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Gut microbiota and colorectal cancer

Gut microbiota and colorectal cancer The mucosal immune system is unique to the gastrointestinal mucosa, in which a large number of immune cells are located and exert multiple functions. Meanwhile, ~100 trillion microorganisms are thought to co-inhabit in the gastrointestinal tract. Furthermore, immune cells and gut microbiota have a mutual influence and the maintenance of this symbiotic relationship results in gut homeostasis. A recent study suggested that a disturbance of gut microbiota—so called “dysbiosis”—is related to various diseases, such as inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). In this review, we discuss the relationship between gut microbiota and the mucosal immune system with regard to the development of IBD and CAC. In addition, we elucidate the possibility of probiotics in treatment against these diseases. Keywords: Gut microbiota, Colorectal cancer, Colitis-associated cancer, Mucosal immune system, Dysbiosis Background inflammation. Furthermore regarding the onset of in- The mammalian gastrointestinal tract, where digestion flammatory bowel disease (IBD) and colitis-associated and absorption occurs, acts as the frontline of defense cancer (CAC), the interaction between the mucosal im- against microorganisms from the environment. There- mune system and gut microbiota is important, because fore there is an established unique immune surveillance in germfree animal models of these diseases, no symp- system called the mucosal immune system. It is sup- toms are observed [4, 5]. In this review, we discuss the posed that a half of immunocompetent cells reside in roles of gut microbiota and the mucosal immune system the gut mucosa, and the balance between them with a on the development of IBD and CAC. variety of properties, including T helper 17 (Th17) cells and regulatory T (T ) cells, is thought to be controlled reg Review exquisitely. Characteristics of the mucosal immune sys- Gut microbiota in IBD tem are represented by their contrasted immune func- IBD is categorized into Crohn’s disease (CD) and ulcera- tions, such as the removal of pathogens and immune tive colitis (UC) based on pathophysiological characteris- unresponsiveness to the food antigens and indigenous tics. UC is an inflammatory disease confined to the gut microbiota. Increasing evidence suggests that the gut colonic mucosa, whereas CD has the potential to de- microbiota also plays key roles in homeostatic mainten- velop along the entire gastrointestinal tract with a higher ance of the mucosal immune system. Imbalance of gut occurrence in the small and large intestines. Because microbiota, so called “dysbiosis”, based on dysregulation both diseases exhibit repeated remission and relapse, it of the mucosal immune system affects the development is important that we urgently improve the quality of life and pathogenesis of various diseases such as allergy, dia- of patients with IBD. In accordance with the develop- betes, autoimmune diseases and cancer [1, 2]. In ment of an analytical method, based on bacterial 16S addition, a recent finding has suggested that when feces rDNA and next generation sequencing (NGS), the char- of healthy adults were intra-rectally inoculated into pa- acteristics of gut microbiota in patients with IBD are tients with recurrent Clostridium difficile infection, the rapidly being elucidated. A loss of bacterial diversity and symptoms improved in association with the recovery dysbiosis is present in the gut microbiota of patients from dysbiosis [3], which would be a clear example of with IBD, as commonly detected using NGS. In particu- gut microbiota contributing to restraint of colonic lar, there is a marked decrease in the occupancy of Fir- micutes and Bacteroidetes in gut microbiota, which * Correspondence: mayuko-yamamoto@yakult.co.jp Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan normally predominates in a healthy adult. It has been © 2016 Yamamoto and Matsumoto. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yamamoto and Matsumoto Genes and Environment (2016) 38:11 Page 2 of 7 reported that 46 strains of Clostridium derived from mechanisms underlying the pathogenesis of CAC are mice and 17 strains of Clostridium derived from humans unclear and do not follow the adenoma-carcinoma induced differentiation of Foxp3 T cells, resulting in sequence [13]. It is urgent to clarify the mechanism reg mass production of IL-10, via augmentation of TGF-β underlying development of CAC, because ~20 % of provided by colonic epithelial cells [6, 7]. It was then patients with chronic inflammation in the form of UC demonstrated that Clostridium butyricum when used as develop CAC within 30 years from the onset, with at a probiotic, could induce IL-10 production from macro- least half of the cases resulting in death. A recent study phages in colonic mucosa, which resulted in suppression demonstrated that dysbiosis of gut micobiota plays a key of acute colitis in mice [8]. It has been discussed that bu- role in the pathophysiology of CAC. Bacterial diversity is tyrate participated in suppression of colitis and colorec- remarkably decreased in gut microbiota of sporadic tal cancer. The bacterial metabolite, butyrate, induces colorectal cancer and CAC mice models. When gnoto- the differentiation of colonic Foxp3 T cells and ame- biotic mice are colonized with feces taken from sporadic reg liorates the development of colitis. A possible mechan- colorectal cancer or CAC mice, the incidence and num- ism for this regulation of differentiation may be that ber of tumors are increased in both cases, compared butyrate enhances histone H3 acetylation in the pro- with those colonized with feces of healthy mice. CAC moter and conserved, non-coding sequence regions of can be experimentally induced in rodent models by the the Foxp3 locus [9]. Because the occupancy of Clostrid- combination of introduction