The composition of microbiota and the gut-brain axis is increasingly considered a factor in the development of various pathological conditions. The etiology of multiple sclerosis (MS), a chronic autoimmune disease affecting the CNS, is complex and interactions within the gut-brain axis may be relevant in the development and the course of MS. In this article, we focus on the relationship between gut microbiota and the pathophysiology of MS. We review the contribution of germ-free mouse studies to our understanding of MS pathology and its implications for treatment strategies to modulate the microbiome in MS. This summary highlights the need for a better understanding of the role of the microbiota in patients' responses to disease-modifying drugs in MS and disease activity overall.

• Klíčová slova
• disease-modifying drugs, gut-brain axis, microbiome, multiple sclerosis,
• MeSH
• lidé MeSH
• mikrobiota * MeSH
• myši MeSH
• osa mozek-střevo MeSH
• roztroušená skleróza * MeSH
• střevní mikroflóra * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

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.

• Klíčová slova
• colorectal cancer, germ-free animals, induced tumors, microbiome, spontaneous tumors,
• MeSH
• Bacteria MeSH
• gnotobiologické modely * MeSH
• karcinogeneze MeSH
• mikrobiota * MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Psoriatic patients have altered microbiota, both in the intestine and on the skin. It is not clear, however, whether this is a cause or consequence of the disease. In this study, using an experimental mouse model of psoriasis induced by imiquimod (IMQ), we show that oral treatment with a broad spectrum of antibiotics (MIX) or metronidazole (MET) alone mitigates the severity of skin inflammation through downregulation of Th17 immune response in conventional mice. Since some antibiotics, including MET, can influence immune system reactivity, we also evaluated the effect of MIX in the same model under germ-free (GF) conditions. GF mice treated with MET did not show milder signs of imiquimod-induced skin inflammation (IISI) which supports the conclusion that the therapeutic effect is mediated by changes in microbiota composition. Moreover, compared to controls, mice treated with MIX had a significantly higher abundance of the genus Lactobacillus in the intestine and on the skin. Mice treated with MET had a significantly higher abundance of the genera Bifidobacterium and Enterococcus both on the skin and in the intestine and of Parabacteroides distasonis in the intestine. Additionally, GF mice and mice monocolonized with either Lactobacillus plantarum or segmented filamentous bacteria (SFB) were more resistant to IISI than conventional mice. Interestingly, compared to GF mice, IMQ induced a higher degree of systemic Th17 activation in mice monocolonized with SFB but not with L. plantarum. The present findings provide evidence that intestinal and skin microbiota directly regulates IISI and emphasizes the importance of microbiota in the pathogenesis of psoriasis.

• Klíčová slova
• animal model, antibiotics, germ-free, imiquimod, intestine, microbiota, psoriasis, skin,
• Publikační typ
• časopisecké články MeSH

Germ-free animals have been used to define the vital role of commensal bacteria on the maturation of the host immune system. However, the role of bacterial residues in diet in this setting is poorly understood. Here we investigated the effect of bacterial contamination in sterile diet on the level of allergic sensitization in germ-free mice. Sterile grain-based diets ST1 and R03 were tested for the level of bacterial contamination. ST1 contained higher amount of bacterial DNA, approximately ten times more endotoxin, and induced higher, TLR4-dependent, cytokine production in dendritic cells compared to R03. In a germ-free mouse model of sensitization to the major birch pollen allergen Bet v 1, feeding on ST1 for at least two generations was associated with decreased production of allergen-specific IgE and IgG1 antibodies in sera in comparison to R03. Furthermore, reduced levels of allergen-specific and ConA-induced cytokines IL-4, IL-5 and IL-13 accompanied by increased levels of IFN-γ were detected in splenocytes cultures of these mice. Our results show that contamination of experimental diet with bacterial residues, such as endotoxin, significantly affects the development of allergic sensitization in germ-free mice. Therefore, careful selection of sterile food is critical for the outcomes of germ-free or gnotobiotic experimental models of immune-deviated diseases.

