Disease ⇒ Cancer ⇒ Colorectal cancer {40000123} Record Keys Type:Disease Parent:Cancer Definition:Colorectal cancer Details Initialisation date:2019-05-15 Other Terms:CRC LinksWickipediaMerck Manual Meta Information MedDra ID:10061451 MedDra Level:pt ICD:[ ] Category:Gastroenterology, Oncology Zone:[ ] Mechanism:[ ] Notes: - The elevated abundance of certain bacterial species such as Fusobacterium nucleatum and Parvimonas micra in CRC patients is often associated with the development of the disease - The microbiomes of colorectal cancer subjects have increased abundance of a module for naphthalene degradation (M00534). - The modules for cobalt/nickel transport systems (M00245 and M00246) are depleted in subjects with colorectal cancer. - Enterotoxigenic Bacteroides fragilis (ETBF) secretes Bacteroides fragilis toxin (BFT), which decreases E-cadherin levels. This loosens the attachments between intestinal epithelial cells and results in exposure to many antigens. Moreover, decreased E-cadherin promotes intracellular migration of beta-catenin and accelerates carcinogenic-related signaling such as Wnt signaling. (1) - Ren is a potential agent for colon cancer prevention. - Administration of Ren effectively suppress DMH-induced colonic carcinogenesis. (4) - bacteria like #Acidaminobacter, #Phascolarctobacterium and #Citrobacter were present in significant number in colorectal cancer (CRC) patient’s stool samples.Shared Reference Notes [1.1] - Fusobacterium nucleatum is enriched in human colonic adenomas relative to surrounding tissue, suggesting that it may play a role in early initiation of colorectal cancer. - Further supporting this idea, F. nucleatum colonization promoted and exacerbated tumorigenesis in the gut of APCmin/+ mice, although the mechanism of pathogenesis remains unknown. [1.2] - Chronic inflammation is an established risk factor for CRC, as patients with inflammatory bowel diseases (IBD) consistently have a higher risk than the general population of developing CRC. - An increase in pro-inflammatory species has been repeatedly reported in CRC patients. - The most prevalent and most described bacterium in CRC fecal and mucosa-associated microbiota is #Fusobacterium nucleatum [1.3] - #Odoribacter splanchnicus and Bacteroides sp. D20 were among the dominant strains in the guts of mutant mice. - Both strains induced strong protection against colitis and colorectal cancer when transferred to the gut of control mice. - O. splanchnicus in particular was sufficient to induce the development of intestinal immune cells and confer resistance against colitis and colorectal cancer, likely by inducing the development of specific intestinal immune cells. [1.4] - #Fusobacterium nucleatum expresses adhesins, including FadA and Fap2, which bind to tumour cells and directly promote carcinogenesis by activating oncogenic Wnt/β-catenin signalling and dysregulating immune cell infiltration and antitumour immunity. [1.5] - Fusobacterium nucleatum subsp. vincentii, F. nucleatum subsp. animalis, Porphyromonas asaccharolytica, and Peptostreptococcus stomatis, all of which were found to be enriched in tumor and stool samples from CRC patients. - Patients with Peptostreptococcus bacteremia have an increased risk of developing , in particular Peptostreptococcus stomatis and Peptostreptococcus anaerobius. P. anaerobius has been found to be highly enriched in CRC patient stool and tissue. - Significant overabundance of P. gingivalis was found in fecal samples from CRC patients - Prevotella intermedia was associated with a higher risk of developing CRC and was identified in a multinational multicohort study of 526 metagenomic CRC fecal samples. - Overabundance of Parvimonas micra has been reported in CRC patient stool. Enterotoxigenic Bacteroides fragilis strains (ETBF) have been associated with CRC and is associated with sporadic CRC. - Tissues of patients with familial adenomatous polyposis (FAP) carry B. fragilis and Escherichia coli biofilms. -The genotoxin colibactin is produced by polyketide synthase-positive E. coli and induces DNA double-strand breaks in vitro and in vivo. It increases tumor formation in vitro alone, or in co-colonization with ETBF in FAP patients. - B. fragilis and some Prevotellaceae, but also F. nucleatum, produce succinate, an inducer of proinflammatory pathways via succinate receptor 1 on immune cells . - E. coli catabolism of lysine to succinate involves the intermediate l-2-hydroxyglutarate, an oncometabolite that is involved in epigenetic deregulation in certain cancers. [1.6] [#Antibiotic Therapy] [1.7] - #Clostridiales species are significantly reduced in CRC patients compared with healthy controls. - Oral application of a mix of four #Clostridiales strains (CC4) in mice prevented and even successfully treated CRC as stand-alone therapy. This effect depended on intratumoral infiltration and activation of CD8+ T cells. - Single application of Roseburia intestinalis or Anaerostipes caccae is even more effective than CC4. - The CC4 mix supplementation outperformed anti-PD-1 therapy in mouse models of CRC and melanoma. [1.8] - The direct bond of microbial proteins with E-cadherin of host epithelial cells can activate the β-catenin pathway, as expressed by #Fusobacterium nucleatum, associated with colorectal cancer. - F. nucleatum, expressing Fap2 cell surface protein, inhibits immune cytotoxicity through interaction with T