The Gut Microbiome Modulates Colon Tumorigenesis

ABSTRACT Recent studies have shown that individuals with colorectal cancer have an altered gut microbiome compared to healthy controls. It remains unclear whether these differences are a response to tumorigenesis or actively drive tumorigenesis. To determine the role of the gut microbiome in the development of colorectal cancer, we characterized the gut microbiome in a murine model of inflammation-associated colorectal cancer that mirrors what is seen in humans. We followed the development of an abnormal microbial community structure associated with inflammation and tumorigenesis in the colon. Tumor-bearing mice showed enrichment in operational taxonomic units (OTUs) affiliated with members of the Bacteroides, Odoribacter, and Akkermansia genera and decreases in OTUs affiliated with members of the Prevotellaceae and Porphyromonadaceae families. Conventionalization of germfree mice with microbiota from tumor-bearing mice significantly increased tumorigenesis in the colon compared to that for animals colonized with a healthy gut microbiome from untreated mice. Furthermore, at the end of the model, germfree mice colonized with microbiota from tumor-bearing mice harbored a higher relative abundance of populations associated with tumor formation in conventional animals. Manipulation of the gut microbiome with antibiotics resulted in a dramatic decrease in both the number and size of tumors. Our results demonstrate that changes in the gut microbiome associated with inflammation and tumorigenesis directly contribute to tumorigenesis and suggest that interventions affecting the composition of the microbiome may be a strategy to prevent the development of colon cancer. IMPORTANCE The trillions of bacteria that live in the gut, known collectively as the gut microbiome, are important for normal functioning of the intestine. There is now growing evidence that disruptive changes in the gut microbiome are strongly associated with the development colorectal cancer. However, how the gut microbiome changes with time during tumorigenesis and whether these changes directly contribute to disease have not been determined. We demonstrate using a mouse model of inflammation-driven colon cancer that there are dramatic, continual alterations in the microbiome during the development of tumors, which are directly responsible for tumor development. Our results suggest that interventions that target these changes in the microbiome may be an effective strategy for preventing the development of colorectal cancer.

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The Role of the Gut Microbiome in Colorectal Cancer

Clinics in Colon and Rectal Surgery ◽

10.1055/s-0037-1602239 ◽

2018 ◽

Vol 31 (03) ◽

pp. 192-198 ◽

Cited By ~ 14

Author(s):

Grace Chen

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Microbial Community ◽

Gut Microbiota ◽

Gut Microbiome ◽

Intestinal Health ◽

Genotoxic Effects ◽

Bacterial Populations ◽

Health And Disease

AbstractThere is increasing evidence that the gut microbiome, which consists of trillions of microbes representing over 1,000 species of bacteria with over 3 million genes, significantly impacts intestinal health and disease. The gut microbiota not only is capable of promoting intestinal homeostasis and antitumor responses but can also contribute to chronic dysregulated inflammation as well as have genotoxic effects that lead to carcinogenesis. Whether the gut microbiota maintains health or promotes colon cancer may ultimately depend on the composition of the gut microbiome and the balance within the microbial community of protective and detrimental bacterial populations. Disturbances in the normal balanced state of a healthful microbiome, known as dysbiosis, have been observed in patients with colorectal cancer (CRC); however, whether these alterations precede and cause CRC remains to be determined. Nonetheless, studies in mice strongly suggest that the gut microbiota can modulate susceptibility to CRC, and therefore may serve as both biomarkers and therapeutic targets.

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The Western Dietary Pattern Combined with Vancomycin-Mediated Changes to the Gut Microbiome Exacerbates Colitis Severity and Colon Tumorigenesis

Nutrients ◽

10.3390/nu13030881 ◽

2021 ◽

Vol 13 (3) ◽

pp. 881

Author(s):

Niklas D. Aardema ◽

Daphne M. Rodriguez ◽

Arnaud J. Van Wettere ◽

Abby D. Benninghoff ◽

Korry J. Hintze

Keyword(s):