to azoxymethane (AOM) ium clusters IV and XIVa, in which numerous butyrate- and repeated exposure to the inflammatory agent DSS. producing bacteria exist, have been shown to be de- Results from time-course analysis of the composition of creased in the gut microbiota of patients with IBD, it gut microbiota during development of CAC in this would be expected that clinical applications of these re- model indicated tumor-bearing mice showed enrichment sults would follow. in operational taxonomic units (OTUs) affiliated with With regard to the interaction of the mucosal immune members of the Bacteroides, Odoribacter,and Allobaculum system and gut microbiota, secretory immunoglobulin A genera and decreases in OTUs affiliated with members of (IgA) is important. The presence of secretory IgA in the the Prevotellaceae and Porphyromonadaceae families. intestinal lumen is indispensable for the exclusion of Furthermore, conventionalization (colonization of germ- pathogenic germs and neutralization of toxins. Germ- free mice with gut microbiota) with tumor-bearing mice free mice have few IgA-producing cells in their intestinal significantly increased colon tumorigenesis compared mucosa. Total bacterial numbers increase markedly in to those colonized with feces of healthy mice [14]. the mice deleted activation induced cytidine deaminase However, mice exposed to the chemical mutagen do (AID) gene, which is normally essential for somatic not develop tumors if they receive antibiotics and mice hypermutation and class switch recombination during that received feces of tumor-bearing mice do not de- IgA gene rearrangement. IgA produced in inhibitory re- velop tumors if they are not exposed to the mutagen. ceptor of immune system (programmed cell death-1 These findings suggest that gut microbiota plays a part (PD-1)) gene-deficient mice had a low affinity for bac- in the initiation of colorectal cancer. CAC results from teria, which caused alterations of microbial communities the complex relationship between chronic inflamma- in the gut [10]. In addition, it has been recently reported tion and dysbiosis of gut microbiota, which would that some gut microbiota was coated with IgA, and IgA- induce irreversible changes to intestinal epithelial cells. coated fecal bacteria taken from patients with IBD exac- Bacteroides fragilis toxin, produced by enterotoxigenic erbated dextran sulfate sodium (DSS)-induced colitis in B. fragilis (ETBF), triggers colorectal cancer by binding gnotobiotic mice [11]. to colonic epithelial cells and stimulating cleavage of the cell adhesion molecule E-cadherin, which act as the Gut microbiota in colorectal cancer tumor suppressor protein [15]. Antibody-mediated Colorectal cancer is one of the most common fatal ma- blockade of interleukin-17 (IL-17), a key cytokine for lignancies in the world. The involvement of gut micro- proinflammatory responses, inhibits ETBF-induced col- biota in the development of colorectal cancer has been itis and tumor formation [16]. Gut microbiota of IL-10 noted for some time. IL-10-deficient mice and TCRβ/ deficient mice developing spontaneously severe colitis p53 double knockout mice do not develop colorectal have decreases in bacterial diversity and increases in cancer under germfree environment, providing a ration- theoccupancyof Enterobacteriaceae [17]. IL-10 defi- ale for the association between colorectal cancer and gut cient mice colonized with either Escherichia coli microbiota [12]. Chronic inflammation is known to pre- (E. coli)or Enterococcus faecalis develop colon inflam- dispose an individual to cancer, and as such, the mation, but only the mice receiving E. coli developed presence of IBD increases the risk of colorectal cancer. colon tumors. Moreover, it was reported that Colibactin, Another such example would be CAC. The molecular the product of polyketide synthase (pks) in E. coli NC101, Yamamoto and Matsumoto Genes and Environment (2016) 38:11 Page 3 of 7 cleaved double stranded DNA in colonic epithelial cells extracellular domain of membrane-bound IL-6Rα,or by and promoted invasive carcinoma in AOM-treated IL- the differential splicing of IL-6Rα mRNA. IL-6 shows an 10deficient mice [18]. Because the expression of the affinity to sIL-6Rs, forming the IL-6/sIL-6Rα complex ETBF toxin gene and pks gene of E. coli NC101 is that can interact with gp130 and induce IL-6 signal higher in patients with colorectal cancer when com- transduction, termed IL-6 trans-signaling. IL-6 trans- pared to healthy adults, aberrant proliferation of these signaling can transmit the IL-6 signal in the cells that bacteria caused by dysbiosis of gut microbiota would express only gp130 and promote an inflammatory re- induce disruption of epithelial barrier function and sponse through phosphorylation of Stat3. Because the contribute to the mechanism of CAC development. expression of gp130 is ubiquitous, there is a non-specific However, thereissomeuncertainty,because themurine enhancement of IL-6 trans-signaling is thought to be an AOM/DSS model administered microbes from patients enhancer of canonical IL-6 signal pathway. The import- with colorectal cancer developed unexpectedly fewer ance of IL-6 trans-signaling in the etiology of several tumors than those that received bacteria from healthy chronic inflammations, such as asthma, colitis, and human donors [19]. Therefore, we would need to valid- rheumatoid arthritis, has been well documented [22–24]. ate the evidence, accumulated by studies using animal We previously revealed that the activation of IL-6/Stat3 models of colorectal cancer, in human. Furthermore, it pathway via IL-6 trans-signaling plays a crucial role in has also been revealed that the role of gut microbiota in the development of ileitis in SAMP1/Yit mice and mur- cancer extended to treatment, influencing not only the ine CAC models [25]. We induced CAC in BALB/c mice effectiveness of chemotherapy but also its side effects. by administering 9 