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Gastroenterology Dec 2023Pien Tze Huang (PZH) is a well-established traditional medicine with beneficial effects against inflammation and cancer. We aimed to explore the chemopreventive effect...
BACKGROUND & AIMS
Pien Tze Huang (PZH) is a well-established traditional medicine with beneficial effects against inflammation and cancer. We aimed to explore the chemopreventive effect of PZH in colorectal cancer (CRC) through modulating gut microbiota.
METHODS
CRC mouse models were established by azoxymethane plus dextran sulfate sodium treatment or in Apc mice treated with or without PZH (270 mg/kg and 540 mg/kg). Gut barrier function was determined by means of intestinal permeability assays and transmission electron microscopy. Fecal microbiota and metabolites were analyzed by means of metagenomic sequencing and liquid chromatography mass spectrometry, respectively. Germ-free mice or antibiotic-treated mice were used as models of microbiota depletion.
RESULTS
PZH inhibited colorectal tumorigenesis in azoxymethane plus dextran sulfate sodium-treated mice and in Apc mice in a dose-dependent manner. PZH treatment altered the gut microbiota profile, with an increased abundance of probiotics Pseudobutyrivibrio xylanivorans and Eubacterium limosum, while pathogenic bacteria Aeromonas veronii, Campylobacter jejuni, Collinsella aerofaciens, and Peptoniphilus harei were depleted. In addition, PZH increased beneficial metabolites taurine and hypotaurine, bile acids, and unsaturated fatty acids, and significantly restored gut barrier function. Transcriptomic profiling revealed that PZH inhibited PI3K-Akt, interleukin-17, tumor necrosis factor, and cytokine-chemokine signaling. Notably, the chemopreventive effect of PZH involved both microbiota-dependent and -independent mechanisms. Fecal microbiota transplantation from PZH-treated mice to germ-free mice partly recapitulated the chemopreventive effects of PZH. PZH components ginsenoside-F2 and ginsenoside-Re demonstrated inhibitory effects on CRC cells and primary organoids, and PZH also inhibited tumorigenesis in azoxymethane plus dextran sulfate sodium-treated germ-free mice.
CONCLUSIONS
PZH manipulated gut microbiota and metabolites toward a more favorable profile, improved gut barrier function, and suppressed oncogenic and pro-inflammatory pathways, thereby suppressing colorectal carcinogenesis.
Topics: Mice; Animals; Signal Transduction; Gastrointestinal Microbiome; Dextran Sulfate; Phosphatidylinositol 3-Kinases; Apoptosis; Medicine, Traditional; Colorectal Neoplasms; Carcinogenesis; Azoxymethane
PubMed: 37704113
DOI: 10.1053/j.gastro.2023.08.052 -
Gastroenterology Jan 2022Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut...
BACKGROUND AND AIMS
Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut microbiota and metabolites.
METHODS
HFD or control diet was fed to mice littermates in CRC mouse models of an azoxymethane (AOM) model and Apc model, with or without antibiotics cocktail treatment. Germ-free mice for fecal microbiota transplantation were used for validation. Gut microbiota and metabolites were detected using metagenomic sequencing and high-performance liquid chromatography-mass spectrometry, respectively. Gut barrier function was determined using lipopolysaccharides level and transmission electron microscopy.
RESULTS
HFD promoted colorectal tumorigenesis in both AOM-treated mice and Apc mice compared with control diet-fed mice. Gut microbiota depletion using antibiotics attenuated colon tumor formation in HFD-fed mice. A significant shift of gut microbiota composition with increased pathogenic bacteria Alistipessp.Marseille-P5997 and Alistipessp.5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFD-modulated gut microbiota promotes colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota was essential in HFD-associated colorectal tumorigenesis. Gut metabolites alteration, including elevated lysophosphatidic acid, which was confirmed to promote CRC cell proliferation and impair cell junction, was also observed in HFD-fed mice. Moreover, transfer of stools from HFD-fed mice to germ-free mice without interference increased colonic cell proliferation, impaired gut barrier function, and induced oncogenic genes expression.
CONCLUSIONS
HFD drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated lysophosphatidic acid, and gut barrier dysfunction in mice.
