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Review Article

Microbe-based management for colorectal cancer

Gao, Zi-Yun1; Cui, Zhe2; Yan, Yu-Qing1; Ning, Li-Jun1; Wang, Zhen-Hua1; Hong, Jie1

Editor(s): Ji, Yuan-Yuan

Author Information
doi: 10.1097/CM9.0000000000001887
  • Open

Abstract

Introduction

Colorectal cancer (CRC) is one of the most common and deadliest cancers in the world, ranking second as a cause of cancer deaths in the United States.[1] Among the new cancers diagnosed in 2018, 10.9% in males and 9.5% in females were CRC.[2] The occurrence and mortality of CRC have increased in economically transitioning countries.[3,4] CRC is one of the leading cancers in China, and the new cases and cancer-related deaths have increased substantially from 2015 to 2020.[5]

CRC development is attributed to hereditary and environmental factors. Overweight and obesity, western dietary habits, smoking, and heavy alcohol consumption affect the risk of CRC and may further alter the gut microbiome.[6] Among these environmental factors, the role of intestinal bacteria in the development of CRC has become highly important and has received widespread attention.

The human intestinal tract consists of abundant microbiota contributing to physiological or pathological functions of the host. The pathogenic mechanism by which bacteria leads to CRC involves many aspects: chronic inflammation, genotoxins and metabolites derived from pathogens.[7] The gut microbiota interacts with the host immune system, leading to an aberrant immune response and inflammatory environment, which further prompt the development of CRC.[8,9] The composition of the gut microbiota influences intestinal barrier function[10] and regulates the mucus layer of the gut.[11] CRC-associated gut dysbiosis induces higher numbers of hypermethylated genes than are found in healthy controls, so it is considered a causal agent of host DNA alterations.[12] Dysbiosis and abnormal metabolites may cause CRC progression and influence the therapeutic effect against CRC. Metabolites in the tumor-associated environment can stimulate immune cell-induced chronic inflammatory responses and tumorigenesis.[13] The imbalance between pathogenic bacteria and probiotics can lead to the disruption of intestinal homeostasis. Particularly, Bacteroides, Fusobacterium, Campylobacter, Escherichia, Streptococcus, Clostridium, and Peptostreptococcus contribute to the pathogenesis and poor prognosis of CRC.[14,15] In contrast, probiotics such as butyric acid-producing bacteria and Akkermansia muciniphila (A. muciniphila) can suppress tumor growth and metastasis.

The management of CRC involves many approaches. Despite conventional therapies, including endoscopic and surgical treatment, chemotherapy, radiotherapy and immunotherapy, microbe-based management is novel but has become indispensable.[16] The gut microbiota can serve as a biomarker for detecting tumors and can modulate the effects of CRC treatment and prevention measures.[17] With the growing knowledge of how gut bacteria contribute to carcinogenesis and affect treatment consequences, regulation and modulation of gut bacteria have become potential strategies for CRC prevention and treatment.

In this review, we summarize the mechanisms of the pathogenic processes of CRC-related bacteria and then discuss the latest advances in the prevention and treatment of CRC, including probiotics, prebiotics, postbiotics, fecal microbiota transplantation (FMT) and dietary interventions.

Specific bacteria correlated with CRC

There are some CRC-related bacteria in the tumor microenvironment, based on the combined analysis of 526 metagenomic samples from five countries.[18] In a retrospective analysis of patients diagnosed with CRC, enterotoxigenic Bacteroides fragilis (ETBF), Streptococcus gallolyticus (S. gallolyticus) and other intestinal microbiota entered the bloodstream and then disturbed the gut mucosal barrier, which indicated that some specific intestinal bacteria can promote colorectal carcinogenesis.[19] Most pathogenic bacteria can produce toxins that damage the intestinal epithelial cells (IECs), leading to an inflammatory response and then to tumor growth. Some pathogens exert carcinogenesis effects by adhering to the mucosal surface of IECs or tumor cells.[7]

Immunotherapy has a wide range of applications in CRC. Immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 aim to restore and strengthen the anticancer response by suppressing intrinsic immunoinhibitory pathways. ICIs can be affected by some bacteria as well. The potential mechanisms involve the accumulation of tumor-specific T cells and intratumoral CD8+ T cells, as well as the maturation and activation of dendritic cells. Gut dysbiosis can influence their efficacy in an immune-mediated manner. ICI resistance results from some pathogens, but some bacteria can restore their antitumor efficacy.[20]

By their mechanism of promoting CRC, bacteria can be divided into three groups: (1) direct carcinogenic bacteria, which can directly participate in CRC development; (2) indirect carcinogenic bacteria, which impact CRC pathogenesis via secondary metabolites, or induce immune changes in the tumor microenvironment; and (3) probiotics that are beneficial to human health and exert anticancer effects.[15]

Recently, the use of antibiotics has become widespread and may affect the intestinal microbiota. Antibiotics can induce or exacerbate dysbiosis because they cannot differentiate pathogens from normal bacteria.[21] A case–control study in the UK from 1989 to 2012 suggests that oral antibiotics are positively correlated with the risk of proximal colon cancer but negatively associated with rectal tumors. This might be because oral anti-anaerobic antibiotics markedly disrupt the microbiota composition, leading to dysbiosis, and the proximal colon is the first site exposed to them. Antibiotics impact the proximal colon by disrupting biofilms, a process linked with carcinogenesis.[22] One study in Sweden indicated that there is an association between antibiotics and a high risk of proximal colon cancer.[23] Gut microbiota and site-specific tumorigenesis can be novel targets for CRC treatment.

Below, we cover studies on eight common bacteria related to CRC.