cycles of treatment with 4–5 % DSS Both germfree mice and antibiotic-treated mice show in drinking water for 7 days and normal drinking water cyclophosphamide resistance and in these mice, patho- for 7 days. CAC was microscopically observed in >60– genic Th17 cells are shown to be decreased [20]. Taken 80 % of mice after DSS treatment. Histologically, we ob- together, it is likely that modulating the gut microbiota served the proliferation of gland epithelial cells, resulting will become an effective tool to combat colorectal in the formation of a polypoid mass (Fig. 2a). Our hy- cancer. pothesis of the association between IL-6 trans-signaling and inflammation-based colon tumorigenesis is shown CAC and IL-6/Stat3 pathway in Fig. 1. IL-6 trans-signaling triggered in LP inputs its The mucosal activation of the IL-6/signal transducer and downstream signal into intestinal epithelial cells (IECs) activator of transcription 3 (Stat3) pathway is important and induces the expression of anti-apoptotic gene and for the pathogenesis of IBD and CAC. The inflammatory AID and the production of reactive oxygen species cytokine IL-6 shows multiple functions and modulates (ROS), which leads to the inhibition of cell death, gen- various physiological and immune responses. IL-6 exerts etic instability and DNA damage. Mice which are defi- its biological action by binding to two types of mem- cient in both IL-10 and AID do not develop colon brane receptors, specifically the IL-6 receptor alpha sub- cancer, whereas IL-10-deficient mice develop spontan- unit (IL-6Rα) and gp130. IL-6 binds to IL-6Rα at the cell eous colon cancers [26]. Aberrant AID expression in the membrane of target cells and this complex in turn asso- inflamed colonic mucosa plays an integral role during ciates with gp130, inducing signal transduction via phos- the development of CAC via accumulation of genetic ab- phorylation of Stat3. IL-6Rα is expressed on specific errations. Therefore it is speculated that long-term accu- cells, such as neutrophils, macrophages, hepatocytes, mulation of IL-6 trans-signaling finally leads to colon and several lymphocyte subsets, whereas gp130 is tumorigenesis. Interestingly, the expression of IL-6, expressed on the cell surface of various cell types. TACE and phospho-Stat3 in CAC mucosa was higher Through this mechanism, the canonical IL-6 signal can than those in the colitis mucosa (Fig. 2b). Soluble transmit their signal to limited cells, which express the gp130Fc (sgp130Fc) is a dimerized fusion protein of IL-6Rα. Suppressor of cytokine signaling 3 (SOCS3) is gp130 that competitively suppresses the activation of IL- IL-6/Stat3 responsive protein which inhibits phosphoryl- 6 trans-signaling by preventing the interaction between ation of Stat3 by binding to Janus kinase (JAK) and gp130 and the IL-6/sIL-6Rα complex. Treatment of negatively regulates IL-6-induced signaling. In patients DSS-induced CAC model with sgp130Fc suppressed the with CD and in murine models of CD (SAMP1/Yit), expression of phospho-Stat3 and the incidence and expression of IL-6 and SOCS3 in the gut is enhanced number of tumors were reduced, compared with and Stat3 is excessively phosphorylated [21]. It was also vehicle-treated mice (Fig. 2c). Consequently, it was reported that there is an increase in the serum levels of revealed that the activation of IL-6 trans-signaling in soluble form of IL-6Rα (sIL-6Rα) under inflammatory colonic mucosa was essential for triggering CAC. In our conditions. sIL-6Rα is produced either by TNFα convert- previous study, we indicated that the main source ing enzyme (TACE), which proteolytically cleaves supplying IL-6 in the development of CAC was Yamamoto and Matsumoto Genes and Environment (2016) 38:11 Page 4 of 7 Fig. 1 Representative scheme of how IL-6 trans-signaling modulates inflammation-based colorectal tumorigenesis. Under inflammatory conditions, sIL-6Rα is generated from LPDCs by TACE, which proteolytically cleaves the extracellular domain of membrane-bound IL-6Rα. Gut microbiota had a key role on the activation of TACE. IL-6 is also produced by macrophages (Mϕs) and DCs in LP and binds to sIL-6Rα. The IL-6/ sIL-6Rα complex can associate with gp130 and induces IL-6 signal transduction through the phosphorylation of Stat3, termed IL-6 trans-signaling. IL-6 trans-signaling triggered in LP inputs its downstream signal into intestinal epithelial cells (IECs) and induces the expression of anti-apoptotic gene and AID and the production of reactive oxygen species (ROS), which leads to the inhibition of cell death, genetic instability and DNA damage. It is speculated that long-term accumulation of IL-6 trans-signaling finally leads to colon tumorigenesis macrophages and dendritic cells (DCs) located in colonic been performed in Japan and overseas, the clinical lamina propria (LP). Moreover, it became clear that a effects are dependent on the probiotic strain and the distinct subpopulation of LPDCs was the main sources schedule of probiotic administration. In the trial for the of sIL-6Rα. LP macrophages, purified from mice with patients with mildly to moderately active UC received ongoing chronic colitis, actively cleaved sIL-6Rα into the one of the probiotic Lactobacillus strains, Lactobacillus culture supernatant after stimulation with heat-killed casei strain Shirota (LcS), daily for 8 weeks, significantly commensal bacteria ex vivo. However the presence of a better clinical activity index scores were seen after LcS TACE inhibitor markedly reduced this cleavage. This treatment compared with pre-treatment and control result indicates that gut microbiota participated in the group values [27]. In the trial for people at high-risk of production of sIL-6Rα in colonic LP macrophage developing colorectal cancer, they were administered through TACE activation. Interestingly, the expression of wheat bran, LcS, both or neither. Incidence of tumors membrane-bound IL-6Rα was markedly decreased in with a