Cancer, bacteria, and immunity relationships are much-debated topics in the last decade. Microbiome's importance for metabolic and immunologic modulation of the organism adaptation and responses has become progressively evident, and models to study these relationships, especially about carcinogenesis, have acquired primary importance. The availability of germ-free (GF) animals, i.e., animals born and maintained under completely sterile conditions avoiding the microbiome development offers a unique tool to investigate the role that bacteria can have in carcinogenesis and tumor development. The comparison between GF animals with the conventional (CV) counterpart with microbiome can help to evidence conditions and mechanisms directly involving bacterial activities in the modulation of carcinogenesis processes. Here, we review the literature about spontaneous cancer and cancer modeling in GF animals since the early studies, trying to offer a practical overview on the argument.

• Keywords
• colorectal cancer, germ-free animals, induced tumors, microbiome, spontaneous tumors,
• MeSH
• Bacteria MeSH
• Germ-Free Life * MeSH
• Carcinogenesis MeSH
• Microbiota * MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

The symbiotic relationship between intestinal microbiota and the host is a major mechanism of prevention against the development of chronic and metabolic diseases. The intestinal microbiota provides several physiological functions of the organism from the creation of a natural functional barrier with a subsequent immunostimulatory activity up to affecting the energy metabolism of the host. Disruption of physiological intestinal microbiota is reported as one of the major etiological factors of initiation and progression of colorectal carcinoma (CRC). Chronic low-grade inflammation is associated with the development of CRC, through the production of inflammatory cytokines and reactive oxygen species. CRC occurs in association with high-protein and high-fat diets in combination with low-fiber intake. The problem of intestinal dysbiosis and oncological diseases is a multidisciplinary problem and it is necessary to focus on several fields of medicine such as public health, clinical pharmacology, and internal medicine. The aim of this review is describing the role of gut dysbiosis in pathogenesis of colorectal carcinoma.

• MeSH
• Cytokines immunology   MeSH
• Diet MeSH
• Dysbiosis * MeSH
• Gastrointestinal Tract microbiology   physiopathology   MeSH
• Colorectal Neoplasms microbiology   pathology   MeSH
• Humans MeSH
• Reactive Oxygen Species metabolism   MeSH
• Gastrointestinal Microbiome * MeSH
• Symbiosis MeSH
• Inflammation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Cytokines MeSH
• Reactive Oxygen Species MeSH

Host's physiology is significantly influenced by microbiota colonizing the epithelial surfaces. Complex microbial communities contribute to proper mucosal barrier function, immune response, and prevention of pathogen invasion and have many other crucial functions. The oral cavity and large intestine are distant parts of the digestive tract, both heavily colonized by commensal microbiota. Nevertheless, they feature different proportions of major bacterial and fungal phyla, mostly due to distinct epithelial layers organization and different oxygen levels. A few obligate anaerobic strains inhabiting the oral cavity are involved in the pathogenesis of oral diseases. Interestingly, these microbiota components are also enriched in gut inflammatory and tumor tissue. An altered microbiota composition - dysbiosis - and formation of polymicrobial biofilms seem to play important roles in the development of oral diseases and colorectal cancer. In this review, we describe the differences in composition of commensal microbiota in the oral cavity and large intestine and the mechanisms by which microbiota affect the inflammatory and carcinogenic response of the host.

• Keywords
• Fusobacterium, biofilm, dysbiosis, microbiome, mycobiome, oral diseases, pathobiont,
• Publication type
• Journal Article MeSH
• Review MeSH

This brief review is dedicated to the legacy of Prof. Jaroslav Šterzl and his colleagues, who laid the foundation for gnotobiology in the former Czechoslovakia 55 years. Prof. Sterzl became one of the founders of modern Czechoslovak immunology, which was characterized by work on a wide range of problems needing to be solved. While examining the mechanisms of innate immunity, he focused his studies on the induction of antibody production by immunocompetent cells involved in adaptive immune transmission while using the model of pig fetuses and germ-free piglets and characterizing immunoglobulins in the sera of these piglets. Although not fully appreciated to this day, his experimental proof of the hypothesis focused on the common precursor of cell-forming antibodies of different isotypes was later confirmed in experiments at the gene level. Prof. Sterzl's work represented a true milestone in the development of not solely Czechoslovak but also European and global immunology. He collaborated closely with the World Health Organization for many years, serving there as leader of the Reference Laboratory for Factors of Innate Immunity.

• Keywords
• Germ-free model, Gnotobiology, Host-pathogen interaction, Innate immunity, Microbiota,
• MeSH
• Germ-Free Life * MeSH
• Host-Pathogen Interactions * MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Gastrointestinal Microbiome MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Altered expression and methylation pattern of tumor suppressor and DNA repair genes, in particular involved in mismatch repair (MMR) pathway, frequently occur in primary colorectal (CRC) tumors. However, little is known about (epi)genetic changes of these genes in precancerous and early stages of CRC. The aim of this pilot study was to analyze expression profile and promoter methylation status of important tumor suppressor and DNA repair genes in the early stages of experimentally induced colorectal carcinogenesis. Rats were treated with azoxymethane (AOM), dextran sodium sulphate (DSS) or with their combination, and sacrificed 1 or 4 months post-treatment period. The down-regulation of Apc expression in left colon, detectable in animals treated with DSS-AOM and sacrificed 1 month after the end of treatment, represents most early marker of the experimental colorectal carcinogenesis. Significantly reduced gene expressions were also found in 5 out of 7 studied MMR genes (Mlh1, Mlh3, Msh3 Pms1, Pms2), regarding the sequential administration of DSS-AOM at 4 months since the treatment. Strong down-regulation was also discovered for Apc, Apex1, Mgmt and TP53. Tumors developed in rectum-sigmoid region displayed significantly lower Apc and Pms2 expressions. The decreased expression of studied genes was not in any case associated with aberrant methylation of promoter region. Present data suggest that down-regulation of Apc and MMR genes are prerequisite for the development of CRC. In this study we addressed for the first time early functional alterations of tumor suppressor genes with underlying epigenetic mechanisms in experimentally induced CRC in rats.

