Alteration of fecal microbiota by fucoxanthin results in prevention of colorectal cancer in AOM/DSS-treated mice

Abstract Fucoxanthin (Fx), a marine carotenoid found in edible brown algae, is well known for having anti-cancer properties. The gut microbiota has been demonstrated as a hallmark for colorectal cancer (CRC) progression in both humans and rodents. However, it remains unclear whether the gut microbiota is associated with the anti-cancer effect of Fx. We investigated the chemopreventive potency of Fx and its effect on gut microbiota in a mouse model of inflammation-associated CRC (by azoxymethane [AOM]/ dextran sulfate sodium [DSS] treatment). Fx administration (30 mg/kg body weight) during a 14-week period significantly inhibited the multiplicity of colorectal adenocarcinoma in mice. The number of apoptosis-like cleaved caspase-3 high cells increased significantly in both colonic adenocarcinoma and mucosal crypts. Fx administration significantly suppressed Bacteroidlales (f_ui; g_ui) (0.3-fold) and Rikenellaceae (g_ui) (0.6-fold) and increased Lachnospiraceae (g_ui) (2.2-fold), compared with those of control mice. Oral administration of a fecal suspension obtained from Fx-treated mice, aimed to enhance Lachnospiraceae, suppress the number of colorectal adenocarcinomas in AOM/DSS-treated mice with a successful increase in Lachnospiraceae in the gut. Our findings suggested that an alteration in gut microbiota by dietary Fx might be an essential factor in the cancer chemopreventive effect of Fx in AOM/DSS-treated mice.

Download Full-text

Interplay between the Gut Microbiota and Inflammatory Mediators in the Development of Colorectal Cancer

Cancers ◽

10.3390/cancers13040734 ◽

2021 ◽

Vol 13 (4) ◽

pp. 734

Author(s):

Gwangbeom Heo ◽

Yunna Lee ◽

Eunok Im

Keyword(s):

Colorectal Cancer ◽

Gut Microbiota ◽

Inflammatory Mediators ◽

Tumor Metastasis ◽

Intestinal Tract ◽

Fecal Microbiota Transplantation ◽

Fecal Microbiota ◽

Therapeutic Interventions ◽

Potential Therapeutic Target ◽

Necrosis Factor

Inflammatory mediators modulate inflammatory pathways during the development of colorectal cancer. Inflammatory mediators secreted by both immune and tumor cells can influence carcinogenesis, progression, and tumor metastasis. The gut microbiota, which colonize the entire intestinal tract, especially the colon, are closely linked to colorectal cancer through an association with inflammatory mediators such as tumor necrosis factor, nuclear factor kappa B, interleukins, and interferons. This association may be a potential therapeutic target, since therapeutic interventions targeting the gut microbiota have been actively investigated in both the laboratory and in clinics and include fecal microbiota transplantation and probiotics.

Download Full-text

Gut Microbiota Manipulation as a Tool for Colorectal Cancer Management: Recent Advances in Its Use for Therapeutic Purposes

International Journal of Molecular Sciences ◽

10.3390/ijms21155389 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5389

Author(s):

Federica Perillo ◽

Chiara Amoroso ◽

Francesco Strati ◽

Maria Rita Giuffrè ◽

Angélica Díaz-Basabe ◽

...

Keyword(s):

Colorectal Cancer ◽

Gut Microbiota ◽

Targeted Therapies ◽

Inflammatory Responses ◽

Fecal Microbiota Transplantation ◽

Large Body ◽

Cancer Recurrence ◽

Fecal Microbiota ◽

Cancer Management ◽

Host Microbe Interactions

Colorectal cancer (CRC) is a multifaceted disease influenced by both environmental and genetic factors. A large body of literature has demonstrated the role of gut microbes in promoting inflammatory responses, creating a suitable microenvironment for the development of skewed interactions between the host and the gut microbiota and cancer initiation. Even if surgery is the primary therapeutic strategy, patients with advanced disease or cancer recurrence after surgery remain difficult to cure. Therefore, the gut microbiota has been proposed as a novel therapeutic target in light of recent promising data in which it seems to modulate the response to cancer immunotherapy. The use of microbe-targeted therapies, including antibiotics, prebiotics, live biotherapeutics, and fecal microbiota transplantation, is therefore considered to support current therapies in CRC management. In this review, we will discuss the importance of host−microbe interactions in CRC and how promoting homeostatic immune responses through microbe-targeted therapies may be useful in preventing/treating CRC development.

