). In addition, this previous study showed that the relative risk of liver cancer for overweight individuals was 1.17 and for obese individuals was 1.89 compared with that in individuals of a healthy weight (39). Liver cancer associated with obesity or excess body weight was reported to be more prevalent in men compared with women, with individuals with excess body weight suffering from liver cirrhosis or hepatitis C viral infection being more prevalent (40).

The increased incidence and prevalence of obesity among populations have elevated the risk of gastrointestinal cancer development. It has been suggested that excess adiposity is a potential cause of gastrointestinal tract, pancreatic, colorectal, esophageal, stomach and gallbladder cancer. The relationship between obesity and gastrointestinal cancer has been proposed to be associated with changes in insulin and insulin-like growth factor I signaling, altered sex hormone metabolism and chronic low-grade inflammation (41). Previous studies have indicated a strong connection between overall fat content and elevated gastro-esophageal reflux, Barrett's esophagus and esophageal adenocarcinoma (42,43). Although reflux can be adjusted in obese individuals, rates of esophageal adenocarcinoma have been shown to be more prevalent whereas waist circumference (a measure of obesity) is associated with the high occurrence of Barrett's esophagus (44). The importance of obesity (specifically central obesity) as a predisposing factor for colorectal cancer, which is the third most common cause of global cancer mortality, has been frequently reported (45,46). The increased deposition of abdominal fat and associated obesity is highly associated with the prevalence of colorectal cancer (47).

The human gut is inhabited by a diverse microbiome, which forms a complex community along the gastrointestinal tract and contributes to the health and well-being of the host. Although it is well-known that these microbiomes interact and maintain a status of symbiosis with the host, alterations in the microbial flora can adversely affect biological functions in the body (4). A recent study by Hou et al (48) on the role of the human microbiota reported the dynamic role of the gut microbiota in host health and its relation to pathogenesis of cancer. The gut microbiome can influence the systemic functioning of the body through the gut-brain axis, colonization resistance and immunomodulation (48). In addition, the strong influence of the human gut microbiota in developing various ailments, including cancer, respiratory, neurophysiological, hepatic and kidney diseases, has been previously reported (Table I).

Cancer is caused by a multitude of factors, including both genome modulation and environmental causes. However, the association between the human microbiota and cancer development has not been considered until the 1990s. Microbiome involvement in carcinogenesis was first detected in gastric cancer in 1994, resulting in the subsequent recognition of Helicobacter pylori as a group 1 carcinogen by the WHO (49,50). The role of the human microbiota in several types of cancer has since been reported, including oral squamous cell carcinoma (51,52), lung cancer (53), breast cancer (54) and genitourinary cancer (55). Several mechanisms contributing to cancer development have been observed to be mediated by the gut microbiome, including the production of microbiota-derived metabolites, immune dysregulation and the modification of genetic and epigenetic factors (56). Previous studies have demonstrated that the intracellular bacteria Chlamydia psittaci can cause ocular adnexal lymphoma by regulating oxidative DNA damage and modulating the NF-κB pathway connected with anti-apoptotic effects (57,58). In addition, the non-motile gram-negative bacteria Porphyromonas gingivalis has been shown to be associated with oral cancer through the epithelial-mesenchymal transition of oral epithelial cells and by inducing MMP-9 and IL-8 expression (59). The pathogenic Mycobacterium tuberculosis can also promote lung cancer development and metastasis by modulating the T-cell immune response by elevating the activity of the programmed cell death protein-1/programmed death-ligand 1 pathway (60). In addition, the intracellular pathogen Chlamydia pneumoniae can promote lung cancer through by provoking the monocytes into secreting TNF-α, IL-8 and superoxide radicals, which promote cellular and DNA damage (61). The gram-negative bacteria Salmonella typhi leads to gallbladder cancer through typhoid toxin-mediated alteration of the cell cycle and DNA damage (62). Other non-motile gram-positive bacteria, including Streptococcus bovis and Streptococcus gallolyticus, have also been documented to contribute to colorectal cancer by degrading anticancer substances, including tannic acid (63). Furthermore, bacteria can trigger the release of inflammatory cytokines, including TNF-α, IL-1β, IL-6 and IL-8, to cause free radical formation, resulting in DNA alterations and cancer (64).