Enterotoxigenic Bacteroides fragilis

It has been reported that Bacteroides species are enriched in the gut microbiota of CRC and that the abundance of Bacteroides is positively correlated with intestinal tumorigenesis.[24]ETBF can produce B. fragilis toxins (BFT), a 20 kDa zinc-dependent metalloprotease toxin that is the cause of ETBF pathogenicity.[25] A study has suggested that the bft gene is associated with precancerous and cancerous tumors in the colon and that BFT exposure could be a potential screening marker for CRC patients.[26] Consequently, ETBF or BFT exposure is considered a risk factor for advanced CRC.[27]

Owing to the potential causality between colitis and CRC, BFT triggers a series of immune reactions, forming an inflammation-associated environment for CRC genesis. From chronic inflammation to CRC development, the activation of signal transducer and activator of transcription (STAT) 3 and regulatory T-cells (Tregs) are indispensable. After ETBF disrupts the balance of Tregs and T-helper (Th17) cells, interleukin (IL)-2 levels decrease, and then IL-17 is produced. Subsequently, IL-6 is generated and then activates the STAT3 pathway.[28,29] This process causes an inflammatory environment that promotes CRC proliferation. IL-17 also triggers downstream nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and C-X-C chemokine production by IECs in ApcMin/-mice.[30] After incubation with ETBF, exosomes containing microRNA (miRNA) 149-3p are produced by CRC cells. This miRNA can regulate the PHF5A-KAT2A axis to promote CRC development and trigger Th17 cell activation and differentiation to accelerate gut inflammation. Thus, ETBF has been proven to facilitate colitis and tumorigenesis.[31] Additionally, BFT degrades E-cadherin to damage gut barrier function and change the cell morphology and thus the function of IECs.[28]

In short, ETBF is linked to gut inflammation and tumorigenesis. ETBF and BFT are essential therapeutic targets to be further studied.

Fusobacterium nucleatum

Similar to Bacteroides, Fusobacterium was significantly increased in abundance in CRC tissue compared to normal samples in a single cohort.[32] There is also a report that Fusobacterium nucleatum (F. nucleatum) can promote CRC cell proliferation and increase their invasive activity. Indeed, F. nucleatum can recruit tumor-infiltrating myeloid cells to develop an inflammatory microenvironment leading to tumor progression in the ApcMin/+ mouse model.[33] Adhesin FadA, a virulence factor identified from F. nucleatum, can bind E-cadherin to stimulate CRC cell proliferation and to regulate many inflammatory and oncogenic responses. Thus, FadA is considered a therapeutic target for CRC.[34]

In addition, F. nucleatum is closely related to noncoding RNAs. A previous study found that F. nucleatum abundance has a positive relationship with high glucose metabolism in patients with CRC. F. nucleatum regulates glucose metabolism through the axis of long noncoding RNA (lncRNA) enolase1-intronic transcript 1 and KAT7 histone modification.[35]F. nucleatum can activate Toll-like receptor 4 (TLR4) signaling to myeloid differential protein-88 (MyD88) to upregulate NF-kB and miR-21 levels. MiR-21 is responsible for chronic inflammatory processes and the development of colitis-associated cancer (CAC). Both F. nucleatum and miR-21 could become risk markers of CRC.[36]

Since traditional chemotherapy has been widely used in CRC patients, high tumor recurrence is becoming a problem in some patients. Many studies have suggested that that resistance to CRC therapy could be impacted by gut microbes such as F. nucleatum. F. nucleatum has a higher abundance in CRC patients with recurrence after chemotherapy. The mechanism involves TLR4 and MyD88 immune signaling with selective target loss of miR-18a∗ and miR-4802 targets and activation of the autophagy pathway.[37]

These findings strongly indicate that F. nucleatum is a pathogen of CRC in tumorigenesis and chemotherapy resistance. These pathogenic bacteria have an adverse impact on cancer management.

Escherichia coli

Escherichia coli (E. coli) usually acts as a resident bacterium in the human gut. However, some specific strains of E. coli can produce different toxins to impair intestinal homeostasis and cause pathological processes. E. coli strains of group B2 have a genomic island called pks, which can induce cancer. Inactivation of the pks gene reduces tumor development in AOM/IL10-/- mice.[38] Organoid and primary IECs infected by pks+ E. coli and show genotoxic aberrations that can induce multiple features of CRC.[39] Moreover, colibactin, a DNA damage toxin, is produced by the colibactin-producing E. coli (CoPEC) strain and induces tumor growth in mice. Autophagy plays a key role in preventing tumorigenesis of CoPEC.[40] The protein toxin cytotoxic necrotizing factor type 1 (CNF1) is another E. coli toxin that disrupts the function of transformed epithelial cells. CNF1 is considered a new carcinogenic biomarker in CRC.[41]

Since most E. coli in the gut are nonpathogenic, targeting toxin-produced species will be helpful for the management of CRC.

Campylobacter jejuni

Campylobacter is enriched in CRC samples compared to nontumor adjacent tissues in some studies.[42,43] Exposed patients with inflammatory bowel disease (IBD) had higher Campylobacter infection, which is a risk factor for CRC.[44]Campylobacter jejuni (C. jejuni) virulence factors FlaA and FlaB and the major adhesin CadF contribute to the function of C. jejuni. A study found that FlaA and FlaB but not CadF could lead to colitis in mice.[45] FliD of C. jejuni is the terminal cap protein of the flagellin subunits, through which C. jejuni can bind host cells. Glycosaminoglycans are thought to be a target of the interaction between C. jejuni and IECs, so they enhance colonization by C. jejuni.[46] Cytolethal distending toxin produced by C. jejuni 81 to 176, can lead to DNA double-strand breaks. C. jejuni 81 to 176 has strong tumorigenic capability in ApcMin/+mice and alters the microbial composition.[47] In brief, C. jejuni can develop intestinal inflammation and promote tumorigenesis, so it can become a therapeutic target.

Peptostreptococcus anaerobius

Peptostreptococcus is considered a novel microbial driver of intestinal inflammation and cancer.[48]Peptostreptococcus anaerobius (P. anaerobius) selectively adheres to CRC mucosa via a surface protein named putative cell wall binding repeat 2 (PCWBR2). The PCWBR2-integrin α2/β1 axis is the core of the interaction between P. anaerobius and CRC cells. The downstream signaling pathway is PI3K–Akt–NF-κB, which induces CRC development in Apc Min/+ mice. This specific axis might become a potential therapeutic target for CRC.[49]

P. anaerobius is enriched in fecal and biopsy samples from CRC patients compared with healthy people. P. anaerobius can interact with Toll-like receptors TLR2 and TLR 4 to stimulate reactive oxidative species (ROS) production, which can promote the biosynthesis of cholesterol, resulting in tumorigenesis.[50] These studies suggest that P. anaerobius, as a carcinogenic bacterium, can contribute to the CRC development.