Colorectal Cancer ◽

Gut Microbiome ◽

Tumor Development ◽

Alpha Diversity ◽

Basal Diet ◽

Plain Water ◽

Microbiome Composition ◽

Colon Tumorigenesis ◽

Induced Changes ◽

The Impact

Previous work by our group using a mouse model of inflammation-associated colorectal cancer (CAC) showed that the total Western diet (TWD) promoted colon tumor development. Others have also shown that vancomycin-mediated changes to the gut microbiome increased colorectal cancer (CRC). Therefore, the objective of this study was to determine the impact of vancomycin on colon tumorigenesis in the context of a standard mouse diet or the TWD. A 2 × 2 factorial design was used, in which C57Bl/6J mice were fed either the standard AIN93G diet or TWD and with vancomycin in the drinking water or not. While both the TWD and vancomycin treatments independently increased parameters associated with gut inflammation and tumorigenesis compared to AIN93G and plain water controls, mice fed the TWD and treated with vancomycin had significantly increased tumor multiplicity and burden relative to all other treatments. Vancomycin treatment significantly decreased alpha diversity and changed the abundance of several taxa at the phylum, family, and genus levels. Conversely, basal diet had relatively minor effects on the gut microbiome composition. These results support our previous research that the TWD promotes colon tumorigenesis and suggest that vancomycin-induced changes to the gut microbiome are associated with higher tumor rates.

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Deficiency in STAT1 Signaling Predisposes Gut Inflammation and Prompts Colorectal Cancer Development

Cancers ◽

10.3390/cancers10090341 ◽

2018 ◽

Vol 10 (9) ◽

pp. 341 ◽

Cited By ~ 3

Author(s):

Sonia Leon-Cabrera ◽

Armando Vázquez-Sandoval ◽

Emmanuel Molina-Guzman ◽

Yael Delgado-Ramirez ◽

Norma Delgado-Buenrostro ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Activity Index ◽

Tumor Development ◽

Disease Activity Index ◽

Tumor Stroma ◽

Tumor Formation ◽

Janus Kinase ◽

Early Stages

Signal transducer and activator of transcription 1 (STAT1) is part of the Janus kinase (JAK/STAT) signaling pathway that controls critical events in intestinal immune function related to innate and adaptive immunity. Recent studies have implicated STAT1 in tumor–stroma interactions, and its expression and activity are perturbed during colon cancer. However, the role of STAT1 during the initiation of inflammation-associated cancer is not clearly understood. To determine the role of STAT1 in colitis-associated colorectal cancer (CAC), we analyzed the tumor development and kinetics of cell recruitment in wild-type WT or STAT1−/− mice treated with azoxymethane (AOM) and dextran sodium sulfate (DSS). Following CAC induction, STAT1−/− mice displayed an accelerated appearance of inflammation and tumor formation, and increased damage and scores on the disease activity index (DAI) as early as 20 days after AOM-DSS exposure compared to their WT counterparts. STAT1−/− mice showed elevated colonic epithelial cell proliferation in early stages of injury-induced tumor formation and decreased apoptosis in advanced tumors with over-expression of the anti-apoptotic protein Bcl2 at the colon. STAT1−/− mice showed increased accumulation of Ly6G+Ly6C−CD11b+ cells in the spleen at 20 days of CAC development with concomitant increases in the production of IL-17A, IL-17F, and IL-22 cytokines compared to WT mice. Our findings suggest that STAT1 plays a role as a tumor suppressor molecule in inflammation-associated carcinogenesis, particularly during the very early stages of CAC initiation, modulating immune responses as well as controlling mechanisms such as apoptosis and cell proliferation.

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The Protective Role of Bacteroides fragilis in a Murine Model of Colitis-Associated Colorectal Cancer

mSphere ◽

10.1128/msphere.00587-18 ◽

2018 ◽

Vol 3 (6) ◽

Cited By ~ 16

Author(s):

Yun Kyung Lee ◽

Parpi Mehrabian ◽

Silva Boyajian ◽

Wei-Li Wu ◽

Jane Selicha ◽

...

Keyword(s):