and NK cells [1.9] - CRC mouse model > Oral microbiota alterations change > the gut bacterial composition within tumors but not in adjacent peritumor tissues. - Buccal #Fusobacterium nucleatum migrates > to the CRC locus > impairs the therapeutic efficacy and prognosis of #Radiotherapy. Administration of a specific antibiotic, metronidazole > abrogates the adverse effects of oral microbiome fluctuation on #Radiotherapy for CRC. [1.11] - #Helicobacter hepaticus (Hhep) colonization reduces colorectal cancer burden in mice. - Hhep induces CD4+ Tfh cell- and B cell-dependent anti-colorectal cancer immunity [1.12] [#Iron] - #Bifidobacteriaceae > binding Fe in the large intestine > limiting the formation of free radicals associated with Fe >reducing the risk of colorectal cancer [1.13] [#Alzheimer’s disease] - Serum #TMAO levels in AD/CRC patients are higher than those in healthy people, and its concentrations may be positively correlated with AD/cancer progression [#Thyroid carcinoma] [#Hydrogen sulfide] - H2S at a safe and nontoxic concentration can protect not only healthy cells, such as neurons, but also cancerous cells from apoptosis. - In a variety of cancers, including #Ovarian cancer, #Oral cancer, thyroid cancer, colon cancer, #Breast cancer, etc., the upregulation of H2S-producing enzyme CBS > can enhance the proliferation ability of cancer cells and make cancer cells more sensitive to it - #Vitamin D supplementation could regulate the steady state of intestinal flora in colorectal cancer (CRC) mice and regulate the integrity of the #Akkermansia muciniphila-mediated intestinal barrier, thereby playing a role in the reversal of CRC. [#Short Chain Fatty Acid] - SCFAs > maintaining the integrity of the intestinal barrier to reduce the risk of colon cancer [1.14] [#Crohn’s disease, #Inflamatory bowel disease] [#Common consumer products] - #Triclosan (TCS), an antimicrobial agent found in thousands of consumer products > exacerbates #Colitis and #Colitis-associated colorectal tumorigenesis in animal models. - intestinal commensal microbes > microbial β-glucuronidase (GUS) enzymes > mediate metabolic activation of #Triclosan in the colon > gut toxicology. [1.15] - #Enterococcus faecalis levels associated with variants in the MED13L locus, which has been linked to colorectal cancer. [1.16] [#Antibiotic Therapy] [1.17] - Increases in #Enterococcus faecalis and #Escherichia coli enhance the production of intestinal inflammatory signaling molecules, IFN-γ and IL-4. In both IBD and CRC, #Fusobacterium nucleatum elicits strong pro-inflammatory responses [#Tryptophan] - Around 5% of Trp > metabolized by gut bacteria into #Indole and indolic compounds > can bind to pregnane X receptors (PXR) and aryl hydrocarbon receptor (AhR) > promote intestinal homeostasis, enhance barrier function and tight junctions, reduce permeability, regulate intestinal immune tolerance. - Alteration in Trp metabolism begin at early stages of CRC and allow immune evasion umor microenvironment (i.e. the oncogene c-MYC cab accelerate Trp uptake) with an increase in IDO1 and T cell inactivation. - Reduction in indoles production is observed in CRC and the administration of microbial indolic metabolites, diindolylmethane or I3C (AhR ligands), reduces tumor formation - #Tryptophan > #Serotonin > can exhibit both a protective and detrimental role. For example, activation of #Serotonin receptors, 5-HTR1B and 5-HTR2B stimulate tumor angiogenesis and cell proliferation. SCFAs can induce the production and release of #Serotonin though. In normal conditions, #Serotonin seems to have mainly a protective role but dysregulation of its production is linked to cancer promotion. [1.18] [#Bile Acids] - Butyrate producing bacteria such as #Eubacterium spp. are capable of transforming primary BAs to secondary BAs such as: #Lithocholic acid and #Deoxycholic acid, which are potentially cytotoxic and have been linked to colorectal cancer and cholesterol GS formation. [1.19] [#Parvimonas micra] - four species of two genera are found to be associated with CRC: #Parvimonas micra, #Parvimonas sp., #Peptostreptococcus stomatis, and #Peptostreptococcus anaerobius. [#Western-style diet] - higher levels of #Polyketide synthase (pks+) #Escherichia coli in tumors of those who relied on Western-style diets. [1.21] - #Butyrate treatment of epithelial cells boosted IL-18 production via a GPR109a-mediated pathway, promoting stomach homeostasis and defending against colorectal carcinogenesis [1.22] - Betabaculus virus, Epsilon15likevirus, Mulikevirus, and Punalikevirus were particularly enriched in CRC patients and associated with increased severity and mortality. - Viral infections such as human papillomaviruses (HPV), human polyomaviruses,human herpesviruses,human bocavirus, and Inoue–Melnick virus were found in cancer tissues compared with adjacent normal tissues of CRC patients. - Malasseziomycetes and decreased Saccharomycetes were observed in CRC patients. The distribution of fungal genera #Aspergillus, #Malassezia, #Rhodotorula, Pseudogymnoascus, Kwoniella, Talaromyces, Debaryomyces, Moniliophthora, Pneumocystis, and Nosemia was altered in CRC. [1.23] -The #Sulfur microbial diet, was characterized by high intakes of low-calorie beverages, french fries, red meats, and processed meats and low intakes of fruits, yellow vegetables, whole grains, legumes, leafy vegetables, and cruciferous vegetables. - Adherence