Akkermansia muciniphila

Unlike the pathogenetic bacteria above, A. muciniphila serves as an anticancer probiotic that can exert anti-inflammatory effects. A. muciniphila, of the phylum Verrucomicrobia, grows on mucin as its sole carbon and nitrogen source.[51] It has been reported that the abundance of A. muciniphila is decreased in biopsies of IBD patients, which indicates that it has anti-inflammatory properties.[52] Amuc_1100 is a protein isolated from the outer membrane of A. muciniphila. Application of A. muciniphila and Amuc_1100 can block colitis and tumorigenesis through the modulation of CD8+ cytotoxic T lymphocytes.[53]A. muciniphila can induce M1-like macrophage activation and that is mediated via TLR2/NLRP3-dependent signaling.[54] Immunotherapy has become relatively mature and has applications in many diseases, including CRC. However, in some conditions, ICIs are often ineffective. A. muciniphila is targeted by some immunotherapies, such as ICIs targeting the PD-1/PD-L1 axis. A study revealed that A. muciniphila is enriched in responders to PD-1 blockade treatment. FMT given to nonresponders and oral A. muciniphila restored the efficacy of PD-1 blockade in an IL-12–dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T cells.[55] Studies indicate that A. muciniphila can not only decrease the incidence of CAC but also restore the response to PD-1 blockade treatment.

Some bacterial genera have different effects on the host depending on the species. Some species can lead to tumorigenesis, while others serve as probiotics.

Streptococcus

Streptococcus. bovis (S. bovis) strains consist of two different biotypes on account of their ability to ferment mannitol. S. gallolyticus was identified as S. bovis biotype I, which has such biological activity.[56] Many studies have proved that S. gallolyticus has a strong association with CRC.[57,58] Colonization by S. gallolyticus is higher in tumor-burdened mice owing to its bacteriocin gallocin, which can kill Enterococci so that S. gallolyticus can replace it. This bacteriocin can be enhanced by secondary bile acids. The CRC environment provides S. gallolyticus with suitable conditions to survive.[59] The tumorigenic effect of S. gallolyticus depends on the specific cell state, bacterial growth phase and interaction between it and IECs. S. gallolyticus promoted cancer development in an AOM-induced mouse model by upregulating β-catenin, a central signaling molecule in carcinogenic processes. In addition, the abundance of Streptococcus in CRC tissues was higher than that in adjacent noncancer tissues.[60] On the other hand, S. gallolyticus can trigger the production of inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-8. S. gallolyticus can also mediate overexpression of cyclooxygenase-2 to promote cellular proliferation and angiogenesis and inhibit apoptosis.[58]

In contrast, another species of Streptococcus is regarded as a probiotic. Streptococcus thermophilus (S. thermophilus) can prevent gut microbiota infection and is often used in milk products. β-Galactosidase generated by S. thermophilus plays a critical role in reducing colon tumorigenesis in Apcmin/+ mice and AOM-injected mice.[61]

Thus, S. gallolyticus serves as a pathogen, while S. thermophilus is a potential probiotic that remains to be further applied.

Clostridium

Clostridium has been found at significant levels in the intestines of CRC patients compared with healthy controls.[62] The abundance of fecal Clostridium symbiosum increases gradually from colorectal adenoma and early CRC to advanced CRC. This fecal biomarker can be a more effective way to detect Clostridium than F. nucleatum detection, CEA measurement and fecal immunochemical tests (FITs).[63] Collagen binding protein A (CbpA), which is a cell wall anchored protein from Clostridium difficile, is a surface-exposed adhesin that has adhesive properties toward collagen. CbpA can promote the interaction between Clostridium difficile (C. difficile) and the host and thereby contribute to C. difficile colonization of the gut.[64]

Apart from the pathogenic species of Clostridium, Clostridium can also prevent CRC, as discussed next.

Strategies of microbe-based management

Probiotics

Probiotics, which are identified as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”, are widely used to treat many diseases.[65] Probiotics can interact with host cells and other gut microbiota to regulate the intestinal microecological balance, thereby exerting anticancer effects. The mechanisms of action of probiotics include inhibiting the proliferation of cancer cells, regulating the immune system, restoring the gut dysbiosis, restoring the function of the intestinal barrier, producing anticancer substances and decreasing the cancer-promoting substances.[66]

Probiotics play a significant role in preventing and treating CRC. The advantages of probiotics involve many specific aspects: (1) Probiotics can promote mucus secretion and enhance the expression of tight junction proteins to protect the intestinal barrier. (2) Probiotics regulate immune cells and cytokines to reduce intestinal inflammation. (3) Probiotics regulate ROS to reduce IEC damage. (4) Probiotics reduce the activity of pathogenic bacterial enzymes to inhibit the actions of pathogens. (5) Probiotics play a critical role in the regulation of cell proliferation and apoptosis of tumor cells. (6) Probiotics restore the balance of the gut bacteria to enhance host homeostasis.[67] Many studies have administered probiotics as CRC therapies.

In addition to the cancer-promoting efficacy mentioned above, Clostridium can also be used as a probiotic to prevent CRC development. A study found that Clostridium butyricum (C. butyricum), a butyrate-producing bacterium, can reduce the proliferation of CRC cells and suppress high-fat diet-induced gut tumorigenesis in Apcmin/+ mice. C. butyricum can regulate the gut microbiota composition by inhibiting the Wnt/β-catenin signaling pathway, causing pathogen reduction and the grown of short-chain fatty acid (SCFA)-generating bacteria.[68]C. butyricum and Bacillus subtilis (B. subtilis) can inhibit CRC cell growth, cause cell cycle arrest and promote apoptosis in a mouse model. They can reduce inflammation and improve immune homeostasis.[69] These findings indicate that C. butyricum can protect the host from intestinal tumorigenesis, and the scientific application of these bacteria is a strategy of microbe-based management of CRC.