Colorectal Cancer ◽

Chemokine Receptor ◽

Bacteroides Fragilis ◽

Protective Role ◽

Tumor Formation ◽

Protective Function ◽

Content Type ◽

Colon Tumorigenesis ◽

Tlr2 Signaling

ABSTRACT Many patients with chronic inflammation of the gut, such as that observed in inflammatory bowel disease (IBD), develop colorectal cancer (CRC). Recent studies have reported that the development of IBD and CRC partly results from an imbalanced composition of intestinal microbiota and that intestinal inflammation in these diseases can be modulated by the microbiota. The human commensal Bacteroides fragilis is best exemplified playing a protective role against the development of experimental colitis in several animal disease models. In this study, we found that gut inflammation caused by dextran sulfate sodium (DSS) treatment was inhibited by B. fragilis colonization in mice. Further, we reveal a protective role of B. fragilis treatment against colon tumorigenesis using an azoxymethane (AOM)/DSS-induced model of colitis-associated colon cancer in mice and demonstrate that the decreased tumorigenesis by B. fragilis administration is accompanied by inhibited expression of C-C chemokine receptor 5 (CCR5) in the gut. We show direct evidence that the inhibition of tumor formation provided by B. fragilis in colitis-associated CRC animals was dependent on the production of polysaccharide A (PSA) from B. fragilis and that Toll-like receptor 2 (TLR2) signaling was responsible for the protective function of B. fragilis. IMPORTANCE The incidence of colorectal cancer (CRC) is rapidly growing worldwide, and there is therefore a greater emphasis on studies of the treatment or prevention of CRC pathogenesis. Recent studies suggested that consideration of the microbiota is unavoidable to understand inflammation and tumorigenesis in the gastrointestinal tract. We demonstrate, using a mouse model of colitis-associated CRC, that human commensal B. fragilis protects against colon tumorigenesis. The protective role against tumor formation provided by B. fragilis is associated with inhibition of expression of the chemokine receptor CCR5 in the colon. The molecular mechanism for protection against CRC provided by B. fragilis is dependent on polysaccharide A production and is mediated by TLR2 signaling. Our results suggest that the commensal microorganism B. fragilis can be used to prevent inflammation-associated CRC development and may provide an effective therapeutic strategy for CRC.

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TMOD-26. MYC OVEREXPRESSION AND SMARCA4 LOSS IN GRANULE CELL PRECURSORS COOPERATE TO DRIVE MEDULLOBLASTOMA FORMATION IN MICE

Neuro-Oncology ◽

10.1093/neuonc/noab196.887 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi221-vi221

Author(s):

Carolin Göbel ◽

Dörthe Holdhof ◽

Melanie Schoof ◽

Catena Kresbach ◽

Ulrich Schüller

Keyword(s):

Granule Cell ◽

Clinical Course ◽

Tumor Development ◽

Tumor Formation ◽

Human Group ◽

Group 4 ◽

Small Cohort ◽

Group 3 ◽

Granule Cell Precursors

Abstract Mutations in SMARCA4 are frequently identified in medulloblastoma, the most common pediatric malignant brain tumor. However, the functional significance of these mutations and their suitability as a therapeutic target remain largely unclear. Medulloblastomas are divided into 4 subgroups according to their localization, molecular biology, and clinical course: WNT, SHH, Group 3, and Group 4. Group 3 medulloblastomas are associated with the poorest outcome and frequently show amplifications of the oncogene MYC. Additionally, SMARCA4 is mutated in around 15 % of cases. The few mouse models developed for this entity so far all involve the overexpression of MYC, mostly in combination with other drivers. However, none of these models include alterations in Smarca4. In our approach, we combined an overexpression of MYC with a loss of SMARCA4 in granule cell precursors, which successfully induced tumor formation in mice. For this purpose, granule cell precursors were isolated from 7-day-old Math1-creER T2 ::Smarca4 fl/fl pups after tamoxifen induced loss of SMARCA4. MYC overexpression was achieved by lentiviral transduction and transduced cells were transplanted into immunodeficient CD1 nu/nu mice. Preliminary results within a small cohort showed tumor formation in 5/19 transplanted mice (26 %) after 6 months. Immunohistochemically, tumors all stained negative for SMARCA4. In a next step, additional cohorts will elucidate if tumor development is indeed accelerated by or even dependent on the loss of SMARCA4. Additionally, the neoplastic potential of tumor cells will be verified with the aid of secondary recipient mice. To evaluate to what extent the generated tumors are comparable to human Group 3 medulloblastomas, tumors will be extensively analyzed on a morphological, transcriptional, and epigenetic level. Altogether, we hope to establish a suitable mouse model for SMARCA4 mutated Group 3 medulloblastoma that will help to elucidate the role of SMARCA4 in tumor development and to identify new therapeutic targets.

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Biostimulating Gut Microbiome with Bilberry Anthocyanin Combo to Enhance Anti-PD-L1 Efficiency against Murine Colon Cancer

Microorganisms ◽

10.3390/microorganisms8020175 ◽

2020 ◽

Vol 8 (2) ◽

pp. 175 ◽

Cited By ~ 3

Author(s):

Xuerun Liu ◽

Luoyang Wang ◽

Nan Jing ◽

Guoqiang Jiang ◽

Zheng Liu

Keyword(s):

Colon Cancer ◽

Gut Microbiome ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Microbial Consortia ◽