Over the last two decades, there has been an increase in studies investigating the impact of the gut microbiota on cancer. However, the fundamental cause of gut microbiota-induced tumor initiation remains unknown, meaning that it cannot yet be exploited for the treatment of cancer. A number of different hypotheses regarding the impact of the microbiota on cancer prognosis and therapy have been proposed. Microbial metabolites can interrupt cell signaling pathways involved in various processes, such as cell proliferation, division, programmed cell death and interaction with cell from other organs (65). It is also well-known that inflammatory conditions can significantly increase the risk of cancer, representing a pivotal hallmark of the complex process of carcinogenesis. Previous studies have revealed that enteric bacteria can significantly impact the immune system, serving a crucial role in the development of local and systemic inflammation (66,67). Notably, the gut microbiome can inhibit infection by adjusting the niche environment and regulating host immune defense (68). The interaction between cancer cells and other cell types, such as immune cells, myeloid cells and cancer-associated fibroblasts, forms the tumor microenvironment (TME) (69). It is important to note that there is accumulating evidence suggesting an essential link among gut microbiome changes, inflammation and cancer development, in a complex and multifaceted mechanism. High-throughput sequencing has revealed that aspects of bacterial niches can be detected in TME of various types of cancer, which may influence the development of cancer by modulating the immune system (65,68). The mechanistic role of microbes in carcinogenesis is detailed in Table I. In a recent review on the TME in various types of cancer, Chen et al (70) reported that the microbiota tended to differ between cancer and normal tissues (70). A previous comparative case study of gut microbial diversity and composition involving healthy individuals and patients with colon cancer through 16S rDNA sequencing revealed that the levels of beneficial bacteria were decreased, whilst the levels of several harmful bacteria were increased, in the cancer group (71). In another review of the interaction between the microbiota and the immune system, it was described that alterations in the gut microbiome can significantly impact the immune system and related signaling mechanisms through direct cell interaction or microbiota-derived metabolites (72).

Previous studies on the interaction between the gut microbiome and immunity has revealed that the gut microbiome can participate in immune modulation and can promote liver cancer through bile acid metabolism (73,74). Furthermore, assessing the role of microbial metabolites in immune regulation revealed that some of these small to large macromolecules can modulate cell signaling pathways that evoke a positive or negative response in cells (72). Polyamine derivatives found in the microbial metabolites have been reported to activate the Myc oncogene, promoting cancer progression. The c-Myc class of transcription factors are crucial for controlling the expression of genes involved in cell growth, proliferation and differentiation. In addition, butyrate derivatives have been demonstrated to exhibit antitumor proprieties, inhibiting inflammation and carcinogenesis by regulating Wnt and NF-κB signaling pathways (75). The interplay among gut microbiota, inflammation and immune responses can also affect the systemic immune response. These aforementioned observations suggest that the gut microbiome and its metabolites can significantly impact various biological processes, such as cell metabolism and immune regulation, and thus affect health (Fig. 2). Fig. 2 illustrates the intricate interplay between the gut microbiome, cellular processes and cancer progression.

According to the GLOBOCAN database, gastric cancer is the fourth leading cause of cancer-related mortality worldwide (1,76). Gastric cancer is particularly prevalent in developing countries, with a two-fold higher incidence rate in men compared with that in women (74). Several epidemiological studies have highlighted the robust association between obesity and gastric cancer. In a previous meta-analysis, Lin et al identified an association between increased BMI and gastric cancer. In addition, obesity (BMI, ≥30 kg/m²) was found to be associated with an increased risk of gastric cancer compared with being overweight (BMI, 25.1-30 kg/m²) and normal weight (BMI, 18.5-25 kg/m²) (77).

In 2014, Donohoe et al demonstrated the inter-relationship between adipose and the TME in gastric cancer (44). Specifically, inflammation, hypoxia, energy metabolism and angiogenesis were all found to be key factors associating obesity with gastric cancer, which are commonly dysregulated in the TME and adipose tissue Karczewski et al (41) previously demonstrated that the primary pathophysiological mechanisms connecting obesity and gastric cancer include altered levels of insulin signaling, chronic low-grade inflammation in the adipose tissue and altered steroid hormone production and metabolism. Lee et al (78), in a Health Examinees-Gem study, reported that obesity during early adulthood (20-39 years) was significantly associated with an increased risk of gastric cancer.