to the #Sulfur microbial diet was associated with an increased risk of CRC, suggesting a potential mediating role of sulfur-metabolizing bacteria in the associaton between diet and CRC. [1.24] [#End-stage renal disease] - #TMAO is a major risk factor for cardiovascular disease, renal fibrosis and functional impairment, #Atherosclerosis, and colorectal cancer. [#Hepatocellular cancer] [#Secondary bile acids] - excessive production of the secondary BA deoxycholic acid triggers the expression of inflammatory and tumorigenic factors in hepatic stellate cells (HSCs), contributing to hepatocellular carcinoma development. Secondary BAs might also activate farnesoid X receptor (FXR) and elevate the risk of developing colorectal cancer and hepatocellular carcinoma. [1.25] - Luminal microbiota are more strongly implicated in metabolic exchange with the host, while mucosa-associated microbiota can directly contact and affect IECs. - mucosa-associated microbiome in tumors differs from that of non-neoplastic areas within the same individuals. - localization of CRC (proximal vs. distal) may also influence microbiome composition [1.26] - bacteria like #Acidaminobacter, #Phascolarctobacterium and #Citrobacter were present in significant number in colorectal cancer (CRC) patient’s stool samples. - #Butyrate, on the other hand, induces apoptosis in malignant epithelial cells that line the large intestine, lowering the risk of bowel cancer while also providing energy to gut cells. - Genera which produce #Butyrate were almost absent in colorectal cancer patient’s stool. [1.27] - in colon cancers #Candida > predictive of metastatic disease and attenuated cellular adhesions. - #Candida DNA is enriched in tumors and predictive of reduced survival in GI cancers [1.28] - #Ascomycota and #Basidiomycota phyla dominated the intratumor mycobiome. The #Ascomycota to #Basidiomycota ratio (A/B ratio) was highest in colon cancer, due to abundant #Saccharomycetes, and lowest in #Melanoma, due to abundant #Malasseziomycetes. [1.29] [#Inflamatory bowel disease] - Morganella morganii is enriched in the gut microbiota of both IBD and CRC patients. - Morganella morganii-derived small-molecule genotoxins—termed the #Indolimines—that elicited DNA damage in cell-based and cell-free assays. - In a mouse model of colon cancer, M. morganii exacerbated tumor burden, but a mutant form of the bacteria unable to produce indolimine did not. [#Sport] - #Physical activity is associated with reduced risks of colorectal cancer (CRC) incidence, recurrence and mortality. - exercise can modify the gut microbiota, and these changes are inverse to the changes seen with CRC. - exercise mediating changes promote the antitumorigenic characteristics of the gut microbiota. [1.31] [#Crohn’s disease] [#Bacteriophage, #Western-style diet] - the abundance of a class of crAss-like phages, a group of related viruses that includes some of the most abundant viruses of the human gut, were higher in populations with non-westernized dietary habits - several types of crAss-like phages were present at decreased levels in people with #Rheumatoid Arthritis, #Systemic lupus erythematosus, #Ulcerative Colitis and Crohn disease, and at increased levels in people with colon cancer. [1.32] - #Ammonia accumulates in tumors and reduces T cell function in vitro and in vivo. - #Ammonia decreases T cell transsulfuration leading to altered redox status. - Clearance of #Ammonia reactivates T cells and decreases colorectal cancer. [1.33] - 73.0% increase in CRC risk among #Appendectomy cases throughout 20 years follow-up [1.34] [#Pancreatic Cancer] [#Bacteroides fragilis toxin] - Enterotoxigenic #Bacteroides fragilis (ETBF) produces #Bacteroides fragilis toxin (BFT), which is associated with acute diarrheal, inflammatory bowel disease, and colorectal cancer (CRC). [1.35] - Polyamines can feed #Cancer cells for growth and any polyamines, regardless of their sources (i.e., dietary, microbial, and tissues) can drive tumorigenesis. - Tumor cells require more polyamines for growth than healthy cells - #Cancer patients have increased #Polyamine levels in the blood and urine. - #Polyamine concentrations appear to be increased in CRC tissues compared to healthy tissues. [#Colon adenomas] [#Deoxycholic acid, #Secondary bile acids, #Ursodeoxycholic acid] - UDCA has microbiome-changing and DCA‐lowering prpperties. - treatment with UDCA, decreased recurrence of adenomas with high-grade dysplasia. - DCA also stimulates the uptake of polyamines in CRC cells, which also have tumorigenic effects. - CRC patients had lower stool concentrations of #Butyrate, while #Acetate concentrations were increased. - certain bacterial species, such as #Fusobacterium nucleatum, #Streptococcus bovis, and #Bacteroides fragilis have been linked to CRC, either by producing virulence factors or by producing pathogenic microbial metabolites. [#Deoxycholic acid, #Secondary bile acids] - Elevated levels of fecal SBAs, especially DCA, are associated with an increased risk for CRC. - FXR, receptor for #Bile Acids, is downregulated in CRC and low levels of FXR expression correlate with worse clinic outcomes. [#Hydrogen sulfide] - H2S increased the in vitro proliferation of human cells obtained from mucosal biopsies. - Interestingly, this effect was inhibited by #Butyrate. - Plasma #Choline and #TMAO levels correlate with an increased risk for CRC and serum #TMAO