Therapeutic Efficiency ◽

Soil Microbial ◽

Murine Colon ◽

Subdominant Species

Recent advances have revealed the essential role of gut microbiomes in the therapeutic efficiency of immune checkpoint inhibitors (ICIs). Inspired by biostimulation, a method using nutrients to accelerate the growth of soil microorganisms and the recovery of soil microbial consortia, here we propose a bilberry anthocyanin combo containing chitosan and low molecular citrus pectin (LCP), in which LCP–chitosan is used to encapsulate anthocyanins so to enhance its digestive stability and, moreover, modulate the microbiome more favorable for the PD-L1 blockade treatment. Using murine MC38 colon cancer as a model system, we examined the effects of the combo on modulating the gut microbiome and therapeutic efficiency of PD-L1 blockade treatment. It was shown that bilberry anthocyanins enriched the subdominant species, increased both the concentration and the proportion of butyrate in feces and enhanced intratumoral CD8+ T cell infiltrations. The application of the bilberry anthocyanin combo restored the species diversity of gut microbiome decreased by LCP–chitosan and achieved the best control of tumor growth. These preliminary results indicated unprecedented opportunities of probiotics combo in improving the therapeutic efficiency of immune checkpoint inhibitor through manipulating gut microbiome.

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Role of SCFAs in gut microbiome and glycolysis for colorectal cancer therapy

Journal of Cellular Physiology ◽

10.1002/jcp.28436 ◽

2019 ◽

Vol 234 (10) ◽

pp. 17023-17049 ◽

Cited By ~ 17

Author(s):

Gang Wang ◽

Yang Yu ◽

Yu‐Zhu Wang ◽

Jun‐Jie Wang ◽

Rui Guan ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Therapy ◽

Gut Microbiome

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The Role of the Gut Microbiome in Colorectal Cancer: Where Are We? Where Are We Going?

Clinical Colorectal Cancer ◽

10.1016/j.clcc.2019.07.006 ◽

2020 ◽

Vol 19 (1) ◽

pp. 5-12 ◽

Cited By ~ 6

Author(s):

Karina Wieczorska ◽

Małgorzata Stolarek ◽

Rafał Stec

Keyword(s):

Colorectal Cancer ◽

Gut Microbiome

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Association of Flavonifractor plautii, a Flavonoid-Degrading Bacterium, with the Gut Microbiome of Colorectal Cancer Patients in India

mSystems ◽

10.1128/msystems.00438-19 ◽

2019 ◽

Vol 4 (6) ◽

Cited By ~ 10

Author(s):

Ankit Gupta ◽

Darshan B. Dhakan ◽

Abhijit Maji ◽

Rituja Saxena ◽

Vishnu Prasoodanan P.K. ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Gut Microbiome ◽

Association Studies ◽

Bacterial Species ◽

Developed Countries ◽

Learning Approaches ◽

Gene Markers ◽

Degrading Bacterium

ABSTRACT Recently, dysbiosis in the human gut microbiome and shifts in the relative abundances of several bacterial species have been recognized as important factors in colorectal cancer (CRC). However, these studies have been carried out mainly in developed countries where CRC has a high incidence, and it is unclear whether the host-microbiome relationships deduced from these studies can be generalized to the global population. To test if the documented associations between the microbiome and CRC are conserved in a distinct context, we performed metagenomic and metabolomic association studies on fecal samples from 30 CRC patients and 30 healthy controls from two different locations in India, followed by a comparison of CRC data available from other populations. We confirmed the association of Bacteroides and other bacterial taxa with CRC that have been previously reported in other studies. However, the association of CRC with Flavonifractor plautii in Indian patients emerged as a novel finding. The plausible role of F. plautii appears to be linked with the degradation of beneficial anticarcinogenic flavonoids, which was also found to be significantly correlated with the enzymes and modules involved in flavonoid degradation within Indian CRC samples. Thus, we hypothesize that the degradation of beneficial flavonoids might be playing a role in cancer progression within this Indian cohort. We also identified 20 potential microbial taxonomic markers and 33 potential microbial gene markers that discriminate the Indian CRC from healthy microbiomes with high accuracy based on machine learning approaches. IMPORTANCE This study provides novel insights on the CRC-associated microbiome of a unique cohort in India, reveals the potential role of a new bacterium in CRC, and identifies cohort-specific biomarkers, which can potentially be used in noninvasive diagnosis of CRC. The study gains additional significance, as India is among the countries with a very low incidence of CRC, and the diet and lifestyle in India have been associated with a distinct gut microbiome in healthy Indians compared to other global populations. Thus, in this study, we hypothesize a unique relationship between CRC and the gut microbiome in an Indian population.

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