Gut microbiota and colorectal cancer

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: Colitis-associated cancer; Colorectal cancer; Dysbiosis; Gut microbiota; Mucosal immune system.

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

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-left, Incidence and number of CAC. During CAC induction, the mice were treated with LcS, PS-PG1-deficient LcS (LC^ΔPS-PG1) or Saline orally (5 days 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^ΔPS-PG1, or 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^ΔP-SPG1