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.

Colorectal cancer (CRC) accounts for about 10% of all new cancer cases globally. Located at close proximity to the colorectal epithelium, the gut microbiota comprises a large population of microorganisms that interact with host cells to regulate many physiological processes, such as energy harvest, metabolism and immune response. Sequencing studies have revealed microbial compositional and ecological changes in patients with CRC, whereas functional studies in animal models have pinpointed the roles of several bacteria in colorectal carcinogenesis, including Fusobacterium nucleatum and certain strains of Escherichia coli and Bacteroides fragilis. These findings give new opportunities to take advantage of our knowledge on the gut microbiota for clinical applications, such as gut microbiota analysis as screening, prognostic or predictive biomarkers, or modulating microorganisms to prevent cancer, augment therapies and reduce adverse effects of treatment. This Review aims to provide an overview and discussion of the gut microbiota in colorectal neoplasia, including relevant mechanisms in microbiota-related carcinogenesis, the potential of utilizing the microbiota as CRC biomarkers, and the prospect for modulating the microbiota for CRC prevention or treatment. These scientific findings will pave the way to clinically translate the use of gut microbiota for CRC in the near future.

Gut microbiota in colorectal cancer: mechanisms of action and clinical applications

Fusobacterium nucleatum has long been found to cause opportunistic infections and has recently been implicated in colorectal cancer; however, it is a common member of the oral microbiota and can have a symbiotic relationship with its hosts. To address this dissonance, we explore the diversity and niches of fusobacteria and reconsider historic fusobacterial taxonomy in the context of current technology. We also undertake a critical reappraisal of fusobacteria with a focus on F. nucleatum as a mutualist, infectious agent and oncogenic microorganism. In this Review, we delve into recent insights and future directions for fusobacterial research, including the current genetic toolkit, our evolving understanding of its mechanistic role in promoting colorectal cancer and the challenges of developing diagnostics and therapeutics for F. nucleatum.

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Fusobacterium nucleatum - symbiont, opportunist and oncobacterium.

The Intestinal Microbiota in Colorectal Cancer

Exposure to environmental chemicals has been linked to various health disorders, including obesity, type 2 diabetes, cancer and dysregulation of the immune and reproductive systems, whereas the gastrointestinal microbiota critically contributes to a variety of host metabolic and immune functions. We aimed to evaluate the bidirectional relationship between gut bacteria and environmental pollutants and to assess the toxicological relevance of the bacteria–xenobiotic interplay for the host. We examined studies using isolated bacteria, faecal or caecal suspensions—germ-free or antibiotic-treated animals—as well as animals reassociated with a microbiota exposed to environmental chemicals. The literature indicates that gut microbes have an extensive capacity to metabolise environmental chemicals that can be classified in five core enzymatic families (azoreductases, nitroreductases, β-glucuronidases, sulfatases and β-lyases) unequivocally involved in the metabolism of >30 environmental contaminants. There is clear evidence that bacteria-dependent metabolism of pollutants modulates the toxicity for the host. Conversely, environmental contaminants from various chemical families have been shown to alter the composition and/or the metabolic activity of the gastrointestinal bacteria, which may be an important factor contributing to shape an individual’s microbiotype. The physiological consequences of these alterations have not been studied in details but pollutant-induced alterations of the gut bacteria are likely to contribute to their toxicity. In conclusion, there is a body of evidence suggesting that gut microbiota are a major, yet underestimated element that must be considered to fully evaluate the toxicity of environmental contaminants.

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The gut microbiota: a major player in the toxicity of environmental pollutants?

Gut microbial dysbiosis contributes to the development of colorectal cancer (CRC). Here we catalogue the microbial communities in human gut mucosae at different stages of colorectal tumorigenesis. We analyse the gut mucosal microbiome of 47 paired samples of adenoma and adenoma-adjacent mucosae, 52 paired samples of carcinoma and carcinoma-adjacent mucosae and 61 healthy controls. Probabilistic partitioning of relative abundance profiles reveals that a metacommunity predominated by members of the oral microbiome is primarily associated with CRC. Analysis of paired samples shows differences in community configurations between lesions and the adjacent mucosae. Correlations of bacterial taxa indicate early signs of dysbiosis in adenoma, and co-exclusive relationships are subsequently more common in cancer. We validate these alterations in CRC-associated microbiome by comparison with two previously published data sets. Our results suggest that a taxonomically defined microbial consortium is implicated in the development of CRC.

