Chronic inflammation is increasingly recognized as a major contributor of human colorectal cancer (CRC). While gut microbiota can trigger inflammation in the intestinal tract, the precise signaling pathways through which host cells respond to inflammatory bacterial stimulation are unclear. Here, we show that gut microbiota enhances intestinal tumor load in the APC(Min/+) mouse model of CRC. Furthermore, systemic anemia occurs coincident with rapid tumor growth, suggesting a role for intestinal barrier damage and erythropoiesis-stimulating mitogens. Short-term stimulation assays of murine colonic tumor cells reveal that lipopolysaccharide, a microbial cell wall component, can accelerate cell growth via a c-Jun/JNK activation pathway. Colonic tumors are also infiltrated by CD11b+ myeloid cells expressing high levels of phospho-STAT3 (p-Tyr705). Our results implicate the role of gut microbiota, through triggering the c-Jun/JNK and STAT3 signaling pathways in combination with anemia, in the acceleration of tumor growth in APC(Min/+) mice.

The present gold standard for bladder cancer is Mycobacterium bovis, Bacillus Calmette Guerin (BCG) immunotherapy. But it has a non-responder rate of 30-50% and side effects are common. Lactobacillus casei strain Shirota has been reported to reduce the incidence of recurrence in bladder cancer patients and to cure tumor-bearing mice. Our aim was to determine if Lactobacillus rhamnosus GG (LGG) could be as efficacious as BCG in a murine model of bladder cancer. MB49 bladder cancer cells secreting human prostate-specific antigen were implanted orthotopically in female C57BL ⁄ 6 mice and urinary prostate-specific antigen levels were used as a marker of tumor growth. Mice were treated with either live or lyophilized LGG given via intravesical instillation, or both oral and intravesical LGG given once a week for a period of 6 weeks starting at day 4 after tumor implantation. A comparison of LGG and BCG immunotherapy was also carried out. LGG therapy (live or lyophilized) significantly (P = 0.006) increased the number of cured mice. Cytokine arrays and immune cell recruitment analysis revealed differences between untreated, treated, cured, and tumor-bearing mice.LGG therapy restored XCL1 levels to those in healthy bladders.LGG also recruited large numbers of neutrophils and macrophages to the tumor site. Intravesical LGG and BCG immunotherapy had cure rates of 89 and 77%, respectively, compared with 20% in untreated mice.LGG has the potential to replace BCG immunotherapy for the treatment of bladder cancer. (Cancer Sci 2010; 101: 751-758)

Helicobacter pylori, is an invariably commensal resident of the gut microbiome associated with gastric ulcer in adults. In addition, these patients also suffered from a low grade inflammation that activates the immune system and thus increased shunting of energy to host defense mechanisms. To assess whether a H. pylori infection could affect growth in early life, we determined the expression levels of selected metabolic gut hormones in germ free (GF) and specific pathogen-free (SPF) mice with and without the presence of H. pylori. Despite H. pylori-infected (SPFH) mice display alteration in host metabolism (elevated levels of leptin, insulin and peptide YY) compared to non-infected SPF mice, their growth curves remained the same. SPFH mice also displayed increased level of eotaxin-1. Interestingly, GF mice infected with H. pylori (GFH) also displayed increased levels of ghrelin and PYY. However, in contrast to SPFH mice, GFH showed reduced weight gain and malnutrition. These preliminary findings show that exposure to H. pylori alters host metabolism early in life; but the commensal microbiota in SPF mice can attenuate the growth retarding effect from H. pylori observed in GF mice. Further investigations of possible additional side effects of H. pylori are highly warranted.

Lactobacillus species induced cytotoxic effects in bladder cancer cells. Unlike BCG, it requires bacterial protein synthesis. Like BCG, L. casei Shirota induces cell death primarily via necrosis. The cytoxicity of these lactobacilli in bladder cancer cells raises the possibility of using this species of bacteria as intravesical agents for treating bladder cancer.

Summary Mycobacterium bovis, bacillus Calmette–Guérin (BCG) is the current gold standard for bladder cancer therapy. In this study a profile of the gene expression changes that occur after BCG instillation in the bladders of healthy mice was produced and compared to the type of immune cells recruited into the bladder. A similar comparison was made for Lactobacillus rhamnosus strain GG (LGG) instillations in healthy mice to determine its potential in the immunotherapy of bladder cancer. Mice were given six weekly instillations and were killed after the fourth, fifth and sixth instillations of BCG or LGG. Their bladders were harvested for chemokine/cytokine messenger RNA analysis using an array as well as semi‐quantitative reverse transcription–polymerase chain reaction. In a second set of mice both the bladder and draining lymph nodes were harvested for the analysis of immune cells. BCG significantly upregulated genes for T helper type 1 (Th1) chemokines: Cxcl2, Cxcl9, Cxcl10, Xcl1; and increased the expression of Th1/Th2 chemokines: RANTES, Ccl6 and Ccl7; Th1 polarizing cytokines: Il1β and Tnfa; and Fcγr1 and iNOS as early as after four weekly instillations. Most of these genes remained highly expressed after 6 weeks. In contrast, LGG transiently induced Cxcl10, Il16, Fcεr1 and Il1r2. Despite these findings, LGG instillation induced the recruitment of natural killer cells into the bladder and draining lymph nodes, as was observed for BCG instillation.