grade of moderate or high atypia was significantly epithelial cells of chronic colitis and CAC. In contrast, lower in the group administered LcS than the other the expression of gp130 was significantly increased in groups. No significant difference in the development of epithelial cells of CAC. Therefore epithelial cells of new colorectal tumors was observed with administration chronic colitis and CAC are thought to be in a state of either wheat bran or LcS [28]. After 1 year of treat- more suitable for the receiving of IL-6 trans-signaling ment with Bifidobacterium breve strain Yakult and than the canonical IL-6 signal pathway. galacto-oligosaccharides symbiotics, the clinical status was significantly improved, and the amount of myeloper- Probiotics as prevention for IBD/CAC oxidase in the lavage, the number of Bacteroidaceae in Reverting the disturbances of gut microbiota in patients feces and fecal pH was reduced in the patients with mild with IBD and CAC, as previously mentioned, should be- to moderate UC [29]. We had reported previously that come the new strategy for treatment. Although several LcS has the protective efficacy against CAC [30]. LcS clinical trials using probiotics for patients with IBD have suppressed the development of CAC by suppressing Yamamoto and Matsumoto Genes and Environment (2016) 38:11 Page 5 of 7 Fig. 2 (See legend on next page.) Yamamoto and Matsumoto Genes and Environment (2016) 38:11 Page 6 of 7 (See figure on previous page.) Fig. 2 Characteristics of a murine model of CAC and the possibility of probiotic treatment in the prevention of CAC. A-left, Stereomicroscopic observation of a murine model of DSS-induced CAC. CAC was induced in BALB/c mice by nine cycles of treatment with 4–5 % DSS in drinking water for 7 days and normal drinking water for 7 days. The arrow indicates CAC. a-right, Histology of CAC. CAC tissue was fixed and stained with H&E. B-left, Expression of IL-6 and SOCS3 mRNA. Total RNA was isolated from colon tissues of chronic colitis or CAC mice. Quantitative RT-PCR was performed using specific primer sets. The data are represented as the mean ± SD (n = 10). b-right, Expression of phosphorylated transcription factors in the mucosa of colitis or CAC mucosa. Colonic tissue homogenates were subjected to Western blotting with polyclonal antibodies against phospho-Stat3, phospho-SHP-2, phospho-Stat1, phospho-NFκB and phospho-38MAPK. C-left, Incidence of CAC. During the induction of CAC, sgp130Fc (500 or 50 μg/mouse) or vehicle was injected i.p. into BALB/c mice on the first day of each 6–9 DSS cycle (n = 10). c-right, Western blot analysis of phospho-Stat3, phospho-NFκB, TACE, phospho-38MAPK and β-catenin in colonic tissue of sgp130Fc- or vehicle- treated mice. D- ΔPS-PG1 left, Incidence and number of CAC. During CAC induction, the mice were treated with LcS, PS-PG1-deficient LcS (LC ) or Saline orally (5 days ΔPS-PG1 per week). d-right, Quantitative RT-PCR analysis of IL-6 and SOCS3 mRNA in colonic tissues in CAC-induced mice treated with LcS, LC ,or ΔP-SPG1 PBS. *;p < 0.05, **;p < 0.01, a;p < 0.05, aa;p < 0.01 LcS versus Ct, c;p < 0.05, cc;p < 0.01 LcS versus LC IL-6 trans-signaling in a murine CAC model, whereas GOS: galacto-oligosaccharide; IBD: inflammatory bowel disease; IEC: intestinal epithelial cell; JAK: Janus kinase; LcS: Lactobacillus casei strain Shirota; polysaccharide-peptidoglycan complex 1 (PS-PG1) defi- LP: lamina propria; OTU: operational taxonomic units; PD-1: programmed cell cient LcS strain had no effect on the prevention of CAC death-1; pks: polyketide synthase; PS-PG1: polysaccharide-peptidoglycan (Fig. 2d). It was also revealed that this effect of LcS was complex 1; SOCS3: suppressor of cytokine signaling 3; Stat3: signal transducer and activator of transcription 3; TACE: TNFα converting enzyme; accompanied with improvement of dysbiosis of gut TLR: Toll-like receptor; UC: ulcerative colitis. microbiota. As recently reported, transplant of fecal microbiota from healthy individuals is effective in treat- Competing interests ment. However transplant of feces requires considered The authors declare that they have no competing interests. attention in patients with benign disorders, such as IBD, Authors’ contributions because there is a possibility of accidental contamination Both authors made an equal contribution in preparation of manuscript. Both with unknown infectious diseases. By avoiding this, pro- authors read and approved the final manuscript. biotics have guaranteed safeguards against such events. Therefore amelioration of dysbiosis by using probiotics Acknowledgement We would like to thank Dr Stefan Rose-John and Dr Keiichi Mitsuyama for could be a potent tool implemented as a new medical their valuable support on this manuscript. treatment for these diseases as well as their prevention. Received: 21 January 2016 Accepted: 29 March 2016 Conclusion Gastrointestinal mucosa has a unique immune system, in References which many immune cells reside and exert multiple func- 1. Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013;13(11):800–12. tions. Those immune cells and gut microbiota have a mu- 2. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and tual influence on immune response. Recent studies disease. 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IL-6 is required for the development of Th1 cell-mediated murine colitis. J Immunol. and we will help you at every step: 2000;164(9):4878–82. 25. Matsumoto S, Hara T, Mitsuyama K, Yamamoto M, Tsuruta O, Sata M, • We accept pre-submission inquiries Scheller J, Rose-John S, Kado S, Takada T. Essential roles of IL-6 trans- � Our selector tool helps you to find the most relevant journal signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor � We provide round the clock customer support derived from lamina propria macrophages, on the development of colitis- associated premalignant cancer in a murine model. J Immunol. � Convenient online submission 2010;184:1543–51. � Thorough peer review 26. Takai A, Marusawa H, Minaki Y, Watanabe T, Nakase H, Kinoshita K, � Inclusion in PubMed and all major indexing services Tsujimoto G, Chiba T. 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Gut microbiota and colorectal cancer