Transforming growth factor-b-activated kinase-1 (TAK1) is an important signaling pathway in the immune system. Tak1DM/DM mice are resistant to colitis and CAC. Odoribacter splanchnicus is enriched in Tak1DM/DM mice, inducing IL-17A, which plays a protective role in inflammation and tumorigenesis in the murine gut.[70]

The Lactobacillus rhamnosus-derived 8 kDa protein (P8) that induced apoptosis of CRC cells in a mouse xenograft model. Ring finger protein 152 (RNF152) is a downstream target of P8. Overexpression of RNF152 due to application of P8 can prevent the development of CRC.[71]Lactobacillus rhamnosus GG promoted the anti-inflammatory response and exerted antitumor effects in a murine model. The mechanism by which protective bacteria increase the abundance of CD8+ T cells depends on TLR2 expression on dendritic cells.[72]

The lactic acid bacterium Pediococcus pentosaceus (P. pentosaceus) is used as a novel bacterial drug delivery system for CRC therapy. A synthetic probiotic consisting of P. pentosaceus and a small therapeutic protein called P8 can ameliorate CRC development in mice. This new synthetic probiotic sheds light on the treatment of CRC.[73]

Thus, probiotics can treat CRC by producing beneficial metabolites, regulating immune signaling pathways and inhibiting colonic inflammation. Both natural and synthetic probiotics are considered promising candidates for CRC therapy.

Prebiotics and postbiotics

Prebiotics are defined as substrates that are selectively utilized by host microorganisms, conferring a health benefit.[74] Some food ingredients, such as dietary fibers, are considered prebiotics that exert beneficial effects. The mechanisms of prebiotics include stimulating beneficial gut microbiota to modulate the gut microbiota composition, producing fermentation products such as SCFAs, increasing micronutrient absorption in the colon, and regulating xenobiotic metabolizing enzymes and the immune response.[75] Gynostemma pentaphyllum saponins (GpS), a dietary herbal medicine, shows prebiotic properties. GpS can reduce polyps in ApcMin/+ mice, and promote the growth of Bifidobacterium animalis (B. animalis), which suppresses CRC development.[76] This findings reveal that prebiotics can enhance the function of probiotics and the combination of them can prevent gut tumorigenesis.[77]

Postbiotics are soluble factors secreted by live bacteria or released after bacterial lysis.[78] Postbiotics include inactivated microbial cells, cell fractions and cell metabolites. The mechanisms of action of postbiotics are manifold: postbiotics can induce apoptosis of CRC cells, prevent pathogen translocation and restore the gut barrier, regulate immune activity to fight inflammation, inhibit pathogenic bacterial enzymes, exhibit anti-mutagenic and antioxidant effects, decrease the intestinal pH and moderate signaling pathways associated with the carcinogenic procedure.[79] SCFAs are postbiotics that are the major products of bacterial metabolites of dietary fiber. CRC cells can use SCFAs in the process of aerobic glycolysis and show increased sensitivity to SCFAs. Butyrate is the most widely used SCFAs, displaying strong anticancer properties by regulating some signaling pathways.[80]

Prebiotics and postbiotics encourage the probiotics to convert food components into beneficial metabolites and exert anti-inflammatory effects. The combination of probiotics, prebiotics and postbiotics in clinical applications is eagerly awaited.

Fecal microbiota transplantation

FMT delivers feces from donors into the gastrointestinal tract of receivers via colonoscopy or oral administration. FMT can reprogram the gut microbiota composition by disrupting or restoring the gut balance to induce or treat some diseases, such as CRC. A previous study revealed that feces from patients with CRC rather than from healthy controls promoted the development of high-grade dysplasia and polyp production in mice. Moreover, feces from CRC patients can increase proinflammatory genes, immune cell infiltration and oncogenic factors in AOM and GF murine models.[81] In line with this cancer-promoting function, another study has shown that FMT from CRC patients can lead to more tumors in Apcmin/+ mice. The mechanism of tumorigenesis involves upregulating the expression of β-catenin and cyclin D1 and further activating the Wnt signaling pathway. The gut barrier is also damaged, and the proinflammatory cytokine profile is disrupted.[82]

FMT therapy is a novel approach to treat CRC as well. The beneficial fecal microbiota is transplanted from healthy samples to CRC patients to pursue homeostasis but does not change the natural balance of the gut. Rice bran is an agricultural byproduct of white rice milling that has been proven to exhibit efficacy in the suppression of colitis and CRC. CRC survivors who consume rice bran daily are considered a source of protective bacteria. FMT from such patients to AOM/DSS mice resulted in less tumorigenesis. In addition, Flavonifractor and Oscillibacter were enriched, but Parabacteroides was decreased, in the recipient mouse.[83] Consequently, FMT is a promising option for CRC therapy.

Dietary interventions

Diet is a vital environmental factor that may be involved in CRC, and an unhealthy diet might contribute to tumorigenesis. Diet plays an important role in gut microbiota and further impacts the homeostasis of the gut. People consuming different diets have significantly different intestinal microbial compositions and abundances. Long-term dependence on the same diet can lead to a relatively higher risk of specific disease.

Fiber from fruits, vegetables and grain cereals can prevent CRC development, while fat and red meat or processed meat have a positive relationship with the risk of CRC. Butyrate with anti-inflammatory and antineoplastic abilities can protect IECs from tumorigenesis.[84] The Western diet, characterized by a high-fat/low-fiber diet, is correlated with disease recurrence after surgery. The collaboration of a Western diet and antibiotics can promote tumorigenesis by CRC cell anastomosis after surgery in mice.[85] Along with direct interventions, diet-derived metabolites connect the microbiota to CRC. Sulfur-metabolizing microbes can produce pro-carcinogenic hydrogen sulfide, which links sulfur-rich foods with the risk of CRC. In a prospective cohort of young women, high consumption of a sulfur microbial diet was associated with an increased risk for early-onset adenomas.[86]

Dietary intervention has advantages in CRC prevention and anticancer therapy. Changing dietary habits is a potential strategy to modulate the gut microbiota composition. Owing to the modifiable character of the diet, dietary intervention is considered the most reasonable and cost-effective method of CRC treatment.