levels are significantly increased in CRC patients. [#Hydrogen sulfide] - #Fusobacterium nucleatum, a Gram negative, anaerobic bacterium over-represented in CRC tissues, is a H2S-producer. - F. nucleatum also produces the metabolite #Formate, which triggers AhR and increases cancer cell stemness and invasiveness. [#Hydrogen sulfide] - Fecal H2S concentrations are elevated in CRC patients. - Increased levels of H2S can decrease tissue integrity by reducing disulfide bonds in mucosal tissues. - H2S can also directly cause DNA damage. - #Indole derivates support gut homeostasis by promoting epithelial barrier function and immune tolerance, which are important to suppress carcinogenesis in the colon - #Tryptophan metabolism is altered in CRC with a shift towards increased Kyn production by host cells but decreased #Indole production by gut microbes. - Elevated fecal Kyn to #Tryptophan ratios but decreased #Indole to tryptophane ratios were found in patients with colorectal neoplastic lesions. [#kynurenine] - Kyn acts as an endogenous ligand for AhR and can be secreted by cancer cells into the tumor microenvironment, suppressing anti-tumor immunity and promoting tumor cell survival through AhR via autocrine and paracrine signaling. [#Short Chain Fatty Acid] - GPR triggering by SCFAs is an important mechanism to suppress CRC development. - activation of GPRs on intestinal epithelial cells by SCFAs promotes barrier functions and stimulates the production of interleukin (IL)-18 and secretion of anti-microbial peptides. [1.36] [#Parvimonas micra] - grade 3 tumors Colorectal cancer were significantly enriched in #Fusobacterium and #Parvimonas - #Parvimonas micra and #Fusobacterium have been shown to aggregate and form biofilms in vitro. - Biofilm formation is linked to inflammatory bowel disease and CC. [1.37] [#Obesity] [1.38] - The elevated abundance of certain bacterial species such as #Fusobacterium nucleatum and #Parvimonas micra in CRC patients is often associated with the development of the disease. [1.39] [#Inflamatory bowel disease] - #Gemella enriches in the intestinal mucosa of IBD and CRC [#Inflamatory bowel disease] [#Peptostreptococcus stomatis] - Regarding IBD and CRC, P. stomatis is among the oral-derived biomarker panel of CRC either [#Natural oral microbiomes] [#Prevotella intermedia, #Prevotella nigrescens] - A higher abundance of P. intermedia and P. nigrescens (Pretovella species that are commonly resident in the oral cavity) was observed in the intestine of CRC patients [#Periodontal abscess] [#Fusobacterium nucleatum] - patients with F. nucleatum or #Streptococcus pepticus bacteremia are more likely to suffer from subsequent colorectal cancer [#Fusobacterium nucleatum] - 40% of the CRC patients detected identical F. nucleatum strains in both tumor tissue and saliva [#Fusobacterium nucleatum] - Several F. nucleatum subspecies (nucleatum, animalis, vincentii, polymorphum) and potential new subspecies are isolated from the intestine of colorectal cancer patients, and the major encoding virulence factors for F. uncleatum showed evidence of horizontal gene transfer. - intraperitoneal injection successfully established colonization of F. nucleatum in CRC tissue, which suggested the translocation of F. nucleatum through hematogenous route [#Fusobacterium nucleatum] - Regarding CRC, F. nucleatum and its main pathogenic factors (FadA (binding E-cadherin), Fap2 (a galactose-sensitive hemagglutinin and adhesin binding TIGHT receptors), RadD (autotransporter) and FomA) recruit tumor-infiltrating immune cells, generating tumor microenvironment and participating in immunosuppression and tumorigenesis [#Porphyromonas gingivalis] [#Butyrate] - In the intestine, oral-derived microbiotas create an inflammatory and immunosuppressive microenvironment suitable for tumorigenesis. It is detected the existence of oral-originated bacteria (#Fusobacterium nucleatum, P. gingivalis, and #Parvimonas micra) in CRC tissues. [#Porphyromonas gingivalis] - CRC patients’ intestines are pathologically colonized with abnormally abundant P. gingivalis, whose infection gives rise to a poor CRC prognosis [#Porphyromonas gingivalis] - the #Peptidoglycan from P. gingivalis molecules induces programmed cell death 1 ligand 1 (PD-L1) up-regulation in colon carcinoma cells and mediates deep inhibition of T cells - Analogous to the activity of #Niacin, #Butyrate activates GPR109A to suppress colonic inflammation and colon cancer development [1.41] [#Colon adenomas] [#Plant-based diet] - #Flavonifractor plautii and #Bacteroides stercoris transmit the protective or carcinogenic effects of these factors to early carcinogenesis. - #Flavonifractor plautii and #Bacteroides stercoris, for example, were more abundant in people with tubular adenomas than in those with serrated adenomas or in controls. - Both microbes were also less abundant in people with an increased vegetable intake or those who took #Aspirin. [1.42] [#Lung cancer, #Pancreatic Cancer] [#Veillonella atypica] - #Veillonella genus is usually more abundant in treatment-naïve patients with lung, pancreatic (#Veillonella atypica) and colorectal #Cancer. - Furthermore, when comparing patients with advanced-stage #Cancer with and without weight loss, #Veillonella is more abundant in those who lost weight. [#Akkermansia muciniphila, #Faecalibacterium prausnitzii] - in colorectal cancer > the relative abundances of #Fusobacterium, #Porphyromonas and A. muciniphila are increased, and F. prausnitzii is decreased compared to healthy controls. - #Porphyromonas somerae, is reported in the presence of pre-malignant colonic lesions [1.43] - higher levels in #Akkermansia muciniphila among those with CRC. - It is possible that increased levels of #Akkermansia muciniphila among CRC patients compared to cancer-free individuals may be related to an increased production of mucus which serves as a major nutrient source for this bacterium. [#Clostridium clusters XIVa] - bacteria in the Clostridium XIVa cluster participate in maintaining gastrointestinal functions by producing short-chain fatty acids and inducing colonic regulatory T (Treg) cells, both of which are known to be protective in inflammation and CRC development and progression. [1.44] - Certain strains of #Bacteroides fragilis, a known intestinal symbiont, have been shown to up-regulate Wnt/B-catenin and NF–KB signaling in chronic #Colitis and CRC tissue. - These strains secrete a specific exotoxin, associated with increased pro-inflammatory Th17 T-cell activity, promoting cell survival - #Fusobacterium nucleatum has been implicated as a carcinogen in #Oral squamous cell carcinoma (OSCC) and CRC, with a demonstrated bacterial transcript load 400 times that of matched adjacent normal tissue [1.45] [#Vitamin D] - #Vitamin D deficiency is associated with an increased CRC risk. [#Carnobacterium maltaromaticum, #Faecalibacterium prausnitzii] - F. prausnitzii, converts C. maltaromaticum-derived 7-DHC into downstream #Vitamin D metabolites for mediating the anti-CRC effect. [#Carnobacterium maltaromaticum] [#Gender] - C. maltaromaticum was specifically depleted in female patients with CRC. - Oral administration of C. maltaromaticum suppressed intestinal tumorigenesis in two murine CRC models in a female-specific manner. - CRC-suppressing effect of C. maltaromaticum were dependent on estrogen, with SLC3A2 identified as an estrogen-responsive host surface protein for binding to C. maltaromaticum. - female mice expressed higher colonic SLC3A2, and with enough estrogen (mice of adult age), C. maltaromaticum bound to the colonic SLC3A2 via its surface protein, named DD-CPase. [#Carnobacterium maltaromaticum] [#Lipopolysaccharide] - C. maltaromaticum could restore the gut barrier function at the early time points. - The restoration of gut barrier function was associated with increased expression of a number of associated markers, including ZO-1, #Occludin, and E-cadherin in mouse CRC models, enhanced thickness of colonic mucus layer, along with decreased paracellular gap and serum LPS level. - VDR signaling was activated significantly in C. maltaromaticum-treated mice, and the tumor-suppressive effect of C. maltaromaticum was dependent on VDR. [1.46] [#Lung cancer, #Pancreatic Cancer] [#Veillonella atypica] - #Veillonella genus is usually more abundant in treatment-naïve patients with lung, pancreatic (#Veillonella atypica) and colorectal #Cancer. [1.47] [#Short Chain Fatty Acid] [#Zizyphus jujuba cv. Muzao] -ZMP consumption prevented CRC mouse colon shortening, decreased their mortality, reduced pro-inflammatory cytokines, increased the concentration of total short-chain fatty acids (SCFAs) and modulated gut microbiota in their feces. - ZMP also increased the richness of #Bifidobacterium, #Bacteroides and #Lactobacillus. [1.48] - #Colibactin is a genotoxic secondary metabolite produced by certain strains of gut bacteria, such as #Escherichia coli and #Klebsiella pneumoniae. #Colibactin can cause DNA damage and promote the development of colorectal cancer . [1.49] [#Bile Acids] - potential gut microbes capable of conjugating CAs including #Ileibacterium valens. - #Ileibacterium valens has been recently implicated in microbial-induced #Obesity and intestinal inflammation through its production of interleukin-17 - enrichment of #Ileibacterium valens strains in adenocarcinoma mouse models, suggesting that this species may promote tumorigenesis. [#Bile Acids] [#High Fat Diet] - 7 non-classic amino acid-conjugated BAs enriched in HFD-fed mice, > microbially modified #Cholic acid derivatives appear restricted to the gut, distinguishing them from host-conjugated BAs. - non-classic amino acid conjugation selectively modulates #Cholic acid signaling via FXR and TGR5, as well as its ability to promote Wnt signaling and intestinal stem cell proliferation, key steps in CRC initiation and progression. [#Fusobacterium nucleatum] - A high abundance of #Fusobacterium (in particular F. nucleatum) at colorectal cancer sites has been associated with regional lymph node metastases and tumor location (2% in rectum and approx. 