The interaction between microorganisms and tumors has garnered widespread attention, with the aim of delineating the features of the complex microbial communities and their possible role in carcinogenesis (13). Numerous studies have discussed the connection between gut microbes and low-grade inflammation, which can regulate the innate and adaptive immune responses, at least in part contributing to the initiation and progression of oncogenic conditions (5,79).

H. pylori-mediated infection can stimulate immune responses and inflammation to regulate gastric cancer (80). The immune response of epithelial and myeloid cells to H. pylori bacteria is regulated by the gastric microbiota, which in turn determines the outcome of the disease. The contact between H. pylori and gastric epithelial and myeloid cells has been shown to induce signaling through innate pathways, leading to changes in cellular homeostasis, and the release of cytokines and chemokines that can trigger the inflammatory responses. H. pylori infection disturbs the balance between the host gastric microbiota and mucosa-related factors leading to inflammatory changes, dysbiosis and subsequently gastric cancer (81). H. pylori is a group 1 carcinogen that can promote gastric carcinogenesis by aggravating inflammation in the gastric mucosa (81,82). The key virulence factors of H. pylori, namely cytotoxin-associated gene (Cag)A and vacuolating toxin A (VacA), are associated with an increased risk of gastric cancer (13,83). Infection with the H. pylori CagA strain results in an increased accumulation of inflammatory cytokines, including IFN-γ, IL-1, IL-6, IL-7, IL-8, IL-10, IL-18 and TNF-α, which stimulates a diverse range of immune cells, including peripheral mononuclear cells, lymphocytes, eosinophils, macrophages, neutrophils and mast cells (13,84). In addition, infection with the Cag⁺ strain leads to the upregulation of the ERK/MAPK, PI3K/AKT, NF-κB, Wnt/β-Catenin, Sonic Hedgehog and STAT3 signaling pathways, whilst downregulating the activity of tumor suppressor pathways (74,85).

The VacA virulence factor leads to cellular vacuolation and autophagy in human gastric epithelial cells (86,87). VacA has been reported to upregulate MAPK, ERK1/2 and vascular endothelial growth factor expression, whilst also stimulating the Wnt/β-catenin signaling pathway, which is required for cell proliferation and differentiation (88,89). Simultaneously, H. pylori infection can also induce methylation in genes expressing the cell adhesion glycoprotein E-cadherin and various tumor suppressors, such as trefoil factor 2 and fork-head box transcriptional regulator D3, leading to the increased risk of gastric adenocarcinoma (90–92).

Advancements in sequencing technology have improved the understanding into the complexity of the gastric microbiota (13,93). H. pylori-negative individuals harbor distinct microbial populations, including Proteobacteria, Firmicutes and Actinobacteria (94,95). Sequencing-based and quantitative PCR approaches have confirmed that patients with gastric cancer tended to harbor a diverse population of microbiota with a reduced level of Porphyromonas, Neisseria, TM7 group and Streptococcus sinensis, but an enriched level of Klebsiella pneumoniae, Lactobacillus coleohominis and Lachnospiraceae (95,96). The pathogenic components, including the outer-membrane, nickel-binding and BAK proteins of non-H. pylori microbiota, including Helicobacter cinaedi, Lactobacillus coleohominis and Klebsiella pneumoniae, assist their colonization on the gastric mucosal layer, leading to tumorigenesis in the stomach (97).

A high-fat diet large quantities of fatty acids and low amount of vitamins, fibers and minerals are considered the primary cause of obesity (98). Several studies have demonstrated that a high-fat diet can promote gastric cancer through metabolic reprogramming and alteration of intestinal microbes. Arita and Inagaki-Ohara (99) reported that a high-fat diet can increase leptin signaling and promote gastric microbial dysbiosis, leading to intestinal metaplasia. In addition, this previous study found that a high-fat diet given to mice elevated Lactobacillus levels and reduced Bifidobacteria levels. Lactobacillus is a homofermentative probiotic bacterium that converts lactose to lactic acid. Lactic acid is associated with gastric carcinogenesis as it regulates inflammation, metastasis and epithelial-mesenchymal transition (100).