Traditional Chinese medicine (TCM) can be a special dietary invention that can interact with intestinal bacteria and further impact the prevention of CRC. Curcumin, one of the major curcuminoids present in the root of the plant Curcuma longa, can ameliorate intestinal inflammation by regulating gut bacteria levels. It can increase the abundance of butyrate-producing bacteria and reduce the abundance of Ruminococcus species, which is related to CRC.[87] Evodiamine (EVO) is an extract of TCM that can exert antitumor effects by inhibiting inflammation. In EVO-treated mice, the abundances of Enterococcus faecalis and E. coli were reduced, while those of Bifidobacterium, Campylobacter and Lactobacillus were increased. In addition, inflammatory cytokines were decreased, and the IL6/STAT3/P65 signaling pathway is was inhibited.[88] Berberine (BBR) is a component of the Chinese herb Coptis chinensis. BBR can rescue the F. nucleatum-mediated increase in opportunistic pathogens and can reduce tumorigenesis by modulating the mucosal immune system and blocking the activation of tumorigenesis-related pathways.[89] Another study indicated that BBR could induce alterations in the composition of the gut microbiota and bacterial metabolism in AOM/DSS mice, leading to inhibition of colorectal tumorigenesis.[90] Sini decoction (SND) is a classic prescription of TCM. SND extract can ameliorate the degree of tumor malignancy in AOM/DSS mice. In SND-treated mice, the abundance of pathogenic bacteria decreased, while the abundance of some bacteria increased, such as Lactobacillus, Bacillus coagulans and A. muciniphila.[91]

Overall, TCM can effectively prevent CRC development by regulating the intestinal microbiota and further regulating the immune system, including the inflammatory cytokines or tumor-related pathways.

Conclusion

The relationship between gut microbiota and CRC has been widely studied. Some specific pathogens have been shown to impair the gut mucus and further damage intestinal barrier function. Some pathogens disrupt the immune system to promote a tumor-associated microenvironment. However, many bacteria can serve as probiotics to ameliorate gut inflammation, restore the balance of gut microbiota and regulate immune cells and cytokines. Gut bacteria are also known to influence the efficacy of chemotherapy and immunotherapy. Both types of microbes can become the novel targets for treating and preventing of CRC. The bacteria-related mechanisms of the development and prevention of CRC are shown in [Figure 1].

F1
Figure 1:
Bacteria-related mechanisms involved in the development and prevention of CRC. Pathogens secrete toxins and metabolites to damage the intestinal barrier and disrupt the immune system. Pro-inflammatory cytokines, such as TNF-α and IL-17A, are produced and then activate NF-κB or autophagy which can contribute to an inflammatory environment, leading to the carcinogenesis of IECs. Microbe-based management, such as probiotics and dietary invention, can ameliorate the intestinal inflammation through generating postbiotics and other anticancer substances. Treg cells and dendritic cells can exert anti-inflammatory effects and activate apoptosis of CRC cells to restore the gut homeostasis. Gut bacteria can also influence the efficacy of the chemotherapy and immunotherapy. CRC: Colorectal cancer; IECs: Intestinal epithelial cells.

With an abundance of studies on gut microbiota modulation, microbe-based management plays a potential role in CRC management. Compared to the traditional treatment of CRC, some microbe-oriented studies are still in their early stages. However, we hope these experiments in murine models will be translated into clinical applications. The value of such therapies deserves more attention. In the future, intestinal bacteria intervention could be combined with other strategies for CRC management. Further clinical research in the microbiome should clarify more specific bacteria that are related to CRC development and focus on potential applications that will modulate the gut microbiota to broaden the scope of this treatment. Overall, gut-microbiota modulation is a promising approach to prevent and treat CRC.

Conflicts of interest

The authors declare that they have no competing interests.