11% in cecum) [1.51] - #Sulfur-metabolizing microbiome in the human gut has been shown to be associated with a high risk of colorectal cancer [1.52] - reduction of #Bacteroidetes and #Firmicutes and increase of #Proteobacteria in patients undergoing surgery for CRC. [1.53] - bacteria belonging to the #Firmicutes and #Bacteroidetes phyla were the most abundant species in colorectal tumors [1.54] - #Fusobacterium nucleatum has been shown to bind to host epithelial and endothelial cells through FadA adhesin and induce a series of inflammatory reactions mediated by Nuclear Factor-kappa B (NF-κB) and interleukin (IL)-6. - F. nucleatum abundance correlated with high #Glucose metabolism in patients with CRC. - F. nucleatum induces a dramatic decline of m6A modifications in CRC cells and patient-derived xenograft (PDX) tissues by downregulating an m6A methyltransferase, METTL3, contributing to the induction of CRC aggressiveness. - F. nucleatum can also inhibit the cytotoxic functions of tumor-infiltrating lymphocytes and natural killer (NK) cells by binding to the inhibitory immune receptor TIGIT through another adhesin, Fap2, thereby suppressing immune surveillance. - F. nucleatum may contribute to epithelial–mesenchymal transition (EMT), so it is tightly associated with cancer cell invasion, suppression of antitumor immune responses, stemness, and treatment resistance [1.55] [#Human breast milk] - a significant association was observed between being breastfed and increased risk of high-risk adenomas under age 50. - breastfeding was associated with increased risk of CRC among participants aged ≤55 years. [1.56] - #Lactobacillus plantarum (L. plantarum) is a ##Probiotic that has emerged as novel therapeutic agents #Cancer effects by increasing the cytotoxicity and death of CRC cells or reducing NLRP3 and ERK phosphorylation. [#Lactobacillus plantarum] - L. plantarum reduced chronic mucosal inflammation and #Ulcerative Colitis symptoms. Chronic intestinal #inflammation is important because chronic intestinal inflammation can lead to the development of CRC [1.57] [#Cesarean section] - birth by cesarean delivery was not associated with early-onset CRC in the overall population [1.58] - #Butyrate and #Propionate directly upregulate genes involved in cytokine production, antigen processing and MHCI generation in CRC cells, all of which contribute to CD8+ T cell activation. - The activated CD8+ T cells secrete high amounts of IFNγ which then feeds back on the cancer cells to further upregulate CRC cell MHCI, further increasing their capacity to activate CD8+ T cells. - #Butyrate and #Propionate induced greater DNA damage in the DNA repair deficient MSI CRC cells, which are typically quite immunogenic. - CRC patient’s intestinal microbiome > cancer is often associated with an increase of the major #Butyrate producing taxa, #Firmicutes, coupled with decreased levels of #Proteobacteria [#Short Chain Fatty Acid] - direct stimulation of CRC cells with SCFAs upregulates their ability to activate cytotoxic CD8+ T cells but the magnitude of this effect differs according to the CRC subtype and is strongest in those with deficient DNA repair. - the main mechanism by which SCFAs initiate improved antitumor immunity in CRC cells is via their function as HDAC inhibitors. Decondensing chromosomes is known to change susceptibility of DNA to potentially damaging agents and to alter the efficacy of DNA repair at the newly exposed sites. - CRCs exhibiting microsatellite instability (MSI) due to inactivation of DNA mismatch repair were much more sensitive to SCFAs and induced much greater CD8+ T cell activation than chromosomally instable (CIN) CRCs with intact DNA repair, indicating a subtype-dependent response to SCFAs. [1.59] [#Biliary tract cancer, #Esophageal cancer, #Gallbladder cancer, #Pancreatic Cancer] - In CRC, infection of #Fusobacterium nucleatum increases the expression of miR-21 and down-modulation of miR-18a and miR-4802 - #Fusobacterium nucleatum enhanced tumor cell miR-21 levels by turning on the TLR4-MyD88 signaling cascade, which in turn increased CRC cell growth and tumor development in mice. - patients with high miR-21 and #Fusobacterium nucleatum DNA levels consistently had a higher risk of negative outcomes. - #Fusobacterium nucleatum enhances chemoresistance to CRC via changing autophagy in a way that is miRNA-dependen - GPR109a-#Butyrate signaling in the colon not only protects the host from colonic inflammation but also from colon cancer [1.61] [#Inflamatory bowel disease] [#Fusobacterium nucleatum] - Intracellular F. nucleatum is also enriched in inflammatory bowel disease (IBD), a condition predisposing to CRC, especially in patients suffering from an active disease compared to those in remission. [#Bacteroides fragilis, #Fusobacterium nucleatum, #Prevotella intermedia] - F. nucleatum-positive CRC tissues featured non-random co-colonization with commensals such as B. fragilis or P. intermedia, whereas tissues lacking F. nucleatum featured different bacterial colonization patterns [#Fusobacterium nucleatum] - lectin Fap2, expressed on F. nucleatum, binding to Gal-GalNAc on host cells. This interaction, in turn, drives an accumulation of Fusobacteria in CRC, upregulation of inflammatory markers upon invasion, and direct modulation of the TME [#Fusobacterium nucleatum] - CRC mouse model, increased tumor formation occurred upon gavage of F. nucleatum, while demonstrating a key role of FadA in its tumor-promoting activity [#Fusobacterium nucleatum] - An expansion of myeloid-derived immune cells including tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs) in a F. nucleatum-inoculated CRC mouse model was accompanied by T-cell suppression and increased expression of immunosuppressive molecules such as CTLA4 and arginase-1 [#Fusobacterium nucleatum] - 99.9% between F. nucleatum isolates from primary CRC and liver metastasis, indicating likely bacterial migratory characteristics between these tumor sites [#Fusobacterium nucleatum] - Higher intratumoral F. nucleatum abundance is associated with an increase in ALPK1, which in turn results in upregulation