Download Full-text

The Comparison of Fecal Microbiota in Left-Side and Right-Side Human Colorectal Cancer

European Surgical Research ◽

10.1159/000516922 ◽

2021 ◽

pp. 1-7

Author(s):

Toru Miyake ◽

Haruki Mori ◽

Daiki Yasukawa ◽

Zhang Hexun ◽

Hiromitsu Maehira ◽

...

Keyword(s):

Colorectal Cancer ◽

Gut Microbiota ◽

Clinical Status ◽

Intestinal Flora ◽

Tumor Location ◽

Fecal Microbiota ◽

Vital Role ◽

Human Colorectal Cancer ◽

Linear Discriminant ◽

Biological Differences

Introduction: Microbiomes play a vital role in the development and progression of cancer. The clinical status, including prognosis, genetic mutations, and sensitivity to chemotherapy, differs depending on the location of colorectal cancer (CRC); however, the association between gut microbiota and the location of CRC is not entirely understood. This study was conducted to evaluate the differences in the gut microbiota in patients with CRC according to the location of the tumor. Methods: Fifty-six patients who underwent surgery for CRC between August 2018 and November 2019 were included in the study. Three patients who had received neoadjuvant therapy or antibiotic treatment within 1 month before surgery were excluded. The metagenomes of microbiota in preoperative feces were assessed using the V3–V4 region of 16s rRNA amplicon sequences. Results: The beta diversity of the Bray-Curtis distance was significantly higher in left-sided than in right-sided CRC. Fusobacterium predominated in left-sided CRC according to the linear discriminant analysis effect size method. Blautia, Eryspelotrichales, Holdemanella, Faecalibacterium, Subdoligranulum, and Dorea constituted the dominant intestinal flora in right-sided CRC. Pathway analysis revealed that L-lysine fermentation and cob(II)yrinate a,c-diamide biosynthesis I were predominant in left-sided CRC. Discussion: This study demonstrated that fecal microbiota in left-sided CRC constitutionally and functionally differ from those in right-side CRC. These results will help to elucidate the biological differences according to tumor location and develop treatments for human CRC.

Download Full-text

Potential Role of the Gut Microbiome In Colorectal Cancer Progression

Frontiers in Immunology ◽

10.3389/fimmu.2021.807648 ◽

2022 ◽

Vol 12 ◽

Author(s):

Jaeho Kim ◽

Heung Kyu Lee

Keyword(s):

Colorectal Cancer ◽

Gut Microbiota ◽

Cancer Treatment ◽

Cancer Progression ◽

Gut Microbiome ◽

Intestinal Inflammation ◽

Treatment Modalities ◽

Host Immune System ◽

Anti Cancer

An increasing number of studies have revealed that the progression of colorectal cancer (CRC) is related to gut microbiome composition. Under normal conditions, the gut microbiome acts as a barrier to other pathogens or infections in the intestine and modulates inflammation by affecting the host immune system. These gut microbiota are not only related to the intestinal inflammation associated with tumorigenesis but also modulation of the anti-cancer immune response. Thus, they are associated with tumor progression and anti-cancer treatment efficacy. Studies have shown that the gut microbiota can be used as biomarkers to predict the effect of immunotherapy and improve the efficacy of immunotherapy in treating CRC through modulation. In this review, we discuss the role of the gut microbiome as revealed by recent studies of the growth and progression of CRC along with its synergistic effect with anti-cancer treatment modalities.

Download Full-text

Expression of the Deleted in Colorectal Cancer Gene Is Related to Prognosis in DNA Diploid and Low Proliferative Colorectal Adenocarcinoma

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.6.1745 ◽

1999 ◽

Vol 17 (6) ◽

pp. 1745-1745 ◽

Cited By ~ 41

Author(s):

Xiao-Feng Sun ◽

Sabine Rütten ◽

Hong Zhang ◽

Bo Nordenskjöld

Keyword(s):

Colorectal Cancer ◽

Colorectal Adenocarcinoma ◽

Prognostic Significance ◽

S Phase ◽

Phase Fraction ◽

Primary Tumors ◽

Deleted In Colorectal Cancer ◽

Node Metastases ◽

Dcc Gene ◽

Colorectal Adenocarcinomas

PURPOSE: Whether or not the deleted in colorectal cancer (DCC) gene is implicated in metastases or in predicting prognosis in patients with colorectal cancer has not previously been substantiated. Our aims were to investigate DCC expression in primary colorectal cancers and in metastases to identify any prognostic significance. PATIENTS AND METHODS: DCC expression was examined immunohistochemically in 195 primary colorectal adenocarcinomas and in 23 paired primary tumors and lymph node metastases. DNA content and S-phase fraction were measured by flow cytometry. RESULTS: The absence of DCC expression was observed in 55 primary tumors (28%). DCC negativity was significantly related to poor prognosis in patients with DNA diploid tumors (P = .03) and those with a low S-phase fraction (< 5%, P = .02) but not in patients with nondiploid tumors or those with a higher S-phase fraction. Furthermore, DCC expression retained its prognostic significance in the diploid subgroup after adjusting for sex, age, site, stage, growth pattern, and differentiation (P = .01). DCC expression was similar in primary tumors and their metastases. CONCLUSION: The absence of DCC predicted a poor outcome in the patients with diploid tumors and those tumors with a low S-phase fraction. Immunohistochemistry may be considered as a practical test to assess prognosis in this subgroup of patients.

Download Full-text

Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer

Journal of Experimental Medicine ◽

10.1084/jem.20181939 ◽

2019 ◽

Vol 216 (10) ◽

pp. 2378-2393 ◽

Cited By ~ 16

Author(s):

Wenhan Zhu ◽

Naoteru Miyata ◽

Maria G. Winter ◽

Alexandre Arenales ◽

Elizabeth R. Hughes ◽

...

Keyword(s):

Colorectal Cancer ◽

Gut Microbiota ◽

Chronic Inflammation ◽

Mouse Models ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

E Coli ◽

Gut Colonization ◽

Gut Microbiota Dysbiosis ◽

Colitis Model

Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing E. coli strains, are risk factors for the development of colorectal cancer. Here, we sought to determine whether precision editing of gut microbiota metabolism and composition could decrease the risk for tumor development in mouse models of colitis-associated colorectal cancer (CAC). Expansion of experimentally introduced E. coli strains in the azoxymethane/dextran sulfate sodium colitis model was driven by molybdoenzyme-dependent metabolic pathways. Oral administration of sodium tungstate inhibited E. coli molybdoenzymes and selectively decreased gut colonization with genotoxin-producing E. coli and other Enterobacteriaceae. Restricting the bloom of Enterobacteriaceae decreased intestinal inflammation and reduced the incidence of colonic tumors in two models of CAC, the azoxymethane/dextran sulfate sodium colitis model and azoxymethane-treated, Il10-deficient mice. We conclude that metabolic targeting of protumoral Enterobacteriaceae during chronic inflammation is a suitable strategy to prevent the development of malignancies arising from gut microbiota dysbiosis.

Download Full-text

Evaluating the Anti-Cancer Efficacy of Ethanolic Extract of Erythrina variegate Linn. – An In-silico Approach

Journal of Natural Remedies ◽

10.18311/jnr/2021/26223 ◽

2021 ◽

Vol 21 (1) ◽

pp. 45

Author(s):

G. Umarani ◽

S. Nethaji

Keyword(s):

Colorectal Cancer ◽

Colorectal Adenocarcinoma ◽

Ethanolic Extract ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Binding Energies ◽

Tumour Suppressor ◽

Pharmaceutical Ingredients ◽

Lead Compounds ◽

Anti Cancer

Colorectal cancer is one of the deadly diseases and is ranked as third for men and second for women amongst all cancers in the world. Due to 6,08,000 deaths, it ranks as the fourth common cause of death due to cancer (WHO, 2018). The “ethnomedicinal studies” of the therapeutic values of plants evolves a systematic scientific evaluation. In the present study, the lead compounds hit on the GCMS analysis of the ethanolic extract of Erythrina variegata L. Leaf. The extract was studied for its anticancer potential in Insilco molecular docking. The results revealed that the 3-eicosyne have strong binding energies against the colorectal cancer mutated oncogene KRAS G12D and tumour suppressor gene p53 R249S in comparison to other compounds. Finally, it is confirmed that the active pharmaceutical ingredients have potent anti-Cancer activity and have great efficacy against the colorectal adenocarcinoma oncogenes and tumour suppressor regulating genes.

Download Full-text

Dusp6 Depletion Enhances Gut Barrier Integrity and Microbiota Eubiosis Against Dextran Sulfate Sodium-Induced Colitis in Mice

10.21203/rs.3.rs-44154/v1 ◽

2020 ◽

Author(s):

Cherng-Shyang Chang ◽

Yi-Chu Liao ◽

Chih-Ting Huang ◽

Chiao-Mei Lin ◽

Chantal Hoi Yin Cheung ◽

...

Keyword(s):

Gut Microbiota ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Fecal Microbiota Transplantation ◽

Fecal Microbiota ◽

Protective Effects ◽

Gut Barrier ◽

Barrier Integrity ◽

Altered Glucose ◽

Deficient Mice

Abstract Background: Leaky gut and microbiota dysbiosis have been linked to many chronic inflammatory diseases. Strengthening the gut epithelial barrier is a novel but overlooked strategy for management of gut microbiota-associated illnesses. Results: Using the dextran sulfate sodium (DSS)-induced gut barrier injury-based colitis model, we found that DSS-induced weight loss, rectal bleeding, and colonic epithelium damage were ameliorated in dual-specificity phosphatase 6 (Dusp6)-deficient mice. These protective effects could be attributed to the enhanced colon barrier integrity conferred by Dusp6-deficiency. Consistently, DUSP6 mutation in Caco-2 cells elevated transepithelial electrical resistance, enhanced tight-junctions, and increased expression of microvilli-associated genes. DUSP6-deficient Caco-2 cells also showed increased mitochondrial oxygen consumption accompanied by altered glucose metabolism and decreased glycolysis. Remarkably, our microbiome analysis found that Dusp6-deficient mice harbored fewer pathobionts and facultative anaerobes and more obligate anaerobes than wild-type mice after DSS treatment. Our cohousing and fecal microbiota transplantation experiments demonstrated that the gut/fecal microbiota derived from Dusp6-deficient mice also conferred protection against colitis.Conclusion: We have thus identified Dusp6 deficiency as beneficial in enhancing gut barrier integrity, elevating epithelial phosphoxidation, and maintaining the gut microbiota eubiosis necessary to protect against colitis.

Download Full-text

Fecal Microbiota Transplantation Prevents Intestinal Injury, Upregulation of Toll-Like Receptors, and 5-Fluorouracil/Oxaliplatin-Induced Toxicity in Colorectal Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21020386 ◽

2020 ◽

Vol 21 (2) ◽

pp. 386 ◽

Cited By ~ 11

Author(s):

Ching-Wei Chang ◽

Hung-Chang Lee ◽

Li-Hui Li ◽

Jen-Shiu Chiang Chiau ◽

Tsang-En Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Gut Microbiota ◽

Fecal Microbiota Transplantation ◽

Common Adverse Effect ◽

Mucosal Injury ◽

Fecal Microbiota ◽

Intestinal Injury ◽

Toll Like Receptors ◽

Adenocarcinoma Cells ◽

Intestinal Mucositis

FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin), a 5-fluorouracil (5-FU)-based chemotherapy regimen, is one of most common therapeutic regimens for colorectal cancer. However, intestinal mucositis is a common adverse effect for which no effective preventive strategies exist. Moreover, the efficacy and the safety of fecal microbiota transplants (FMT) in cancer patients treated with anti-neoplastic agents are still scant. We investigated the effect of FMT on FOLFOX-induced mucosal injury. BALB/c mice implanted with syngeneic CT26 colorectal adenocarcinoma cells were orally administered FMT daily during and two days after five-day injection of FOLFOX regimen for seven days. Administration of FOLFOX significantly induced marked levels of diarrhea and intestinal injury. FMT reduced the severity of diarrhea and intestinal mucositis. Additionally, the number of goblet cells and zonula occludens-1 decreased, while apoptotic and NF-κB-positive cells increased following FOLFOX treatment. The expression of toll-like receptors (TLRs), MyD88, and serum IL-6 were upregulated following FOLFOX treatment. These responses were attenuated following FMT. The disrupted fecal gut microbiota composition was also restored by FMT after FOLFOX treatment. Importantly, FMT did not cause bacteremia and safely alleviated FOLFOX-induced intestinal mucositis in colorectal cancer-bearing mice. The putative mechanism may involve the gut microbiota TLR-MyD88-NF-κB signaling pathway in mice with implanted colorectal carcinoma cells.

Download Full-text