References

1. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin 2020; 70:145–164. doi: 10.3322/caac.21601.
2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424. doi: 10.3322/caac.21492.
3. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017;66:683–691. doi: 10.1136/gutjnl-2015-310912.
4. Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol 2019;16:713–732. doi: 10.1038/s41575-019-0189-8.
5. Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J 2021;134:783–791. doi: 10.1097/CM9.0000000000001474.
6. Song M, Chan AT, Sun J. Influence of the gut microbiome, diet, and environment on risk of colorectal cancer. Gastroenterology 2020;158:322–340. doi: 10.1053/j.gastro.2019.06.048.
7. Cheng Y, Ling Z, Li L. The intestinal microbiota and colorectal cancer. Front Immunol 2020;11:615056. doi: 10.3389/fimmu.2020.615056.
8. Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer 2013;13:800–812. doi: 10.1038/nrc3610.
9. Saus E, Iraola-Guzman S, Willis JR, Brunet-Vega A, Gabaldon T. Microbiome and colorectal cancer: roles in carcinogenesis and clinical potential. Mol Aspects Med 2019;69:93–106. doi: 10.1016/j.mam.2019.05.001.
10. Takiishi T, Fenero CIM, Camara NOS. Intestinal barrier and gut microbiota: shaping our immune responses throughout life. Tissue Barriers 2017;5:e1373208. doi: 10.1080/21688370.2017.1373208.
11. Paone P, Cani PD. Mucus barrier, mucins and gut microbiota: the expected slimy partners? Gut 2020;69:2232–2243. doi: 10.1136/gutjnl-2020-322260.
12. Sobhani I, Bergsten E, Couffin S, Amiot A, Nebbad B, Barau C, et al. Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. Proc Natl Acad Sci USA 2019;116:24285–24295. doi: 10.1073/pnas.1912129116.
13. Janney A, Powrie F, Mann EH. Host-microbiota maladaptation in colorectal cancer. Nature 2020;585:509–517. doi: 10.1038/s41586-020-2729-3.
14. Tilg H, Adolph TE, Gerner RR, Moschen AR. The intestinal microbiota in colorectal cancer. Cancer Cell 2018;33:954–964. doi: 10.1016/j.ccell.2018.03.004.
15. Xu S, Yin W, Zhang Y, Lv Q, Yang Y, He J. Foes or friends? Bacteria enriched in the tumor microenvironment of colorectal cancer. Cancers (Basel) 2020;12:372. doi: 10.3390/cancers12020372.
16. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet 2019;394:1467–1480. doi: 10.1016/s0140-6736(19)32319-0.
17. Wong SH, Yu J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat Rev Gastroenterol Hepatol 2019;16:690–704. doi: 10.1038/s41575-019-0209-8.
18. Dai Z, Coker OO, Nakatsu G, Wu WKK, Zhao L, Chen Z, et al. Multi-cohort analysis of colorectal cancer metagenome identified altered bacteria across populations and universal bacterial markers. Microbiome 2018;6:70. doi: 10.1186/s40168-018-0451-2.
19. Kwong TNY, Wang X, Nakatsu G, Chow TC, Tipoe T, Dai RZW, et al. Association between bacteremia from specific microbes and subsequent diagnosis of colorectal cancer. Gastroenterology 2018;155:383–390. e8. doi: 10.1053/j.gastro.2018.04.028.
20. Lau HCH, Sung JJ, Yu J. Gut microbiota: impacts on gastrointestinal cancer immunotherapy. Gut Microbes 2021;13:1–21. doi: 10.1080/19490976.2020.1869504.
21. Dixit K, Chaudhari D, Dhotre D, Shouche Y, Saroj S. Restoration of dysbiotic human gut microbiome for homeostasis. Life Sci 2021;278:119622. doi: 10.1016/j.lfs.2021.119622.
22. Zhang J, Haines C, Watson AJM, Hart AR, Platt MJ, Pardoll DM, et al. Oral antibiotic use and risk of colorectal cancer in the United Kingdom, 1989-2012: a matched case-control study. Gut 2019;68:1971–1978. doi: 10.1136/gutjnl-2019-318593.
23. Lu SSM, Mohammed Z, Haggstrom C, Myte R, Lindquist E, Gylfe A, et al. Antibiotics use and subsequent risk of colorectal cancer: a Swedish nationwide population-based study. J Natl Cancer Inst 2021;djab125. doi: 10.1093/jnci/djab125. Epub ahead of print.
24. Wu N, Yang X, Zhang R, Li J, Xiao X, Hu Y, et al. Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb Ecol 2013;66:462–470. doi: 10.1007/s00248-013-0245-9.
25. Sears CL. Enterotoxigenic Bacteroides fragilis: a rogue among symbiotes. Clin Microbiol Rev 2009;22:349–369. doi: 10.1128/CMR.00053-08.
26. Zamani S, Taslimi R, Sarabi A, Jasemi S, Sechi LA, Feizabadi MM. Enterotoxigenic bacteroides fragilis: a possible etiological candidate for bacterially-induced colorectal precancerous and cancerous lesions. Front Cell Infect Microbiol 2019;9:449. doi: 10.3389/fcimb.2019.00449.
27. Boleij A, Hechenbleikner EM, Goodwin AC, Badani R, Stein EM, Lazarev MG, et al. The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients. Clin Infect Dis 2015;60:208–215. doi: 10.1093/cid/ciu787.
28. Cheng WT, Kantilal HK, Davamani F. The mechanism of bacteroides fragilis toxin contributes to colon cancer formation. Malays J Med Sci 2020;27:9–21. doi: 10.21315/mjms2020.27.4.2.
29. Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 2009;15:1016–1022. doi: 10.1038/nm.2015.
30. Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, et al. Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells. Cell Host Microbe 2018;23:203–214. e205. doi: 10.1016/j.chom.2018.01.007.
31. Cao Y, Wang Z, Yan Y, Ji L, He J, Xuan B, et al. Enterotoxigenic Bacteroides fragilis promotes intestinal inflammation and malignancy by inhibiting exosomes-packaged miR-149-3p. Gastroenterology 2021;161:1552–1566. e12. doi: 10.1053/j.gastro.2021.08.003.
32. Viljoen KS, Dakshinamurthy A, Goldberg P, Blackburn JM. Quantitative profiling of colorectal cancer-associated bacteria reveals associations between fusobacterium spp., enterotoxigenic Bacteroides fragilis (ETBF) and clinicopathological features of colorectal cancer. PLoS One 2015;10:e0119462. doi: 10.1371/journal.pone.0119462.
33. Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 2013;14:207–215. doi: 10.1016/j.chom.2013.07.007.
34. Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin. Cell Host Microbe 2013;14:195–206. doi: 10.1016/j.chom.2013.07.012.
35. Hong J, Guo F, Lu SY, Shen C, Ma D, Zhang X, et al. F. nucleatum targets lncRNA ENO1-IT1 to promote glycolysis and oncogenesis in colorectal cancer. Gut 2021;70:2123–2137. doi: 10.1136/gutjnl-2020-322780.
