The role of intestinal bacteria in the development and progression of gastrointestinal tract neoplasms
Introduction
Cancer in the gastrointestinal tract is a leading cause of death worldwide [1]. Accumulating evidence indicates that gastrointestinal tract cancers develop through the accumulation of genetic and epigenetic alterations, which are influenced by host immunity, diet, and environmental and microbial exposures [2].
The human intestinal microbiome encompasses at least 100 trillion microorganisms, which can influence the immune system and health conditions, including cancer [3], [4], [5]. A growing body of evidence indicates that diet, lifestyle, and drugs can influence the composition of the gut microbiota and that the gut microbiota can modulate the development and progression of gastrointestinal tract neoplasms [6], [7]. Recent data have shown that some bacterial species produce tumor-promoting metabolites such as secondary bile acids, which potentiate the development and progression of gastrointestinal tract neoplasms, whereas other species produce short-chain fatty acids (SCFAs) such as butyrate, which can suppress inflammation and carcinogenesis in the gastrointestinal tract [8], [9].
Here, we review clinical studies on intestinal bacteria in relation to gastrointestinal tract cancers, including esophageal, gastric, and colorectal cancers. In addition, we describe emerging evidence for roles of intestinal bacteria in the efficacy of cancer chemotherapies and novel targeted immunotherapies such as anti-CTLA4 and anti-CD274 therapies, the process of absorption, and the occurrence of complications after gastrointestinal surgery.
Section snippets
Bacterial genotoxins
Intestinal bacteria have been shown to potentiate carcinogenesis through specific toxins that induce DNA damage. Colibactin is encoded by the polyketide synthase island, which is expressed by Escherichia coli from phylogroup B2, and has been shown to induce DNA damage, affect genomic instability [10], [11], and promote colon carcinogenesis in Il10−/− mice [12], [13].
Enterococcus faecalis has been shown to produce extracellular superoxide that induces DNA damage and genomic instability in
Esophageal cancer
Esophageal carcinoma consists of two main histological types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC constitutes the large majority of esophageal cancer cases worldwide and more than 90% of the cases in high-risk areas, such as China, Iran, and Japan [1]. EAC is one of the most rapidly increasing cancers in the United States [84]. Clinical studies have suggested associations of specific bacteria and bacterial dysbiosis (the condition of having
Gut microbiota, chemotherapy, and immunotherapy
Emerging data demonstrate that intestinal bacteria can modulate the efficacy of cancer chemotherapies. Colorectal cancers with unresectable distant metastases are treated with chemotherapy regimens that are based on oxaliplatin and irinotecan combined with molecularly targeted therapies such as a humanized monoclonal antibody against VEGFA (bevacizumab) and anti-EGFR antibodies (cetuximab or panitumumab) [134]. ROS are important for DNA damage and apoptosis in response to oxaliplatin [135]. The
Gut microbiota and surgery for gastrointestinal tract cancers
Surgery for gastrointestinal tract cancers and intestinal reconstructions has been shown to influence the composition of the gut microbiota. Patients after Roux-en-Y gastric bypass (RYGB) are at increased risk of malabsorption, trace element deficiency, and dumping syndrome [154]. In a mouse model of RYGB, the amount of Bacteroidetes, Verrucomicrobia, and Proteobacteria in stool increased, and transfer of the gut microbiota from RYGB-treated mice to non-operated, germ-free mice resulted in
Future directions
Accumulating evidence indicates that intestinal bacteria can influence the tumor development and progression in the gastrointestinal tract. Considering that diet, lifestyle, pharmacological factors (including antibiotics), and probiotics and prebiotics can influence the composition of the intestinal microbiota, future investigations may be warranted to examine the potential influences of these modifiable factors on the intestinal microflora and tumorigenic processes.
The main cause of
Funding
This work was supported by grants from the U.S. National Institutes of Health (NIH) [R35 CA197735 to S.O.] and the Nodal Award (to S.O.) of the Dana-Farber/Harvard Cancer Center. K.M. is supported by grants from the Takeda Science Foundation, Kanae Foundation for the Promotion of Medical Science, YOKOYAMA Foundation for Clinical Pharmacology, and JSPS KAKENHI Grant Number 17H05094. The content is solely the responsibility of the authors and does not necessarily represent the official views of
Author contributions
Kosuke Mima and Shuji Ogino contributed equally as co-first authors. All authors contributed to review and revision. Kosuke Mima, Shuji Ogino, Yoichi Yamashita, Naoya Yoshida, Akira Chikamoto, Takatoshi Ishiko, and Hideo Baba developed the main concept and designed the study. Kosuke Mima, Shuji Ogino, and Hideo Baba wrote grant applications. Kosuke Mima and Shuji Ogino drafted the manuscript. Shigeki Nakagawa, Hiroshi Sawayama, Koichi Kinoshita, Ryuichi Krashima, Takatsugu Ishimoto, Katsunori
Potential competing interests
All authors declare that they have no competing financial interests.
Use of standardized official symbols
We use HUGO (Human Genome Organisation)-approved official symbols for genes and gene products, including AKT, BRAF, CCL20, CD274, CDH1, CTLA4, EGFR, IL6, IL10, IL17, IL18, IL22, IL23, MAPK, MMP9, NFKB, PDCD1, PIK3CA, PTGS2, STAT3, TLR2, TLR4, TP53, VEGFA, and WNT; all are described at www.genenames.org.
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2020, Food BioscienceCitation Excerpt :The microbiome of the human gastrointestinal (GI) tract (T) consists of >~100 million microorganisms known as gut microflora/microbiota. The ecosystem of this bacterial, fungal, and viral population can produce a large number of bio-functional compounds like lactic acid, short-chain fatty acids (SCFA), linolic acid, vitamins, and some peptides influencing their ecosystem and the host (Mima et al., 2017; Qamar et al., 2017; Sivaprakasam et al., 2017; Tlaskalova-Hogenova et al., 2011). Among these products, SCFA produced by anaerobic fermentation of indigestible fiber (as prebiotics) by the gut bacterium and have various roles in cancer prevalence and influences the immune system (Dahl et al., 2017; Esgalhado et al., 2017).
Postbiotics in colorectal cancer: intervention mechanisms and perspectives
2024, Frontiers in Microbiology
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K.M. and S.O. contributed equally.