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Gut mucosal microbiome across stages of colorectal carcinogenesis

Colorectal cancer remains the third most common cause of death from cancer worldwide. MicroRNA emerges as a good area of research for current cancer therapy. Here, we identified miR-135b to be a contributor to anti-apoptosis and chemoresistance in colorectal cancer. We observed high levels of miR-135b in colorectal cancer cell lines and clinical tissues, compared to colorectal epithelium cell line and noncancerous tissues. Furthermore, enforced expression of miR-135b attenuated doxorubicin-induced apoptosis in colorectal cells. (Doxorubicin alone can trigger significant apoptosis). In elucidating the molecular mechanism by which miR-135b participate in the regulation of apoptosis and chemoresistance in colorectal cancer, we discovered that large tumor suppressor kinase 2 (LATS2) is a direct target of miR-135b. The role of miR-135b was confirmed in colorectal tumor xenograft models. The growth of established tumors was suppressed by an inhibition of miR-135b expression and enhanced apoptosis was further assessed by TUNEL assay. Taken together, our results reveal that miR-135b and LATS2 axis may be a novel therapeutic target for colorectal cancer.

MicroRNA-135b regulates apoptosis and chemoresistance in colorectal cancer by targeting large tumor suppressor kinase 2

Abstract Background Opioid prescription for inflammatory bowel disease (IBD)-related pain is on the rise. However, the use of strong opioids can result in severe complications, and even death, in IBD patients. This study aimed to define the role of fentanyl and morphine, two representative strong opioids, in the pathogenesis of dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced colitis. Method DSS and TNBS models were induced in C57BL/6J and Balb/c mice, respectively. Disease activity index (DAI), histopathology, enzyme-linked immunosorbent assay (ELISA), multiplex ELISA, and flow cytometry were performed to evaluate the effects of fentanyl and morphine. Result Fentanyl exacerbated DSS- and TNBS-induced colitis, while morphine exhibited no significant immunomodulatory effect. Fentanyl and morphine had no obvious effects on the serum levels of adrenocorticotropic hormone (ACTH), glucocorticoid (GC), and prostaglandin E2 (PGE-2) in DSS and TNBS models. Fentanyl elevated the proportions of Th1 cells, μ-opioid receptor (MOR) + Th1 cells, and MOR + macrophages in the colonic mucosa of DSS-treated mice, and enhanced the proportions of Th1 cells, macrophages, MOR + Th1 cells, and MOR + macrophages in the colonic mucosa of TNBS-treated mice. We found that fentanyl upregulated the levels of inflammatory cytokines/chemokines in MOR + macrophages of the colonic lamina propria mononuclear cells (LPMCs) from DSS-treated mice, whereas it had no effect on the expression of most inflammatory cytokines/chemokines in MOR + macrophages in the colonic LPMCs from TNBS-treated mice. Conclusion Our findings suggest that fentanyl exacerbates murine colitis via Th1 cell- and macrophage-mediated mechanisms, while morphine exhibits no significant immunomodulatory effect.

Immunomodulatory effects of fentanyl and morphine on DSS- and TNBS-induced colitis

Yangjie Li The Second School of Clinical Medicine, Southern Medical University Yuanming Pan Department of Gastroenterology, the Seventh Medical Center of Chinese PLA General Hospital Jianxun Wang School of Basic Medical Sciences, Qingdao University Tao Zuo Insititute of Digistive Disease State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong Lishu Zhang College of Life Science and Bioengineering, Beijing Jiaotong University, Xiutang Feng The Second School of clinical Medicine, Southern Medical University Qian Kang Department of Gastroenterology, Seventh Medical Center of Chinese PLA General Hospital Xiaojuan Lu Department of Gastroenterology, Seventh Medical Center of Chinese PLA General Hospital Jianqiu Sheng Department of Gastroenterology, Seventh Medical Center of Chinese PLA General Hospital Yuqi He Department of Gastroenterology, the Seventh Medical Center of Chinese PLA General Hospital Jiheng Wang (  acewjh@aliyun.com ) The Second School of Clinical Medicine, Southern Medical University, 253 Middle Industrial Avenue, Guangzhou, Guangdong 510282, China. https://orcid.org/0000-0002-5556-8731

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Qian Kang

Papers

Gut mucosal microbiome across stages of colorectal carcinogenesis

MicroRNA-135b regulates apoptosis and chemoresistance in colorectal cancer by targeting large tumor suppressor kinase 2

Immunomodulatory effects of fentanyl and morphine on DSS- and TNBS-induced colitis

ITRAQ-based Bioinformatics Analysis Reveals the Potential Anticancer Effects of ATP4B in Gastric Cancer