• MeSH
• Colon metabolism   pathology   MeSH
• Rats MeSH
• DNA Methylation genetics   MeSH
• Tumor Suppressor Proteins genetics   metabolism   MeSH
• Colonic Neoplasms genetics   MeSH
• Pilot Projects MeSH
• Polymerase Chain Reaction MeSH
• Rats, Wistar MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Tumor Suppressor Proteins MeSH

BACKGROUND: Microbial sensing by Toll-like receptors (TLR) and its negative regulation have an important role in the pathogenesis of inflammation-related cancer. In this study, we investigated the role of negative regulation of Toll-like receptors signaling and gut microbiota in the development of colitis-associated cancer in mouse model. METHODS: Colitis-associated cancer was induced by azoxymethane and dextran sodium sulfate in wild-type and in interleukin-1 receptor-associated kinase M (IRAK-M)-deficient mice with or without antibiotic (ATB) treatment. Local cytokine production was analyzed by multiplex cytokine assay or enzyme-linked immunosorbent assay, and regulatory T cells were analyzed by flow cytometry. Changes in microbiota composition during tumorigenesis were analyzed by pyrosequencing, and β-glucuronidase activity was measured in intestinal content by fluorescence assay. RESULTS: ATB treatment of wild-type mice reduced the incidence and severity of tumors. Compared with nontreated mice, ATB-treated mice had significantly lower numbers of regulatory T cells in colon, altered gut microbiota composition, and decreased β-glucuronidase activity. However, the β-glucuronidase activity was not as low as in germ-free mice. IRAK-M-deficient mice not only developed invasive tumors, but ATB-induced decrease in β-glucuronidase activity did not rescue them from severe carcinogenesis phenotype. Furthermore, IRAK-M-deficient mice had significantly increased levels of proinflammatory cytokines in the tumor tissue. CONCLUSIONS: We conclude that gut microbiota promotes tumorigenesis by increasing the exposure of gut epithelium to carcinogens and that IRAK-M-negative regulation is essential for colon cancer resistance even in conditions of altered microbiota. Therefore, gut microbiota and its metabolic activity could be potential targets for colitis-associated cancer therapy.

• MeSH
• Azoxymethane toxicity   MeSH
• Cytokines genetics   metabolism   MeSH
• Gastrointestinal Tract microbiology   MeSH
• Carcinogens toxicity   MeSH
• Interleukin-1 Receptor-Associated Kinases physiology   MeSH
• Colitis chemically induced   complications   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• RNA, Messenger genetics   MeSH
• Metagenome * MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Colonic Neoplasms etiology   metabolism   pathology   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Flow Cytometry MeSH
• Receptors, Interleukin-1 metabolism   MeSH
• T-Lymphocytes, Regulatory immunology   metabolism   pathology   MeSH
• Signal Transduction MeSH
• Dextran Sulfate toxicity   MeSH
• Toll-Like Receptors genetics   metabolism   MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Azoxymethane MeSH
• Cytokines MeSH
• Irak3 protein, mouse MeSH Browser
• Carcinogens MeSH
• Interleukin-1 Receptor-Associated Kinases MeSH
• RNA, Messenger MeSH
• Receptors, Interleukin-1 MeSH
• Dextran Sulfate MeSH
• Toll-Like Receptors MeSH

Metagenomic approaches are currently being used to decipher the genome of the microbiota (microbiome), and, in parallel, functional studies are being performed to analyze the effects of the microbiota on the host. Gnotobiological methods are an indispensable tool for studying the consequences of bacterial colonization. Animals used as models of human diseases can be maintained in sterile conditions (isolators used for germ-free rearing) and specifically colonized with defined microbes (including non-cultivable commensal bacteria). The effects of the germ-free state or the effects of colonization on disease initiation and maintenance can be observed in these models. Using this approach we demonstrated direct involvement of components of the microbiota in chronic intestinal inflammation and development of colonic neoplasia (i.e., using models of human inflammatory bowel disease and colorectal carcinoma). In contrast, a protective effect of microbiota colonization was demonstrated for the development of autoimmune diabetes in non-obese diabetic (NOD) mice. Interestingly, the development of atherosclerosis in germ-free apolipoprotein E (ApoE)-deficient mice fed by a standard low-cholesterol diet is accelerated compared with conventionally reared animals. Mucosal induction of tolerance to allergen Bet v1 was not influenced by the presence or absence of microbiota. Identification of components of the microbiota and elucidation of the molecular mechanisms of their action in inducing pathological changes or exerting beneficial, disease-protective activities could aid in our ability to influence the composition of the microbiota and to find bacterial strains and components (e.g., probiotics and prebiotics) whose administration may aid in disease prevention and treatment.

• MeSH
• Autoimmune Diseases etiology   microbiology   MeSH
• Gastrointestinal Tract microbiology   MeSH
• Germ-Free Life * MeSH
• Immunity MeSH
• Humans MeSH
• Metagenome immunology   MeSH
• Disease Models, Animal MeSH
• Neoplasms etiology   microbiology   MeSH
• Mucous Membrane immunology   MeSH
• Inflammation etiology   microbiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH