Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver-bile acid-microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states. An examination of recent research progress in this area is urgently needed. In this Review, we discuss the mechanistic links between bile acids and gastrointestinal carcinogenesis in CRC and HCC, which involve two major bile acid-sensing receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). We also highlight the strategies and cutting-edge technologies to target gut-microbiota-dependent alterations in bile acid metabolism in the context of cancer therapy.

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Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.

A host's microbiota may increase, diminish, or have no effect at all on cancer susceptibility. Assigning causal roles in cancer to specific microbes and microbiotas, unraveling host-microbiota interactions with environmental factors in carcinogenesis, and exploiting such knowledge for cancer diagnosis and treatment are areas of intensive interest. This Review considers how microbes and the microbiota may amplify or mitigate carcinogenesis, responsiveness to cancer therapeutics, and cancer-associated complications.

http://science.sciencemag.org/content/sci/348/6230/80.full.pdf

Cancer and the microbiota

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%–5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli. CRC is caused by mutations that target oncogenes, tumour suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic (70%); inherited (5%) and familial (25%). The pathogenic mechanisms leading to this situation can be included in three types, namely chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Within these types of CRC, common mutations, chromosomal changes and translocations have been reported to affect important pathways (WNT, MAPK/PI3K, TGF-β, TP53), and mutations; in particular, genes such as c-MYC, KRAS, BRAF, PIK3CA, PTEN, SMAD2 and SMAD4 can be used as predictive markers for patient outcome. In addition to gene mutations, alterations in ncRNAs, such as lncRNA or miRNA, can also contribute to different steps of the carcinogenesis process and have a predictive value when used as biomarkers. In consequence, different panels of genes and mRNA are being developed to improve prognosis and treatment selection. The choice of first-line treatment in CRC follows a multimodal approach based on tumour-related characteristics and usually comprises surgical resection followed by chemotherapy combined with monoclonal antibodies or proteins against vascular endothelial growth factor (VEGF) and epidermal growth receptor (EGFR). Besides traditional chemotherapy, alternative therapies (such as agarose tumour macrobeads, anti-inflammatory drugs, probiotics, and gold-based drugs) are currently being studied to increase treatment effectiveness and reduce side effects.

/pdf/colorectal-carcinoma-a-general-overview-and-future-2e96vugrtz.pdf

Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer

Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life We identified patchy bacterial biofilms composed predominately of Escherichia coli and Bacteroides fragilis  Genes for colibactin ( clbB ) and Bacteroides fragilis toxin ( bft ), encoding secreted oncotoxins, were highly enriched in FAP patients’ colonic mucosa compared to healthy individuals Tumor-prone mice cocolonized with E coli (expressing colibactin), and enterotoxigenic B fragilis showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria

Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria

With the advent of next-generation sequencing, we have an unprecedented ability to study tumor and host genomes as well as those of the vast array of microorganisms that exist within living organisms. Evidence now suggests that these microbes may confer susceptibility to certain cancers and may also influence response to therapeutics. A prime example of this is seen with immunotherapy, for which gut microbes have been implicated in influencing therapeutic responses in preclinical models and patient cohorts. However, these microbes may influence responses to other forms of therapy as well and may also affect treatment-associated toxicity. Based on these influences, there is growing interest in targeting these microbes in the treatment of cancer and other diseases. Yet complexities exist, and a deeper understanding of host-microbiome interactions is critical to realization of the full potential of such approaches. These concepts and the means through which such findings may be translated into the clinic will be discussed herein.

The microbiome, cancer, and cancer therapy.

Background. Enterotoxigenic Bacteroides fragilis (ETBF) produces the Bacteroides fragilis toxin, which has been associated with acute diarrheal disease, inflammatory bowel disease, and colorectal cancer (CRC). ETBF induces colon carcinogenesis in experimental models. Previous human studies have demonstrated frequent asymptomatic fecal colonization with ETBF, but no study has investigated mucosal colonization that is expected to impact colon carcinogenesis.

Methods. We compared the presence of the bft gene in mucosal samples from colorectal neoplasia patients (cases, n = 49) to a control group undergoing outpatient colonoscopy for CRC screening or diagnostic workup (controls, n = 49). Single bacterial colonies isolated anaerobically from mucosal colon tissue were tested for the bft gene with touch-down polymerase chain reaction.

Results. The mucosa of cases was significantly more often bft-positive on left (85.7%) and right (91.7%) tumor and/or paired normal tissues compared with left and right control biopsies (53.1%; P = .033 and 55.5%; P = .04, respectively). Detection of bft was concordant in most paired mucosal samples from individual cases or controls (75% cases; 67% controls). There was a trend toward increased bft positivity in mucosa from late- vs early-stage CRC patients (100% vs 72.7%, respectively; P = .093). In contrast to ETBF diarrheal disease where bft-1 detection dominates, bft-2 was the most frequent toxin isotype identified in both cases and controls, whereas multiple bft isotypes were detected more frequently in cases (P ≤ .02).

Conclusions. The bft gene is associated with colorectal neoplasia, especially in late-stage CRC. Our results suggest that mucosal bft exposure is common and may be a risk factor for developing CRC.

Ruchi Badani

Papers

The Bacteroides fragilis Toxin Gene Is Prevalent in the Colon Mucosa of Colorectal Cancer Patients