Genes and Environment , Volume 38 (1) – Jun 1, 2016

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Springer Journals
Copyright
Copyright © 2016 by The Author(s)
Subject
Biomedicine; Human Genetics
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1880-7062
DOI
10.1186/s41021-016-0038-8
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27350830
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Abstract

The mucosal immune system is unique to the gastrointestinal mucosa, in which a large number of immune cells are located and exert multiple functions. Meanwhile, ~100 trillion microorganisms are thought to co-inhabit in the gastrointestinal tract. Furthermore, immune cells and gut microbiota have a mutual influence and the maintenance of this symbiotic relationship results in gut homeostasis. A recent study suggested that a disturbance of gut microbiota—so called “dysbiosis”—is related to various diseases, such as inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). In this review, we discuss the relationship between gut microbiota and the mucosal immune system with regard to the development of IBD and CAC. In addition, we elucidate the possibility of probiotics in treatment against these diseases. Keywords: Gut microbiota, Colorectal cancer, Colitis-associated cancer, Mucosal immune system, Dysbiosis Background inflammation. Furthermore regarding the onset of in- The mammalian gastrointestinal tract, where digestion flammatory bowel disease (IBD) and colitis-associated and absorption occurs, acts as the frontline of defense cancer (CAC), the interaction between the mucosal im- against microorganisms from the environment. There- mune system and gut microbiota is important, because fore there is an established unique immune surveillance in germfree animal models of these diseases, no symp- system called the mucosal immune system. It is sup- toms are observed [4, 5]. In this review, we discuss the posed that a half of immunocompetent cells reside in roles of gut microbiota and the mucosal immune system the gut mucosa, and the balance between them with a on the development of IBD and CAC. variety of properties, including T helper 17 (Th17) cells and regulatory T (T ) cells, is thought to be controlled reg Review exquisitely. Characteristics of the mucosal immune sys- Gut microbiota in IBD tem are represented by their contrasted immune func- IBD is categorized into Crohn’s disease (CD) and ulcera- tions, such as the removal of pathogens and immune tive colitis (UC) based on pathophysiological characteris- unresponsiveness to the food antigens and indigenous tics. UC is an inflammatory disease confined to the gut microbiota. Increasing evidence suggests that the gut colonic mucosa, whereas CD has the potential to de- microbiota also plays key roles in homeostatic mainten- velop along the entire gastrointestinal tract with a higher ance of the mucosal immune system. Imbalance of gut occurrence in the small and large intestines. Because microbiota, so called “dysbiosis”, based on dysregulation both diseases exhibit repeated remission and relapse, it of the mucosal immune system affects the development is important that we urgently improve the quality of life and pathogenesis of various diseases such as allergy, dia- of patients with IBD. In accordance with the develop- betes, autoimmune diseases and cancer [1, 2]. In ment of an analytical method, based on bacterial 16S addition, a recent finding has suggested that when feces rDNA and next generation sequencing (NGS), the char- of healthy adults were intra-rectally inoculated into pa- acteristics of gut microbiota in patients with IBD are tients with recurrent Clostridium difficile infection, the rapidly being elucidated. A loss of bacterial diversity and symptoms improved in association with the recovery dysbiosis is present in the gut microbiota of patients from dysbiosis [3], which would be a clear example of with IBD, as commonly detected using NGS. In particu- gut microbiota contributing to restraint of colonic lar, there is a marked decrease in the occupancy of Fir- micutes and Bacteroidetes in gut microbiota, which * Correspondence: mayuko-yamamoto@yakult.co.jp Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo 186-8650, Japan normally predominates in a healthy adult. It has been © 2016 Yamamoto and Matsumoto. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yamamoto and Matsumoto Genes and Environment (2016) 38:11 Page 2 of 7 reported that 46 strains of Clostridium derived from mechanisms underlying the pathogenesis of CAC are mice and 17 strains of Clostridium derived from humans unclear and do not follow the adenoma-carcinoma induced differentiation of Foxp3 T cells, resulting in sequence [13]. It is urgent to clarify the mechanism reg mass production of IL-10, via augmentation of TGF-β underlying development of CAC, because ~20 % of provided by colonic epithelial cells [6, 7]. It was then patients with chronic inflammation in the form of UC demonstrated that Clostridium butyricum when used as develop CAC within 30 years from the onset, with at a probiotic, could induce IL-10 production from macro- least half of the cases resulting in death. A recent study phages in colonic mucosa, which resulted in suppression demonstrated that dysbiosis of gut micobiota plays a key of acute colitis in mice [8]. It has been discussed that bu- role in the pathophysiology of CAC. Bacterial diversity is tyrate participated in suppression of colitis and colorec- remarkably decreased in gut microbiota of sporadic tal cancer. The bacterial metabolite, butyrate, induces colorectal cancer and CAC mice models. When gnoto- the differentiation of colonic Foxp3 T