He et al (101) found that 12 weeks of a high-fat diet feeding in C57BL/6 mice resulted in dysbiosis of the gastric microbiota, with a reduced level of community diversity. This high-fat diet also increased the levels of Proteobacteria and Firmicutes, whilst downregulating those of Bacteroidetes and Verrucomicrobiota. Furthermore, enriched levels of Enterobacteriaceae were detected, which are associated with increased plasma and fecal endotoxin production. Endotoxin is known to trigger chronic inflammation and can induce obesity (102). Previously, Xiao et al (103) reported that endotoxin-producing opportunistic pathogens, such as Enterobacteriaceae and Desulfovibrionaceae, can produce lipopolysaccharide (LPS) and lead to metabolic endotoxemia. LPS can enhance C-X-C chemokine receptor type 7 expression in gastric cancer, subsequently regulating the proliferation and migration of gastric cancer cells through the toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 signaling pathway (104). Furthermore, Desulfovibrionaceae can reduce sulfate to hydrogen sulfide (H₂S) (105). H₂S then activates the fatty acid receptor CD36 in gastric cancer cells to stimulate lipid metabolic reprogramming and gastric cancer metastasis (7).

Colorectal cancer is the third most common cancer diagnosed worldwide, with incidence rates 30% higher in men compared with those in women (2). Several epidemiological studies have demonstrated the relationship between obesity and colorectal cancer. Bardou et al (106) reported that obesity is associated with 11% colorectal cancer cases in the European population. Among the list of obesity conditions, visceral fat and abdominal obesity are associated with a higher risk of colorectal cancer compared with subcutaneous obesity. It has also been previously reported that obese individuals exhibit a 20-40% higher risk of colorectal cancer compared with normal-weight individuals (107,108).

Obesity leads to colorectal cancer development through inflammation, metabolic regulation and signaling processes (109). In a meta-analysis on the relationship between BMI and colorectal cancer, Ma et al (110) reported the relevant risk of colorectal cancer to be 1.334 (95% CI, 1.253-1.420) for obese individuals compared with individuals of a healthy weight. In a pooled analysis of eight population-based cohort studies, Matsuo et al (111) also revealed a strong association between obesity and colorectal cancer. The association was stronger in men compared with that in women, with the association higher in the proximal colon compared with the rectum. Recently, Socol et al (112) demonstrated that genetic variation and aberrant signaling in the leptin pathway were associated with obesity and colorectal cancer. Leptin receptor (LEPR) expression is critical for the proliferation of colorectal carcinoma cells (Table II). Higher expression of LEPR has been shown to lead to neoangiogenesis and increased metastatic potential of colorectal carcinoma. By contrast, a lack of LEPR expression reduces tumor proliferation in colorectal carcinoma (113).

A high-fat diet has been shown to promote colorectal cancer progression and metastasis. Niku et al (114) previously demonstrated that a Western diet, containing high fat and low fiber, calcium, vitamin D and folate, acts as a risk factor for the development of colorectal adenoma, through the heterozygous loss of adenomatous polyposis coli and overactivation of the AKT, mTOR and ERK1/2 signaling pathways in C57BL/6 J Min/+ mice. Park et al (115) demonstrated in another study that high-fat diet-related obesity can lead to inflammation-associated colorectal cancer by activating the PI3K/AKT signaling pathway and triggering the expression of IL-12, monocyte chemoattractant protein-1 and TNF-α in the TME.

Several studies have highlighted the altered gut microbiota signatures in colorectal cancer development (6,7). The lower population of the butyrate-producing Clostridium cluster IV and XIV bacteria has previously been associated with colorectal cancer (116). Besides, the population of Firmicutes, Actinobacteria and Lachnospiraceae have also been reported to be increased in pre-malignant colorectal adenoma, whereas Proteobacteria, Enterobacteriaceae and Sutterella species have been shown to be increased during colorectal cancer progression (117). Apart from the bacterial population, temperate phages have also been associated with the development of colorectal cancer. The bacteriophages interact with the host bacteria and stimulate the progression of colorectal cancer by changing the bacterial community structure and regulating the immune microenvironment (118).