Topics: Animals; Anti-Bacterial Agents; Azoxymethane; Bacteria; Bacterial Translocation; Cell Proliferation; Cell Transformation, Neoplastic; Colon; Colorectal Neoplasms; Diet, High-Fat; Disease Models, Animal; Dysbiosis; Fecal Microbiota Transplantation; Feces; Gastrointestinal Microbiome; Genes, APC; Germ-Free Life; Humans; Lysophospholipids; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Permeability; Tumor Cells, Cultured; Mice
PubMed: 34461052
DOI: 10.1053/j.gastro.2021.08.041 -
Gastroenterology Mar 2021Streptococcus thermophilus was identified to be depleted in patients with colorectal cancer (CRC) by shotgun metagenomic sequencing of 526 multicohort fecal samples....
BACKGROUND & AIMS
Streptococcus thermophilus was identified to be depleted in patients with colorectal cancer (CRC) by shotgun metagenomic sequencing of 526 multicohort fecal samples. Here, we aim to investigate whether this bacterium could act as a prophylactic for CRC prevention.
METHODS
The antitumor effects of S thermophilus were assessed in cultured colonic epithelial cells and in 2 murine models of intestinal tumorigenesis. The tumor-suppressive protein produced by S thermophilus was identified by mass spectrometry and followed by β-galactosidase activity assay. The mutant strain of S thermophilus was constructed by homologous recombination. The effect of S thermophilus on the gut microbiota composition was assessed by shotgun metagenomic sequencing.
RESULTS
Oral gavage of S thermophilus significantly reduced tumor formation in both Apc and azoxymethane-injected mice. Coincubation with S thermophilus or its conditioned medium decreased the proliferation of cultured CRC cells. β-Galactosidase was identified as the critical protein produced by S thermophilus by mass spectrometry screening and β-galactosidase activity assay. β-Galactosidase secreted by S thermophilus inhibited cell proliferation, lowered colony formation, induced cell cycle arrest, and promoted apoptosis of cultured CRC cells and retarded the growth of CRC xenograft. The mutant S thermophilus without functional β-galactosidase lost its tumor-suppressive effect. Also, S thermophilus increased the gut abundance of known probiotics, including Bifidobacterium and Lactobacillus via β-galactosidase. β-Galactosidase-dependent production of galactose interfered with energy homeostasis to activate oxidative phosphorylation and downregulate the Hippo pathway kinases, which partially mediated the anticancer effects of S thermophilus.
CONCLUSION
S thermophilus is a novel prophylactic for CRC prevention in mice. The tumor-suppressive effect of S thermophilus is mediated at least by the secretion of β-galactosidase.
Topics: Adenomatous Polyposis Coli Protein; Animals; Azoxymethane; Bacterial Proteins; Cell Line, Tumor; Cell Transformation, Neoplastic; Colon; Colorectal Neoplasms; Humans; Intestinal Mucosa; Male; Mice; Mice, Transgenic; Neoplasms, Experimental; Probiotics; Streptococcus thermophilus; beta-Galactosidase
PubMed: 32920015
DOI: 10.1053/j.gastro.2020.09.003 -
Gastroenterology Mar 2022Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine...
BACKGROUND & AIMS
Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX), which generates spermidine (Spd), regulates colitis. Here we determined whether Spd treatment reduces colitis and carcinogenesis.
METHODS
SMOX was quantified in human colitis and associated dysplasia using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. We used wild-type (WT) and Smox C57BL/6 mice treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Mice with epithelial-specific deletion of Apc were used as a model of sporadic colon cancer. Animals were supplemented or not with Spd in the drinking water. Colonic polyamines, inflammation, tumorigenesis, transcriptomes, and microbiomes were assessed.
RESULTS
SMOX messenger RNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. DSS colitis and AOM-DSS-induced dysplasia and tumorigenesis were worsened in Smox vs WT mice and improved in both genotypes with Spd. Tumor development caused by Apc deletion was also reduced by Spd. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of α-defensins, which was reduced by Spd. A shift in the microbiome, with reduced abundance of Prevotella and increased Proteobacteria and Deferribacteres, occurred in Smox mice and was reversed with Spd.
CONCLUSIONS
Loss of SMOX is associated with exacerbated colitis and CAC, increased α-defensin expression, and dysbiosis of the microbiome. Spd supplementation reverses these phenotypes, indicating that it has potential as an adjunctive treatment for colitis and chemopreventive for colon carcinogenesis.