cells and ame- biotic mice are colonized with feces taken from sporadic reg liorates the development of colitis. A possible mechan- colorectal cancer or CAC mice, the incidence and num- ism for this regulation of differentiation may be that ber of tumors are increased in both cases, compared butyrate enhances histone H3 acetylation in the pro- with those colonized with feces of healthy mice. CAC moter and conserved, non-coding sequence regions of can be experimentally induced in rodent models by the the Foxp3 locus [9]. Because the occupancy of Clostrid- combination of introduction to azoxymethane (AOM) ium clusters IV and XIVa, in which numerous butyrate- and repeated exposure to the inflammatory agent DSS. producing bacteria exist, have been shown to be de- Results from time-course analysis of the composition of creased in the gut microbiota of patients with IBD, it gut microbiota during development of CAC in this would be expected that clinical applications of these re- model indicated tumor-bearing mice showed enrichment sults would follow. in operational taxonomic units (OTUs) affiliated with With regard to the interaction of the mucosal immune members of the Bacteroides, Odoribacter,and Allobaculum system and gut microbiota, secretory immunoglobulin A genera and decreases in OTUs affiliated with members of (IgA) is important. The presence of secretory IgA in the the Prevotellaceae and Porphyromonadaceae families. intestinal lumen is indispensable for the exclusion of Furthermore, conventionalization (colonization of germ- pathogenic germs and neutralization of toxins. Germ- free mice with gut microbiota) with tumor-bearing mice free mice have few IgA-producing cells in their intestinal significantly increased colon tumorigenesis compared mucosa. Total bacterial numbers increase markedly in to those colonized with feces of healthy mice [14]. the mice deleted activation induced cytidine deaminase However, mice exposed to the chemical mutagen do (AID) gene, which is normally essential for somatic not develop tumors if they receive antibiotics and mice hypermutation and class switch recombination during that received feces of tumor-bearing mice do not de- IgA gene rearrangement. IgA produced in inhibitory re- velop tumors if they are not exposed to the mutagen. ceptor of immune system (programmed cell death-1 These findings suggest that gut microbiota plays a part (PD-1)) gene-deficient mice had a low affinity for bac- in the initiation of colorectal cancer. CAC results from teria, which caused alterations of microbial communities the complex relationship between chronic inflamma- in the gut [10]. In addition, it has been recently reported tion and dysbiosis of gut microbiota, which would that some gut microbiota was coated with IgA, and IgA- induce irreversible changes to intestinal epithelial cells. coated fecal bacteria taken from patients with IBD exac- Bacteroides fragilis toxin, produced by enterotoxigenic erbated dextran sulfate sodium (DSS)-induced colitis in B. fragilis (ETBF), triggers colorectal cancer by binding gnotobiotic mice [11]. to colonic epithelial cells and stimulating cleavage of the cell adhesion molecule E-cadherin, which act as the Gut microbiota in colorectal cancer tumor suppressor protein [15]. Antibody-mediated Colorectal cancer is one of the most common fatal ma- blockade of interleukin-17 (IL-17), a key cytokine for lignancies in the world. The involvement of gut micro- proinflammatory responses, inhibits ETBF-induced col- biota in the development of colorectal cancer has been itis and tumor formation [16]. Gut microbiota of IL-10 noted for some time. IL-10-deficient mice and TCRβ/ deficient mice developing spontaneously severe colitis p53 double knockout mice do not develop colorectal have decreases in bacterial diversity and increases in cancer under germfree environment, providing a ration- theoccupancyof Enterobacteriaceae [17]. IL-10 defi- ale for the association between colorectal cancer and gut cient mice colonized with either Escherichia coli microbiota [12]. Chronic inflammation is known to pre- (E. coli)or Enterococcus faecalis develop colon inflam- dispose an individual to cancer, and as such, the mation, but only the mice receiving E. coli developed presence of IBD increases the risk of colorectal cancer. colon tumors. Moreover, it was reported that Colibactin, Another such example would be CAC. The molecular the product of polyketide synthase (pks) in E. coli NC101, Yamamoto and Matsumoto Genes and Environment (2016) 38:11 Page 3 of 7 cleaved double stranded DNA in colonic epithelial cells extracellular domain of membrane-bound IL-6Rα,or by and promoted invasive carcinoma in AOM-treated IL- the differential splicing of IL-6Rα mRNA. IL-6 shows an 10deficient mice [18]. Because the expression of the affinity to sIL-6Rs, forming the IL-6/sIL-6Rα complex ETBF toxin gene and pks gene of E. coli NC101 is that can interact with gp130 and induce IL-6 signal higher in patients with colorectal cancer when com- transduction, termed IL-6 trans-signaling. IL-6 trans- pared to healthy adults, aberrant proliferation of these signaling can transmit the IL-6 signal in the cells that bacteria caused by dysbiosis of gut microbiota would express only gp130 and promote an inflammatory re- induce disruption of epithelial barrier function and sponse through phosphorylation of Stat3. Because the contribute to the mechanism of CAC development. expression of gp130 is ubiquitous, there is a non-specific However, thereissomeuncertainty,because themurine enhancement of IL-6 trans-signaling is thought to be an AOM/DSS model administered microbes from patients enhancer of canonical IL-6 signal pathway. The import- with colorectal cancer developed unexpectedly fewer ance of IL-6 trans-signaling in the etiology of several tumors than those that received bacteria from healthy chronic inflammations, such as asthma, colitis, and human donors [19]. Therefore, we would need