Intestinal microbes can regulate polyamine synthesis, LPS production, butyrate metabolism and oxidative phosphorylation to facilitate the occurrence and development of colorectal cancer (119,120). Schulz et al (121) reported that a high-fat diet can lead to small intestinal tumor formation in K-ras^G12Dint mice by altering the composition of intestinal microbes. Gaines et al showed that a Western pattern diet can enhance the levels of collagenase-producing microbes, including Proteus mirabilis, Candida parapsilosis and Enterococcus faecalis, in the intestine of the BALB/c mice (122). Colonization by these microbes leads to the transmigration of colorectal cancer cells and promotes colorectal cancer recurrence. Furthermore, the intestinal microbes in obesity can enhance bile acid secretion in the intestine (123). The gram-positive Clostridium converts primary bile acids to secondary bile acids, where the excessive accumulation of secondary bile acids can lead to colorectal cancer (124). In addition, high-fat diet- and Western diet-mediated obesity can reduce the abundance of Parabacteroides in the intestine. Parabacteroides antagonize the TLR4 and AKT signaling pathways (125), which are upregulated during colorectal cancer development and progression. Therefore, antagonizing Parabacteroides in the intestine through high-fat diet-related obesity can promote colorectal cancer. Sánchez-Alcoholado et al demonstrated that obese patients with colorectal cancer exhibit a reduced population of butyrate-producing gut microbes, including Butyricimonas, Roseburia, Faecalibacterium and Ruminococcus, with an abundance of opportunistic pathogens, including Fusobacterium, Desulfovibrio, Clostridium and Enterococcus (120). The enrichment of these proinflammatory pathogens and reduction in butyrate-producing bacteria results in dysbiosis and leads to tumor formation, through elevated levels of the deleterious microbial metabolite trimethylamine N-oxide, the proinflammatory cytokine IL-1β and the intestinal permeability marker Zonulin, in addition to the reduced levels of the anti-inflammatory factor IL-10.

Obesity and high-fat-content food are closely associated with the progression of liver cancer. Liver cancer progression is associated with the modified gut microbiome. Previous reports have explored the involvement of the gut microbiome in chronic liver disease and liver cancer (126,127). Liver inflammation causes changes in the gut microbiome, causing microbiome dysbiosis and variations in the intestinal barrier, resulting in a leaky gut (128). In the majority of cases, liver cirrhosis leads to leakiness and dysbiosis, whilst increasing the risk of liver cancer. Patients with liver cirrhosis can also exhibit sudden bacterial peritonitis, contributing to hepatocellular carcinoma (129). Fatty liver disease is also associated with liver carcinoma, even in non-alcoholic patients without cirrhosis (130). Intestinal microbiome dysbiosis in non-alcoholic patients has also been characterized in the pathogenesis of fatty liver disease (130).

Inflammatory bowel disease, type 1 diabetes, autism, cardiovascular diseases, and obesity favor gut microbiome alterations. Gut metabolites produced during gut dysbiosis induced by obesity in the enterohepatic circulation have been reported to promote hepatocellular carcinoma (7,131). A previous study reported that circulation of deoxycholic acid triggers the senescence-associated secretory phenotype in hepatic stellate cells (HSCs), which can result in the secretion of several tumor-promoting factors in the liver of C57BL/6 mice (131,132). The gut microflora-derived bacterial products, such as LPS and bacterial DNA, and endogenous substances, including free fatty acids, trigger the activation of hepatic TLR4, which leads to liver inflammation, fibrosis and cancer (132).

In a previous microbiome analysis of patients and healthy individuals, patients with carcinoma induced by hepatitis B were reported to possess an abundance of Escherichia, Shigella and Enterococcus, whereas decreased levels of Faecalibacterium, Ruminococcus, Ruminoclostridium sp. Clostridium, Corynebacterium, Bacillus, Desulfovibrio and Rhodococcus sp. were observed in non-alcoholic patients with steatohepatitis-associated hepatocellular carcinoma. By contrast, in patients with cirrhosis-related carcinoma, higher levels of Epsilonproteobacteria, Actinobacteria, Clostridia, Fusobacterium and Oribacterium were observed compared with in healthy volunteers (133).