Topics: Adenomatous Polyposis Coli Protein; Animals; Azoxymethane; Carcinogenesis; Colitis; Colitis, Ulcerative; Colon; Colonic Neoplasms; Dextran Sulfate; Gastrointestinal Microbiome; Gene Expression Regulation; Humans; Intestinal Mucosa; Male; Mice; Oxidoreductases Acting on CH-NH Group Donors; Precancerous Conditions; Protective Factors; RNA, Messenger; Severity of Illness Index; Spermidine; Weight Loss; alpha-Defensins; Polyamine Oxidase
PubMed: 34767785
DOI: 10.1053/j.gastro.2021.11.005 -
Carbohydrate Polymers Sep 2021This study investigated the effects of water-soluble polysaccharide extracted from the sporoderm-removed spores of Ganoderma lucidum (GLP) against AOM/DSS-induced...
This study investigated the effects of water-soluble polysaccharide extracted from the sporoderm-removed spores of Ganoderma lucidum (GLP) against AOM/DSS-induced inflammation, tumorigenesis, and gut microbiota modification, which has never been reported before. Our data revealed that GLP (200 and 300 mg/kg) decreased AOM/DSS-induced colitis and tumorigenesis, manifested by significantly reduced disease activity index score, and total number and size of tumors. Furthermore, GLP ameliorated AOM/DSS-induced microbiota dysbiosis, increased short-chain fatty acid production, and alleviated endotoxemia by inhibiting TLR4/MyD88/NF-κB signaling. Besides, GLP profoundly improved gut barrier function as evidenced by increased numbers of goblet cells, MUC2 secretion, and tight junction protein expressions. GLP treatment inhibited macrophage infiltration and downregulated IL-1β, iNOS, and COX-2 expressions. Additionally, GLP inhibited lipopolysaccharides (LPS)-induced inflammation markers and MAPK (JNK and ERK) activation in macrophage RAW264.7, intestinal HT-29, and NCM460 cells. In conclusion, these results indicate that GLP is a promising prebiotic for the treatment of colorectal cancer.
Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Azoxymethane; Carcinogenesis; Cell Line, Tumor; Colitis; Colon; Colonic Neoplasms; Dextran Sulfate; Dysbiosis; Fungal Polysaccharides; Gastrointestinal Microbiome; Humans; Inflammation; Macrophage Activation; Male; Mice; Mice, Inbred C57BL; RAW 264.7 Cells; Reishi; Signal Transduction
PubMed: 34119183
DOI: 10.1016/j.carbpol.2021.118231 -
Gastroenterology Apr 2023Colorectal cancer is a leading cause of cancer death, and a major risk factor is chronic inflammation. Despite the link between colitis and cancer, the mechanism by...
BACKGROUND & AIMS
Colorectal cancer is a leading cause of cancer death, and a major risk factor is chronic inflammation. Despite the link between colitis and cancer, the mechanism by which inflammation leads to colorectal cancer is not well understood.
METHODS
To investigate whether different forms of inflammation pose the same risk of cancer, we compared several murine models of colitis (dextran sodium sulfate [DSS], 2,4,6-trinitrobenzene sulfonic acid, 4-ethoxylmethylene-2-phenyloxazol-5-one, Citrobacter rodentium, Fusobacterium nucleatum, and doxorubicin) with respect to their ability to lead to colonic tumorigenesis. We attempted to correlate the severity of colitis and inflammatory profile with the risk of tumorigenesis in both azoxymethane-dependent and Dclk1/APC murine models of colitis-associated cancer.
RESULTS
DSS colitis reproducibly led to colonic tumors in both mouse models of colitis-associated cancer. In contrast, all other forms of colitis did not lead to cancer. When compared with the colitis not associated with tumorigenesis, DSS colitis was characterized by significantly increased CD11bF4/80Ly6C macrophages and CD11bLy6G neutrophils. Interestingly, depletion of the CD11bF4/80Ly6C macrophages inhibited tumorigenesis, whereas depletion of CD11bLy6G neutrophils had no effect on tumorigenesis. Furthermore, the macrophage-derived cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-6 were significantly increased in DSS colitis and promoted stemness of Dclk1 tuft cells that serve as the cellular origin of cancer.