of intercellular adhesion molecule 1 (ICAM-1) on the host cell surface > increased attachment of CRC cells to endothelial cells > promote EMT and ultimately metastasis [#Fusobacterium nucleatum] - Keratin7 (KRT7) is reported to be upregulated in tumors upon F. nucleatum presence and was suggested to enhance lung metastasis in a murine CRC model [#Fusobacterium nucleatum, #Porphyromonas gingivalis] - most CRC-associated microbes, such as F. nucleatum, P. gingivalis, and #Prevotella intermedia (P. intermedia) are suggested to reside intracellularly. [#Fusobacterium nucleatum] [#Antibiotic Therapy] - F. nucleatum-positive colorectal tumors were subcutaneously transplanted into immunodeficient mice and tracked over time. - viable F. nucleatum could be maintained over time, while antibiotic administration reduced tumor growth [#Fusobacterium nucleatum] [#Antibiotic Therapy] - antibiotic treatment of mice transplanted with F. nucleatum-positive patient-derived CRC xenografts reduces tumor size and cancer cell proliferation, indicating that bacterial suppression may support tumor growth suppression [#Fusobacterium nucleatum] [#Bacteriophage] - phages targeting F. nucleatum, combined with irinotecan were able to reduce tumor growth, while selectively inhibiting CRC-associated bacterium F. nucleatum in vivo [#Fusobacterium nucleatum] - F. nucleatum is suggested to enhance CRC progression through its FadA adhesin, which attaches to epithelial cadherin (#E-cadherin) and may activate the Wnt/β-catenin signaling pathway86 leading to enhanced proliferation [#Fusobacterium nucleatum] [#Short Chain Fatty Acid] - F. nucleatum-derived short-chain fatty acid #Formate > CRC cell stemness and invasion [#Fusobacterium necrophorum] - #Fusobacterium necrophorum (F. necrophorum), another member of the #Fusobacterium genus with an invasive behavior88, has also been associated with CRC [#Porphyromonas gingivalis] - In CRC, invasive P. gingivalis is enriched and correlated with higher levels of #Butyrate, possibly inducing SASP [#Prevotella intermedia] - CRC > a higher abundance of P. intermedia was detected in adenocarcinoma samples [1.62] [#Colon adenomas] - The abundance of fecal #Veillonella parvula (V. parvula) decreased significantly after #Berberine administration and increased through the development from CRA to CRC. [#Veillonella parvula] - Patients with CRC with a higher V. parvula abundance had worse tumor staging and a higher lymph node metastasis rate. [1.63] - #Campylobacter jejuni, was found to promote the growth and enlargement of colorectal tumors in mice, and induces changes in microbial composition and transcriptomic responses, a process dependent on #Cytolethal Distending Toxin (CDT) production [#Fusobacterium nucleatum] - Cancer of the colon-associated bacterium F. nucleatum can specifically inhibit antitumor immunity by involving certain T cells, immunoglobulin receptor cells, and natural killer cells, and by preventing its ability to damage tumor cells [#Fusobacterium nucleatum] - F. nucleatum can protect tumor cells from antitumor agents, which leads to chemotherapy resistance in CRC patients. - Infection with #Streptococcus gallolyticus in the form of endocarditis or even bacteremia is correlated to colorectal cancer. - This class is also enriched in the tissue of the tumor itself [1.64] - #Ethanol as the metabolite most affected by loss of cross-feeding in individuals with Colorectal Cancer (CRC). - Moderate to heavy #Alcohol Consumption is associated with a 1.17 – 1.44 higher risk of developing CRC via a process that is at least partially mediated by the microbiome, as gut bacteria metabolise #Ethanol to produce the carcinogenic #Acetaldehyde [1.65] [#Hepatocellular cancer] - Elevated #Methionine adenosyl transferase 2A (MAT2A) levels were observed in various types of #Cancer, including CRC, hepatocellular carcinoma (HCC) - #Methanethiol as a biomarker for non-invasive early #Cancer detection. - Commensal #Bacteria residing in the colonic lumen can convert dietary #Methionine to #Methanethiol through MGL-catalyzed α,γ-elimination and γ-replacement reactions. - #Fusobacterium nucleatum, #Citrobacter freundii, #Morganella morganii,and several #Proteus species have been reported to contribute to intestinal #Methanethiol production [1.66] - #Lachnospiraceae UCG-003 can potentially protect against colon cancer by #Butyrate production [1.67] [#Escherichia coli] - #Colibactin-producing pks+ E. coli+ promotes CRC development by causing double-stranded DNA breakage and a specific pattern of mutational signature, namely SBS88 and ID18. - early-life exposure to pks+ E. coli+ may influence early-onset tumorigenesis. - Pks+ E. coli+ is a common gut bacteria found in ~31% of healthy #Infants by 1-month post-birth. - prolonged exposure to this bacteria may be necessary to result in DNA damage. - pks+ E. coli+ does not cause a highly immunogenic tumour microenvironment (TME), at least at the time of CRC diagnosis/resection. [#Fusobacterium nucleatum] - F. nucleatum was associated with MMRd related to Lynch syndrome as well as sporadic MMRd CRCs related to MLH1 promoter methylation and double MMR somatic mutations. - F. nucleatum colonisation in the tumour is not related to MMRd etiology. - F. nucleatum causing opportunistic infections, exploiting the specific tumour microenvironment of MMRd CRCs. - F. nucleatum is found to be highly abundant in CRC