36. Yang Y, Weng W, Peng J, Hong L, Yang L, Toiyama Y, et al. Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating toll-like receptor 4 signaling to nuclear factor-kappaB, and up-regulating expression of MicroRNA-21. Gastroenterology 2017;152:851–866. e824. doi: 10.1053/j.gastro.2016.11.018.
37. Yu T, Guo F, Yu Y, Sun T, Ma D, Han J, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 2017;170:548–563. e16. doi: 10.1016/j.cell.2017.07.008.
38. Wassenaar TM. E. coli and colorectal cancer: a complex relationship that deserves a critical mindset. Crit Rev Microbiol 2018;44:619–632. doi: 10.1080/1040841X.2018.1481013.
39. Iftekhar A, Berger H, Bouznad N, Heuberger J, Boccellato F, Dobrindt U, et al. Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells. Nat Commun 2021;12:1003. doi: 10.1038/s41467-021-21162-y.
40. Salesse L, Lucas C, Hoang MHT, Sauvanet P, Rezard A, Rosenstiel P, et al. Colibactin-producing Escherichia coli induce the formation of invasive carcinomas in a chronic inflammation-associated mouse model. Cancers (Basel) 2021;13:2060. doi: 10.3390/cancers13092060.
41. Fabbri A, Travaglione S, Ballan G, Loizzo S, Fiorentini C. The cytotoxic necrotizing factor 1 from E. coli: a janus toxin playing with cancer regulators. Toxins (Basel) 2013;5:1462–1474. doi: 10.3390/toxins5081462.
42. Xu K, Jiang B. Analysis of mucosa-associated microbiota in colorectal cancer. Med Sci Monit 2017;23:4422–4430. doi: 10.12659/msm.904220.
43. Allali I, Delgado S, Marron PI, Astudillo A, Yeh JJ, Ghazal H, et al. Gut microbiome compositional and functional differences between tumor and non-tumor adjacent tissues from cohorts from the US and Spain. Gut Microbes 2015;6:161–172. doi: 10.1080/19490976.2015.1039223.
44. Gradel KO, Nielsen HL, Schonheyder HC, Ejlertsen T, Kristensen B, Nielsen H. Increased short- and long-term risk of inflammatory bowel disease after salmonella or campylobacter gastroenteritis. Gastroenterology 2009;137:495–501. doi: 10.1053/j.gastro.2009.04.001.
45. Schmidt AM, Escher U, Mousavi S, Tegtmeyer N, Boehm M, Backert S, et al. Immunopathological properties of the Campylobacter jejuni flagellins and the adhesin CadF as assessed in a clinical murine infection model. Gut Pathog 2019;11:24. doi: 10.1186/s13099-019-0306-9.
46. Freitag CM, Strijbis K, van Putten JPM. Host cell binding of the flagellar tip protein of Campylobacter jejuni. Cell Microbiol 2017;19:e12714. doi: 10.1111/cmi.12714.
47. He Z, Gharaibeh RZ, Newsome RC, Pope JL, Dougherty MW, Tomkovich S, et al. Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut 2019;68:289–300. doi: 10.1136/gutjnl-2018-317200.
48. Yang Y, Jobin C. Novel insights into microbiome in colitis and colorectal cancer. Curr Opin Gastroenterol 2017;33:422–427. doi: 10.1097/MOG.0000000000000399.
49. Long X, Wong CC, Tong L, Chu ESH, Ho Szeto C, Go MYY, et al. Peptostreptococcus anaerobius promotes colorectal carcinogenesis and modulates tumour immunity. Nat Microbiol 2019;4:2319–2330. doi: 10.1038/s41564-019-0541-3.
50. Tsoi H, Chu ESH, Zhang X, Sheng J, Nakatsu G, Ng SC, et al. Peptostreptococcus anaerobius induces intracellular cholesterol biosynthesis in colon cells to induce proliferation and causes dysplasia in mice. Gastroenterology 2017;152:1419–1433. e5. doi: 10.1053/j.gastro.2017.01.009.
51. Derrien M, van Passel MW, van de Bovenkamp JH, Schipper RG, de Vos WM, Dekker J. Mucin-bacterial interactions in the human oral cavity and digestive tract. Gut Microbes 2010;1:254–268. doi: 10.4161/gmic.1.4.12778.
52. Derrien M, Belzer C, de Vos WM. Akkermansia muciniphila and its role in regulating host functions. Microb Pathog 2017;106:171–181. doi: 10.1016/j.micpath.2016.02.005. P.
53. Wang L, Tang L, Feng Y, Zhao S, Han M, Zhang C, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8(+) T cells in mice. Gut 2020;69:1988–1997. doi: 10.1136/gutjnl-2019-320105.
54. Fan L, Xu C, Ge Q, Lin Y, Wong CC, Qi Y, et al. A. Muciniphila suppresses colorectal tumorigenesis by inducing TLR2/NLRP3-mediated M1-like TAMs. Cancer Immunol Res 2021;9:1111–1124. doi: 10.1158/2326-6066.CIR-20-1019.
55. Bertrand Routy, Emmanuelle Le Chatelier, Lisa Derosa, Connie P.M. Duong, Maryam Tidjani Alou, Romain Daillère, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science 2018;359:91–97.
56. Schlegel L, Grimont F, Ageron E, Grimont PAD, Bouvet A. Reappraisal of the taxonomy of the Streptococcus bovis/Streptococcus equinus complex and related species: description of Streptococcus gallolyticus subsp. gallolyticus subsp. nov., S. gallolyticus subsp. macedonicus subsp. nov. and S. gallolyticus subsp. pasteurianus subsp. nov. Int J Syst Evol Microbiol 2003;53 (Pt 3):631–645. doi: 10.1099/ijs.0.02361-0.
57. Boleij A, van Gelder MM, Swinkels DW, Tjalsma H. Clinical Importance of Streptococcus gallolyticus infection among colorectal cancer patients: systematic review and meta-analysis. Clin Infect Dis 2011;53:870–878. doi: 10.1093/cid/cir609.
58. Ahmed S Abdulamir, Rand R Hafidh, Bakar FA. The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and the underlying mechanisms of its etiological role. J Exp Clin Cancer Res 2011;30:11. doi: 10.1186/1756-9966-30-11.
59. Aymeric L, Donnadieu F, Mulet C, du Merle L, Nigro G, Saffarian A, et al. Colorectal cancer specific conditions promote Streptococcus gallolyticus gut colonization. Proc Natl Acad Sci USA 2018;115:E283–E291. doi: 10.1073/pnas.1715112115.
60. Kumar R, Herold JL, Schady D, Davis J, Kopetz S, Martinez-Moczygemba M, et al. Streptococcus gallolyticus subsp. gallolyticus promotes colorectal tumor development. PLoS Pathog 2017;13:e1006440. doi: 10.1371/journal.ppat.1006440.
61. Li Q, Hu W, Liu WX, Zhao LY, Huang D, Liu XD, et al. Streptococcus thermophilus inhibits colorectal tumorigenesis through secreting beta-galactosidase. Gastroenterology 2021;160:1179–1193. e1114. doi: 10.1053/j.gastro.2020.09.003.
62. Allali I, Boukhatem N, Bouguenouch L, Hardi H, Boudouaya HA, Cadenas MB, et al. Gut microbiome of Moroccan colorectal cancer patients. Med Microbiol Immunol 2018;207:211–225. doi: 10.1007/s00430-018-0542-5.
63. Xie YH, Gao QY, Cai GX, Sun XM, Sun XM, Zou TH, et al. Fecal clostridium symbiosum for noninvasive detection of early and advanced colorectal cancer: test and validation studies. EBioMedicine 2017;25:32–40. doi: 10.1016/j.ebiom.2017.10.005.