to valid- rheumatoid arthritis, has been well documented [22–24]. ate the evidence, accumulated by studies using animal We previously revealed that the activation of IL-6/Stat3 models of colorectal cancer, in human. Furthermore, it pathway via IL-6 trans-signaling plays a crucial role in has also been revealed that the role of gut microbiota in the development of ileitis in SAMP1/Yit mice and mur- cancer extended to treatment, influencing not only the ine CAC models [25]. We induced CAC in BALB/c mice effectiveness of chemotherapy but also its side effects. by administering 9 cycles of treatment with 4–5 % DSS Both germfree mice and antibiotic-treated mice show in drinking water for 7 days and normal drinking water cyclophosphamide resistance and in these mice, patho- for 7 days. CAC was microscopically observed in >60– genic Th17 cells are shown to be decreased [20]. Taken 80 % of mice after DSS treatment. Histologically, we ob- together, it is likely that modulating the gut microbiota served the proliferation of gland epithelial cells, resulting will become an effective tool to combat colorectal in the formation of a polypoid mass (Fig. 2a). Our hy- cancer. pothesis of the association between IL-6 trans-signaling and inflammation-based colon tumorigenesis is shown CAC and IL-6/Stat3 pathway in Fig. 1. IL-6 trans-signaling triggered in LP inputs its The mucosal activation of the IL-6/signal transducer and downstream signal into intestinal epithelial cells (IECs) activator of transcription 3 (Stat3) pathway is important and induces the expression of anti-apoptotic gene and for the pathogenesis of IBD and CAC. The inflammatory AID and the production of reactive oxygen species cytokine IL-6 shows multiple functions and modulates (ROS), which leads to the inhibition of cell death, gen- various physiological and immune responses. IL-6 exerts etic instability and DNA damage. Mice which are defi- its biological action by binding to two types of mem- cient in both IL-10 and AID do not develop colon brane receptors, specifically the IL-6 receptor alpha sub- cancer, whereas IL-10-deficient mice develop spontan- unit (IL-6Rα) and gp130. IL-6 binds to IL-6Rα at the cell eous colon cancers [26]. Aberrant AID expression in the membrane of target cells and this complex in turn asso- inflamed colonic mucosa plays an integral role during ciates with gp130, inducing signal transduction via phos- the development of CAC via accumulation of genetic ab- phorylation of Stat3. IL-6Rα is expressed on specific errations. Therefore it is speculated that long-term accu- cells, such as neutrophils, macrophages, hepatocytes, mulation of IL-6 trans-signaling finally leads to colon and several lymphocyte subsets, whereas gp130 is tumorigenesis. Interestingly, the expression of IL-6, expressed on the cell surface of various cell types. TACE and phospho-Stat3 in CAC mucosa was higher Through this mechanism, the canonical IL-6 signal can than those in the colitis mucosa (Fig. 2b). Soluble transmit their signal to limited cells, which express the gp130Fc (sgp130Fc) is a dimerized fusion protein of IL-6Rα. Suppressor of cytokine signaling 3 (SOCS3) is gp130 that competitively suppresses the activation of IL- IL-6/Stat3 responsive protein which inhibits phosphoryl- 6 trans-signaling by preventing the interaction between ation of Stat3 by binding to Janus kinase (JAK) and gp130 and the IL-6/sIL-6Rα complex. Treatment of negatively regulates IL-6-induced signaling. In patients DSS-induced CAC model with sgp130Fc suppressed the with CD and in murine models of CD (SAMP1/Yit), expression of phospho-Stat3 and the incidence and expression of IL-6 and SOCS3 in the gut is enhanced number of tumors were reduced, compared with and Stat3 is excessively phosphorylated [21]. It was also vehicle-treated mice (Fig. 2c). Consequently, it was reported that there is an increase in the serum levels of revealed that the activation of IL-6 trans-signaling in soluble form of IL-6Rα (sIL-6Rα) under inflammatory colonic mucosa was essential for triggering CAC. In our conditions. sIL-6Rα is produced either by TNFα convert- previous study, we indicated that the main source ing enzyme (TACE), which proteolytically cleaves supplying IL-6 in the development of CAC was Yamamoto and Matsumoto Genes and Environment (2016) 38:11 Page 4 of 7 Fig. 1 Representative scheme of how IL-6 trans-signaling modulates inflammation-based colorectal tumorigenesis. Under inflammatory conditions, sIL-6Rα is generated from LPDCs by TACE, which proteolytically cleaves the extracellular domain of membrane-bound IL-6Rα. Gut microbiota had a key role on the activation of TACE. IL-6 is also produced by macrophages (Mϕs) and DCs in LP and binds to sIL-6Rα. The IL-6/ sIL-6Rα complex can associate with gp130 and induces IL-6 signal transduction through the phosphorylation of Stat3, termed IL-6 trans-signaling. IL-6 trans-signaling triggered in LP inputs its downstream signal into intestinal epithelial cells (IECs) and induces the expression of anti-apoptotic gene and AID and the production of reactive oxygen species (ROS), which leads to the inhibition of cell death, genetic instability and DNA damage. It is speculated that long-term accumulation of IL-6 trans-signaling finally leads to colon tumorigenesis macrophages and dendritic cells (DCs) located in colonic been performed in Japan and overseas, the clinical lamina propria (LP). Moreover, it became clear that a effects are dependent on the probiotic strain and the distinct subpopulation of LPDCs was the main sources schedule of probiotic administration. In the trial for the of sIL-6Rα. LP macrophages, purified from mice with patients with mildly to moderately active UC received ongoing chronic colitis, actively cleaved sIL-6Rα into the one of the probiotic Lactobacillus strains, Lactobacillus culture supernatant after stimulation with heat-killed casei strain Shirota (LcS), daily for 8 weeks, significantly commensal bacteria