tumours [1.68] - #IL-17 has been shown to play a role in the progression of colorectal cancer through various signaling pathways, including signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. [#Ursodeoxycholic acid] - UDCA has been found to activate the epidermal growth factor receptor (EGFR)/ Raf-1/ extracellular regulating kinase (ERK) signaling pathway in colorectal cancer. [1.69] [#Akkermansia muciniphila] - supplementation of Akkermansia mucinophilia suppressed colorectal tumorigenesis in mice models by reprogramming the tumor microenvironment. - #Akkermansia and #Bacteroides emerged as notable microbes enriched in yoCRC tumors as compared to Bacillus, #Staphylococcus, #Listeria, #Enterococcus, #Pseudomonas, #Fusobacterium, and #Escherichia/#Shigella which have consistently been implicated with higher relative abundance in aoCRC tumors - CRC tumors, particularly in patients with metastatic disease, were relatively enriched with the #Fusobacterium genus [#Esophageal cancer, #Gastric carcinoma] - #Ferrichrome, produced by the #Probiotic #Lactobacillus casei, exhibited anti-tumor effects in various gastrointestinal cancers, including colorectal and gastric cancers, with minimal effects on non-cancerous intestinal cells. [1.71] - #Fusobacterium nucleatum species are normal members of the human oral microbiota, and strains from the oral cavity are thought to seed CRC tumours. - Fna is bifurcated into two distinct clades: Fna C1, which is largely restricted to the oral cavity, and Fna C2, which dominates the human CRC tumour niche. - Only Fna C2 induced tumours and altered intestinal metabolism towards increased oxidative stress within a CRC animal model. - The analysis revealed 195 genetic differences between the clades. - this Fna C2 lineage in approximately 50% of cases. - Fna C2 levels were consistently higher in colorectal cancer. - patients with colorectal tumors containing #Fusobacterium nucleatum have poor survival and poorer prognosis compared with patients without the microbe [1.72] - inflammation induced by gut #Bacteria impacts the metabolism of all-trans #Retinoic acid (AtRA), resulting in diminished levels of AtRA, this reduction in AtRA levels has been implicated in the advancement of #Ulcerative Colitis (UC) and its associated CRC [1.73] [#Teenager] - well-known CRC-associated taxa, such as #Clostridium symbiosum, #Peptostreptococcus stomatis, #Parvimonas micra and #Hungatella hathewayi were significantly enriched in both old- and young-onset patients. - Similar strain-level patterns of #Fusobacterium nucleatum, #Bacteroides fragilis and #Escherichia coli were observed for oCRC and yCRC. - Almost all oCRC-associated metagenomic pathways had directionally concordant changes in young patients. [1.74] - Concentrations of the secondary bile acid, #Deoxycholic acid (DCA), are aberrantly elevated in colorectal cancer (CRC) patients, - DCA is a negative regulator for CD8+ T cell effector function. - DCA suppressed CD8+ T cell responses by targeting plasma membrane Ca2+ ATPase (PMCA) to inhibit Ca2+-nuclear factor of activated T cells (NFAT)2 signaling. In CRC patients, CD8+ T cell effector function negatively correlated with both DCA concentration and expression of a bacterial DCA biosynthetic gene. - Bacteria harboring DCA biosynthetic genes suppressed CD8+ T cells effector function and promoted tumor growth in mice. This effect was abolished by disrupting bile acid metabolism via bile acid chelation, genetic ablation of bacterial DCA biosynthetic pathway, or specific #Bacteriophage. [1.75] - #Fusobacterium nucleatum, did not significantly associate with CRC diagnostic groups (healthy, adenoma and carcinoma) when controlling for covariates transit time, fecal #Calprotectin (intestinal inflammation) and body mass index as primary microbial covariates. - In contrast, the associations of #Anaerococcus vaginalis, #Dialister pneumosintes, #Parvimonas micra, #Peptostreptococcus anaerobius, #Porphyromonas asaccharolytica and #Prevotella intermedia remained robust, highlighting their future target potential. [1.76] [#Escherichia coli, #Fusobacterium nucleatum] - in CRC > M1 macrophages promote cytotoxicity and effectuate a tumor-suppressive microenvironment while M2 macrophages are associated with immunosuppression and the expression of cytokines that promote tumor survival and proliferation. - Both E. coli and F. nucleatum have been shown to shift this balance in favor of the M2 state. [#Escherichia coli] - #Cytotoxic necrotizing factor 1 (CNF1), a bacterial toxin produced by E. coli, plays a role in the quiescence of disseminated CRC cells. CNF1 blocks cytokinesis, elicits endoreplication and polyploidization, and drives cells into a reversible dormant state. [#Fusobacterium nucleatum] - F. nucleatum-derived succinic acid confers resistance to anti-PD-1 therapy, reversible by fecal microbiota transfer or #Metronidazole. [1.77] - Studies have demonstrated an enrichment of Fusobacterium nucleatum in human colorectal adenomas and carcinomas compared to adjacent normal tissue. - Experimental studies have shown that Fusobacterium nucleatum activates the WNT signaling pathway in colorectal carcinoma cells and may promote colorectal tumour growth - a higher amount of tissue Fusobacterium nucleatum DNA has been associated with advanced disease stage and a lower density of T-cells in human colorectal carcinoma tissue.References Notes[ ]