64. Tulli L, Marchi S, Petracca R, Shaw HA, Fairweather NF, Scarselli M, et al. CbpA: a novel surface exposed adhesin of Clostridium difficile targeting human collagen. Cell Microbiol 2013;15:1674–1687. doi: 10.1111/cmi.12139.
65. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11:506–514. doi: 10.1038/nrgastro.2014.66.
66. Tripathy A, Dash J, Kancharla S, Kolli P, Mahajan D, Senapati S, et al. Probiotics: a promising candidate for management of colorectal cancer. Cancers (Basel) 2021;13:3178. doi: 10.3390/cancers13133178.
67. Ding S, Hu C, Fang J, Liu G. The protective role of probiotics against colorectal cancer. Oxid Med Cell Longev 2020;2020:8884583. doi: 10.1155/2020/8884583.
68. Chen D, Jin D, Huang S, Wu J, Xu M, Liu T, et al. Clostridium butyricum, a butyrate-producing probiotic, inhibits intestinal tumor development through modulating WNT signaling and gut microbiota. Cancer Lett 2020;469:456–467. doi: 10.1016/j.canlet.2019.11.019.
69. Chen ZF, Ai LY, Wang JL, Ren LL, Yu YN, Xu J, et al. Probiotics Clostridium butyricum and Bacillus subtilis ameliorate intestinal tumorigenesis. Future Microbiol 2015;10:1433–1445. doi: 10.2217/fmb.15.66.
70. Xing C, Wang M, Ajibade AA, Tan P, Fu C, Chen L, et al. Microbiota regulate innate immune signaling and protective immunity against cancer. Cell Host Microbe 2021;29:959–974. e7. doi: 10.1016/j.chom.2021.03.016.
71. Kim BK, Yoon YS, Ryu Y, Chung MJ. Probiotic-derived p8 protein induce apoptosis via regulation of RNF152 in colorectal cancer cells. Am J Cancer Res 2021;11:746–759.
72. Owens JA, Saeedi BJ, Naudin CR, Hunter-Chang S, Barbian ME, Eboka RU, et al. Lactobacillus rhamnosus GG orchestrates an anti-tumor immune response. Cell Mol Gastroenterol Hepatol 2021;12:1311–1327. doi: 10.1016/j.jcmgh.2021.06.001.
73. Chung Y, Ryu Y, An BC, Yoon YS, Choi O, Kim TY, et al. A synthetic probiotic engineered for colorectal cancer therapy modulates gut microbiota. Microbiome 2021;9:122. doi: 10.1186/s40168-021-01071-4.
74. Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, et al. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol 2017;14:491–502. doi: 10.1038/nrgastro.2017.75.
75. Raman M, Ambalam P, Kondepudi KK, Pithva S, Kothari C, Patel AT, et al. Potential of probiotics, prebiotics and synbiotics for management of colorectal cancer. Gut Microbes 2013;4:181–192. doi: 10.4161/gmic.23919.
76. Liao W, Khan I, Huang G, Chen S, Liu L, Leong WK, et al. Bifidobacterium animalis: the missing link for the cancer-preventive effect of Gynostemma pentaphyllum. Gut Microbes 2021;13:1847629. doi: 10.1080/19490976.2020.1847629.
77. Fei Y, Chen Z, Han S, Zhang S, Zhang T, Lu Y, et al. Role of prebiotics in enhancing the function of next-generation probiotics in gut microbiota. Crit Rev Food Sci Nutr 2021;1–18. doi: 10.1080/10408398.2021.1958744.
78. Aguilar-Toalá JE, Garcia-Varela R, Garcia HS, Mata-Haro V, González-Córdova AF, Vallejo-Cordoba B, et al. Postbiotics: an evolving term within the functional foods field. Trends Food Sci Technol 2018;75:105–114. doi: 10.1016/j.tifs.2018.03.009.
79. Rad AH, Aghebati-Maleki L, Kafil HS, Abbasi A. Molecular mechanisms of postbiotics in colorectal cancer prevention and treatment. Crit Rev Food Sci Nutr 2021;61:1787–1803. doi: 10.1080/10408398.2020.1765310.
80. Wang G, Yu Y, Wang YZ, Wang JJ, Guan R, Sun Y, et al. Role of SCFAs in gut microbiome and glycolysis for colorectal cancer therapy. J Cell Physiol 2019;234:17023–17049. doi: 10.1002/jcp.28436.
81. Wong SH, Zhao L, Zhang X, Nakatsu G, Han J, Xu W, et al. Gavage of fecal samples from patients with colorectal cancer promotes intestinal carcinogenesis in germ-free and conventional mice. Gastroenterology 2017;153:1621–1633. e6. doi: 10.1053/j.gastro.2017.08.022.
82. Min Ho PY, Hu W, Lee YY, Gao C, Tan YZ, Cheen HH, et al. Health-related quality of life of patients with inflammatory bowel disease in Singapore. Intest Res 2019;17:107–118. doi: 10.5217/ir.2018.00099.
83. Parker KD, Maurya AK, Ibrahim H, Rao S, Hove PR, Kumar D, et al. Dietary rice bran-modified human gut microbial consortia confers protection against colon carcinogenesis following fecal transfaunation. Biomedicines 2021;9:144. doi: 10.3390/biomedicines9020144.
84. Yang J, Yu J. The association of diet, gut microbiota and colorectal cancer: what we eat may imply what we get. Protein Cell 2018;9:474–487. doi: 10.1007/s13238-018-0543-6.
85. Gaines S, van Praagh JB, Williamson AJ, Jacobson RA, Hyoju S, Zaborin A, et al. Western diet promotes intestinal colonization by collagenolytic microbes and promotes tumor formation after colorectal surgery. Gastroenterology 2020;158:958–970. e2. doi: 10.1053/j.gastro.2019.10.020.
86. Nguyen LH, Cao Y, Hur J, Mehta RS, Sikavi DR, Wang Y, et al. The sulfur microbial diet is associated with increased risk of early-onset colorectal cancer precursors. Gastroenterology 2021;161:1423–1432. e4. doi: 10.1053/j.gastro.2021.07.008.
87. Weng W, Goel A. Curcumin and colorectal cancer: an update and current perspective on this natural medicine. Semin Cancer Biol 2020. S1044-579X(20)30044-4. doi: 10.1016/j.semcancer.2020.02.011.
88. Zhu LQ, Zhang L, Zhang J, Chang GL, Liu G, Yu DD, et al. Evodiamine inhibits high-fat diet-induced colitis-associated cancer in mice through regulating the gut microbiota. J Integr Med 2021;19:56–65. doi: 10.1016/j.joim.2020.11.001.
89. Yu YN, Yu TC, Zhao HJ, Sun TT, Chen HM, Chen HY, et al. Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment. Oncotarget 2015;6:32013–32026. doi: 10.18632/oncotarget.5166.
90. Chen H, Zhang F, Zhang J, Zhang X, Guo Y, Yao Q. A holistic view of berberine inhibiting intestinal carcinogenesis in conventional mice based on microbiome-metabolomics analysis. Front Immunol 2020;11:588079. doi: 10.3389/fimmu.2020.588079.
91. Wang Y, Zhang X, Li J, Zhang Y, Guo Y, Chang Q, et al. Sini decoction ameliorates colorectal cancer and modulates the composition of gut microbiota in mice. Front Pharmacol 2021;12:609992. doi: 10.3389/fphar.2021.609992.
Keywords:

Colorectal cancer; Intestinal bacteria; Management; Fecal microbiota transplantation

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