CONCLUSIONS
We have identified CD11bF4/80Ly6C macrophages as key mediators of cancer initiation in colitis-associated cancer. Development of new therapies that target these cells may provide an effective preventative strategy for colitis-associated cancer.
Topics: Animals; Mice; Azoxymethane; Carcinogenesis; Cell Plasticity; Colitis; Colitis-Associated Neoplasms; Dextran Sulfate; Disease Models, Animal; Inflammation; Macrophages; Mice, Inbred C57BL
PubMed: 36634827
DOI: 10.1053/j.gastro.2023.01.002 -
Cell Reports Jan 2020Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how...
Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how periostin actively contributes to inflammation-associated tumorigenesis remains elusive. Here, we demonstrate that periostin deficiency significantly inhibits the occurrence of colorectal cancer in azoxymethane/dextran sulfate sodium-treated mice and in Apc mice. Moreover, periostin deficiency attenuates the severity of colitis and reduces the proliferation of tumor cells. Mechanistically, stromal fibroblast-derived periostin activates FAK-Src kinases through integrin-mediated outside-in signaling, which results in the activation of YAP/TAZ and, subsequently, IL-6 expression in tumor cells. Conversely, IL-6 induces periostin expression in fibroblasts by activating STAT3, which ultimately facilitates colorectal tumor development. These findings provide the evidence that periostin promotes colorectal tumorigenesis, and identify periostin- and IL-6-mediated tumor-stroma interaction as a promising target for treating colitis-associated colorectal cancer.
Topics: Adaptor Proteins, Signal Transducing; Adenomatous Polyposis Coli; Animals; Azoxymethane; Carcinogenesis; Cell Adhesion Molecules; Cell Proliferation; Colitis; Colorectal Neoplasms; Dextran Sulfate; Focal Adhesion Protein-Tyrosine Kinases; Humans; Inflammation; Integrins; Interleukin-6; Intestines; Mice, Inbred C57BL; Myofibroblasts; Precancerous Conditions; STAT3 Transcription Factor; Signal Transduction; Stromal Cells; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP-Signaling Proteins; src-Family Kinases
PubMed: 31968254
DOI: 10.1016/j.celrep.2019.12.075 -
Gastroenterology Dec 2020Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon...
BACKGROUND & AIMS
Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic.
METHODS
We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2'-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients.
RESULTS
High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients.
CONCLUSIONS
We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aurora Kinase B; Azoxymethane; Carcinogenesis; Cell Line, Tumor; Chromosomal Instability; Colon; Colorectal Neoplasms; Cytogenetic Analysis; Dextrans; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Intestinal Mucosa; Male; Mice; Mice, Transgenic; Neoplasms, Experimental; Organoids; Primary Cell Culture; Proto-Oncogene Proteins c-myc; RNA, Long Noncoding; RNA-Binding Proteins; Signal Transduction
PubMed: 32805281
DOI: 10.1053/j.gastro.2020.08.018 -
Phytomedicine : International Journal... Jul 2022Colitis-associated cancer (CAC) is known to be a complex combination of tumor cells, non-tumor cells and a large intestinal flora. The increasing role of intestinal...
BACKGROUND
Colitis-associated cancer (CAC) is known to be a complex combination of tumor cells, non-tumor cells and a large intestinal flora. The increasing role of intestinal flora in CAC may represent a new approach to improving CAC treatment. Berberine can reduce colorectal adenoma recurrence and inhibit colorectal carcinogenesis.
PURPOSE
Berberine has demonstrated efficacy for the control and suppression of CAC. Given the low oral absorption into the blood and large intestinal excretion of berberine, intestinal flora may be one of the important targets of berberine inhibiting the occurrence of colorectal cancer (CRC). The purpose of this study was to investigate the effects of berberine on intestinal flora in CAC mice and its ability to remodel intestinal flora to improve short-chain fatty acid metabolism.
STUDY DESIGN AND METHODS
The CAC model in mice was induced by Azoxymethane/Dextran sodium sulfate (AOM/DSS). Berberine was administered daily at doses of 50 and 100 mg/kg, and aspirin was used as the positive control. The effect of berberine on colitis-associated colorectal tumorigenesis was assessed by general imaging, tumor counting, and Ki67 staining. Intestinal flora changes were detected by 16S rDNA sequencing technology. Targeted short-chain fatty acid detection was performed by GC-MS/MS, and Lipopolysaccharide (LPS) levels in feces were quantified with an ELISA kit. The signaling pathway of TLR4/NF-κB P65/IL-6/p-STAT3 was evaluated by Western blotting and immunofluorescence. The expression levels of intestinal barrier functional biomarkers Occludin and ZO-1 were detected by immunohistochemistry. Fecal flora transplantation (FMT) was used to evaluate the effect of intestinal flora in inhibiting inflammatory cancer transformation by berberine.