Data from model systems, such as rodents, coupled with those from robust clinical trials, have provided evidence on the role of the gut microbiome in the progression of obesity-associated cancer, where insights have been gained on potential therapeutic interventions. Previous pre-clinical and clinical trials have studied the effect of microbial inflammation on the development of the pathophysiology of different types of cancer (14,134). Several pre-biotics have shown anticancer properties against colorectal cancer models. Prenyl flavonoids have been reported to improve the gut microbiome in in vitro models of colorectal cancer and to exert anticancer activity (134). In addition, a high-fat diet (HFD) is known to induce gut dysbiosis. The oral intake of agaro-oligosaccharides (AGO) has been shown to prevent HFD-mediated gut dysbiosis and to thus inhibit colon carcinogenesis in C57BL/6N mice. This previous study reported that phospholipids and bile acids were downregulation in C57BL/6N mice receiving a HFD alone, whereas this downregulation was recovered with the administration of AGO supplements (135). A double-blind crossover study involving healthy human adult volunteers (n=31) reported that polydextrose (PDX) can modulate the composition and function of the colonic microbiota. Besides, PDX was found to be associated with the change in microbial metabolism, including production of butyrate and reduction in metabolic byproducts of bacterial putrefaction including branched-chain fatty acids. This previous study demonstrated that PDX significant reduced the fecal water genotoxicity of volunteers after consumption, thus indicating the potential of PDX for reducing the risk factors associated with colorectal cancer (136). Fermentation of sugar in the colon tends to favor butyrate-producing bacteria, Ruminococcus and Clostridium clusters I, II and IV (136). Administration of the antibiotic cefoxitin in a murine model has been shown to reduce enterotoxigenic Bacteroides fragilis-driven inflammation and colon cancer (13,137). In addition, short-chain fatty acids favor the restoration of intestinal health and the gut microbiome to prevent colon cancer. Several mice and human studies have demonstrated the role of short-chain fatty acid-synthesizing bacteria in the treatment and prevention of cancer (138,139).

In a mouse model, altered intestinal microbiota can in turn alter antitumor immune surveillance, which can increase the risk of liver disease and therefore cancer development. NEMO^∆EMOc/Nlrp6^−/− mice exhibited the hallmarks of intestinal dysbiosis, as well as aggravated steatohepatitis and increased tumor burden. A significant finding of this previous study was that the loss of intestinal Akkermansia muciniphila could increase the abundance of hepatic monocytic myeloid-derived suppressor cells and T cells associated with the proliferation and expansion of liver cancer cells (140). Understanding the gut-liver axis and microbiome involvement in liver carcinoma development may facilitate the design of effective therapeutic methods. Data from rodent models and clinical trials have suggested using the gut-liver axis as a target for inhibiting liver cancer but not for the complete treatment. Several drugs, such as antibiotics, probiotics, TLR4 antagonists and prokinetics, have been shown to control non-cancerous liver disease and carcinoma progression in rodent models and human patients (141). In a previous retrospective study, patients with liver cirrhosis who received rifaximin exhibited a reduced risk of liver carcinoma development (142). In another study involving patients with liver cirrhosis, administration of different antibiotics and probiotics was found to reduce the development of primary hepatocellular carcinoma and mortality (143). Fecal microbiota transplantation (FMT) is one of the methods used to modulate the gut microbiota and reverse dysbiosis. During this process, a new bacterial population is transferred to the recipient to reverse the dysbiosis that occurred. Microbial species equilibrium is maintained in the gut by introducing fecal transplants from healthy individuals (140). FMT has been reported to improve survival in patients with metastatic gastro-esophageal cancer studied in randomized, double-blind, placebo-controlled pilot trials (143,144). By contrast, the transfer of allogenic FMT from an obese donor to a lean recipient can induce the obese phenotype and its associated metabolic dysfunctions in the lean recipient (145). Another study previously revealed the effectiveness of FMT along with anti-programmed cell death protein 1 in six out of 15 patients with melanoma (146). Several mouse model studies and clinical trials have provided information on FMT and its ability to reverse the intestinal dysbiosis, relieve colon and hepatocellular carcinoma symptoms, whilst facilitating their management (147,148).

The Gut microbiota aids in the homeostasis of health and disease. The commensal gut microbiome helps to maintain homeostasis by producing beneficial metabolites. However, under the conditions of altered microbiomes induced by various factors, it can promote carcinogenesis. The present review discussed the close association between gut microbes and gastric, colorectal and liver cancer, whilst also discussing potential prevention strategies. It has been observed that microbiome dysbiosis leads to alterations in the profile of essential metabolites, which in turn causes the production of toxins. These metabolites enhance inflammation in the host and can lead to the formation of tumors. Obesity has been reported to serve as a factor associated with the initiation and progression of 13 types of cancer. Therefore, exploring and employing appropriate microbes or microbial-derived molecules is recommended to develop a beneficial gut microbiota that can elicit appropriate immune responses against cancer cells. Probiotics and other cancer therapies are recommended for re-establishing gut microbiota and producing an anti-tumorigenesis environment. In the future, more personalized trials or approaches are sorted to verify the effects of probiotics on different types of cancer by modulating the microbiome.