ex vivo. However the presence of a better clinical activity index scores were seen after LcS TACE inhibitor markedly reduced this cleavage. This treatment compared with pre-treatment and control result indicates that gut microbiota participated in the group values [27]. In the trial for people at high-risk of production of sIL-6Rα in colonic LP macrophage developing colorectal cancer, they were administered through TACE activation. Interestingly, the expression of wheat bran, LcS, both or neither. Incidence of tumors membrane-bound IL-6Rα was markedly decreased in with a grade of moderate or high atypia was significantly epithelial cells of chronic colitis and CAC. In contrast, lower in the group administered LcS than the other the expression of gp130 was significantly increased in groups. No significant difference in the development of epithelial cells of CAC. Therefore epithelial cells of new colorectal tumors was observed with administration chronic colitis and CAC are thought to be in a state of either wheat bran or LcS [28]. After 1 year of treat- more suitable for the receiving of IL-6 trans-signaling ment with Bifidobacterium breve strain Yakult and than the canonical IL-6 signal pathway. galacto-oligosaccharides symbiotics, the clinical status was significantly improved, and the amount of myeloper- Probiotics as prevention for IBD/CAC oxidase in the lavage, the number of Bacteroidaceae in Reverting the disturbances of gut microbiota in patients feces and fecal pH was reduced in the patients with mild with IBD and CAC, as previously mentioned, should be- to moderate UC [29]. We had reported previously that come the new strategy for treatment. Although several LcS has the protective efficacy against CAC [30]. LcS clinical trials using probiotics for patients with IBD have suppressed the development of CAC by suppressing Yamamoto and Matsumoto Genes and Environment (2016) 38:11 Page 5 of 7 Fig. 2 (See legend on next page.) Yamamoto and Matsumoto Genes and Environment (2016) 38:11 Page 6 of 7 (See figure on previous page.) Fig. 2 Characteristics of a murine model of CAC and the possibility of probiotic treatment in the prevention of CAC. A-left, Stereomicroscopic observation of a murine model of DSS-induced CAC. CAC was induced in BALB/c mice by nine cycles of treatment with 4–5 % DSS in drinking water for 7 days and normal drinking water for 7 days. The arrow indicates CAC. a-right, Histology of CAC. CAC tissue was fixed and stained with H&E. B-left, Expression of IL-6 and SOCS3 mRNA. Total RNA was isolated from colon tissues of chronic colitis or CAC mice. Quantitative RT-PCR was performed using specific primer sets. The data are represented as the mean ± SD (n = 10). b-right, Expression of phosphorylated transcription factors in the mucosa of colitis or CAC mucosa. Colonic tissue homogenates were subjected to Western blotting with polyclonal antibodies against phospho-Stat3, phospho-SHP-2, phospho-Stat1, phospho-NFκB and phospho-38MAPK. C-left, Incidence of CAC. During the induction of CAC, sgp130Fc (500 or 50 μg/mouse) or vehicle was injected i.p. into BALB/c mice on the first day of each 6–9 DSS cycle (n = 10). c-right, Western blot analysis of phospho-Stat3, phospho-NFκB, TACE, phospho-38MAPK and β-catenin in colonic tissue of sgp130Fc- or vehicle- treated mice. D- ΔPS-PG1 left, Incidence and number of CAC. During CAC induction, the mice were treated with LcS, PS-PG1-deficient LcS (LC ) or Saline orally (5 days ΔPS-PG1 per week). d-right, Quantitative RT-PCR analysis of IL-6 and SOCS3 mRNA in colonic tissues in CAC-induced mice treated with LcS, LC ,or ΔP-SPG1 PBS. *;p < 0.05, **;p < 0.01, a;p < 0.05, aa;p < 0.01 LcS versus Ct, c;p < 0.05, cc;p < 0.01 LcS versus LC IL-6 trans-signaling in a murine CAC model, whereas GOS: galacto-oligosaccharide; IBD: inflammatory bowel disease; IEC: intestinal epithelial cell; JAK: Janus kinase; LcS: Lactobacillus casei strain Shirota; polysaccharide-peptidoglycan complex 1 (PS-PG1) defi- LP: lamina propria; OTU: operational taxonomic units; PD-1: programmed cell cient LcS strain had no effect on the prevention of CAC death-1; pks: polyketide synthase; PS-PG1: polysaccharide-peptidoglycan (Fig. 2d). It was also revealed that this effect of LcS was complex 1; SOCS3: suppressor of cytokine signaling 3; Stat3: signal transducer and activator of transcription 3; TACE: TNFα converting enzyme; accompanied with improvement of dysbiosis of gut TLR: Toll-like receptor; UC: ulcerative colitis. microbiota. As recently reported, transplant of fecal microbiota from healthy individuals is effective in treat- Competing interests ment. However transplant of feces requires considered The authors declare that they have no competing interests. attention in patients with benign disorders, such as IBD, Authors’ contributions because there is a possibility of accidental contamination Both authors made an equal contribution in preparation of manuscript. Both with unknown infectious diseases. By avoiding this, pro- authors read and approved the final manuscript. biotics have guaranteed safeguards against such events. Therefore amelioration of dysbiosis by using probiotics Acknowledgement We would like to thank Dr Stefan Rose-John and Dr Keiichi Mitsuyama for could be a potent tool implemented as a new medical their valuable support on this manuscript. treatment for these diseases as well as their prevention. Received: 21 January 2016 Accepted: 29 March 2016 Conclusion Gastrointestinal mucosa has a unique immune system, in References which many immune cells reside and exert multiple func- 1. Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013;13(11):800–12. tions. Those immune cells and gut microbiota have a mu- 2. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and tual influence on immune response. Recent studies disease. 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Published: Jun 1, 2016

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