RESULTS
Berberine reduced the number and load of tumors in CAC mice. Berberine remodeled the composition of pathogenic and beneficial bacteria in mice with colitis-associated colorectal tumorigenesis. Berberine treatment resulted in increases in fecal butyric acid, acetic acid and propionic acid levels, but did not alter isobutyric acid, isovaleric acid, valeric acid and caproic acid. In addition, berberine reduced LPS content in feces in mice with colitis-associated colorectal tumorigenesis. Occludin and ZO-1 were upregulated, and the TLR4/p-NF-κB p65/IL-6/p-STAT3 inflammatory-cancer transformation pathway was inhibited with berberine. The FMT results further verified that the berberine-treated intestinal flora was sufficient to alleviate the occurrence of colonic tumors associated with colitis in mice.
CONCLUSION
Our study showed that berberine alleviated the colitis-associated colorectal tumorigenesis from three equilibrium levels: (1) Pathogenic and beneficial bacteria; (2) Short-chain fatty acids and LPS produced by intestinal flora; and (3) Inflammatory cancer transformation signaling and intestinal barrier function. This study provided a new approach and experimental basis for the application of berberine in the treatment of CAC in clinical practice.
Topics: Animals; Azoxymethane; Berberine; Carcinogenesis; Cell Transformation, Neoplastic; Colitis; Colorectal Neoplasms; Dextran Sulfate; Disease Models, Animal; Fatty Acids, Volatile; Gastrointestinal Microbiome; Interleukin-6; Lipopolysaccharides; Mice; Mice, Inbred C57BL; NF-kappa B; Occludin; Tandem Mass Spectrometry; Toll-Like Receptor 4
PubMed: 35660350
DOI: 10.1016/j.phymed.2022.154217 -
Gut Nov 2022Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC....
OBJECTIVE
Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC. Here, we aim to determine oncogenic function of SQLE and its interplay with gut microbiota in promoting colorectal tumourigenesis.
DESIGN
Paired adjacent normal tissues and CRC from two cohorts were analysed (n=202). Colon-specific Sqle transgenic (Sqle tg) mice were generated by crossing Rosa26-lsl-Sqle mice to Cdx2-Cre mice. Stools were collected for metagenomic and metabolomic analyses.
RESULTS
SQLE messenger RNA and protein expression was upregulated in CRC (p<0.01) and predict poor survival of patients with CRC. SQLE promoted CRC cell proliferation by inducing cell cycle progression and suppressing apoptosis. In azoxymethane-induced CRC model, Sqle tg mice showed increased tumourigenesis compared with wild-type mice (p<0.01). Integrative metagenomic and metabolomic analyses unveiled gut dysbiosis in Sqle tg mice with enriched pathogenic bacteria, which was correlated to increased secondary bile acids. Consistent with detrimental effect of secondary bile acids, gut barrier function was impaired in Sqle tg mice, with reduced tight junction proteins Jam-c and occludin. Transplantation of Sqle tg mice stool to germ-free mice impaired gut barrier function and stimulated cell proliferation compared with control mice stool. Finally, we demonstrated that terbinafine, a SQLE inhibitor, could be repurposed for CRC by synergising with oxaliplatin and 5-fluorouracil to inhibit CRC growth.
CONCLUSION
This study demonstrates that SQLE mediates oncogenesis via cell intrinsic effects and modulation of gut microbiota-metabolite axis. SQLE represents a therapeutic target and prognostic marker in CRC.
Topics: Animals; Azoxymethane; Bile Acids and Salts; Carcinogenesis; Cell Proliferation; Cholesterol; Colorectal Neoplasms; Dysbiosis; Fluorouracil; Mice; Occludin; Oxaliplatin; RNA, Messenger; Squalene Monooxygenase; Terbinafine
PubMed: 35232776
DOI: 10.1136/gutjnl-2021-325851