• MeSH
• alergie imunologie   patologie   MeSH
• antigeny rostlinné imunologie   MeSH
• buněčná diferenciace účinky léků   MeSH
• chov MeSH
• cytokiny biosyntéza   MeSH
• dendritické buňky účinky léků   MeSH
• dieta * MeSH
• DNA bakterií analýza   MeSH
• endotoxiny toxicita   MeSH
• epitopy imunologie   MeSH
• gnotobiologické modely MeSH
• HEK293 buňky MeSH
• imunizace * MeSH
• imunoglobulin A imunologie   MeSH
• imunoglobulin G imunologie   MeSH
• kontaminace DNA MeSH
• kultivované buňky MeSH
• lidé MeSH
• ligandy MeSH
• mitogeny farmakologie   MeSH
• myši inbrední BALB C MeSH
• slezina patologie   MeSH
• toll-like receptor 4 metabolismus   MeSH
• trávicí systém imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny rostlinné MeSH
• Bet v 1 allergen, Betula MeSH Prohlížeč
• cytokiny MeSH
• DNA bakterií MeSH
• endotoxiny MeSH
• epitopy MeSH
• imunoglobulin A MeSH
• imunoglobulin G MeSH
• ligandy MeSH
• mitogeny MeSH
• toll-like receptor 4 MeSH

Psoriasis is a chronic inflammatory skin disease in which Th17 cells play a crucial role. Since indigenous gut microbiota influences the development and reactivity of immune cells, we analyzed the link among microbiota, T cells and the formation of psoriatic lesions in the imiquimod-induced murine model of psoriasis. To explore the role of microbiota, we induced skin inflammation in germ-free (GF), broad-spectrum antibiotic (ATB)-treated or conventional (CV) BALB/c and C57BL/6 mice. We found that both mice reared in GF conditions for several generations and CV mice treated with ATB were more resistant to imiquimod-induced skin inflammation than CV mice. The ATB treatment dramatically changed the diversity of gut bacteria, which remained stable after subsequent imiquimod application; ATB treatment resulted in a substantial increase in the order Lactobacillales and a significant decrease in Coriobacteriales and Clostridiales. Moreover, as compared to CV mice, imiquimod induced a lower degree of local and systemic Th17 activation in both GF and ATB-treated mice. These findings suggest that gut microbiota control imiquimod-induced skin inflammation by altering the T cell response.

• MeSH
• Actinobacteria účinky léků   fyziologie   MeSH
• aktivace lymfocytů účinky léků   MeSH
• aminochinoliny farmakologie   MeSH
• antibakteriální látky farmakologie   MeSH
• buňky Th17 účinky léků   imunologie   mikrobiologie   MeSH
• Clostridiales účinky léků   fyziologie   MeSH
• druhová specificita MeSH
• exprese genu MeSH
• gnotobiologické modely MeSH
• imichimod MeSH
• interleukin-17 genetika   imunologie   MeSH
• jaderné receptory - podrodina 1, skupina F, člen 3 genetika   imunologie   MeSH
• kůže účinky léků   imunologie   mikrobiologie   patologie   MeSH
• Lactobacillales účinky léků   fyziologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• psoriáza chemicky indukované   imunologie   mikrobiologie   patologie   MeSH
• receptory antigenů T-buněk gama-delta genetika   imunologie   MeSH
• střevní mikroflóra účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aminochinoliny MeSH
• antibakteriální látky MeSH
• imichimod MeSH
• interleukin-17 MeSH
• jaderné receptory - podrodina 1, skupina F, člen 3 MeSH
• receptory antigenů T-buněk gama-delta MeSH
• Rorc protein, mouse MeSH Prohlížeč

The microbiota is a crucial modulator of the immune system. Here, we evaluated how its absence or reduction modifies the inflammatory response in the murine model of experimental autoimmune uveoretinitis (EAU). We induced EAU in germ-free (GF) or conventionally housed (CV) mice and in CV mice treated with a combination of broad-spectrum antibiotics either from the day of EAU induction or from one week prior to induction of disease. The severity of the inflammation was assessed by fundus biomicroscopy or by histology, including immunohistology. The immunophenotyping of T cells in local and distant lymph nodes was performed by flow cytometry. We found that GF mice and mice where the microbiota was reduced one week before EAU induction were protected from severe autoimmune inflammation. GF mice had lower numbers of infiltrating macrophages and significantly less T cell infiltration in the retina than CV mice with EAU. GF mice also had reduced numbers of IFN-γ and IL-17-producing T cells and increased numbers of regulatory T cells in the eye-draining lymph nodes. These data suggest that the presence of microbiota during autoantigen recognition regulates the inflammatory response by influencing the adaptive immune response.

• MeSH
• adaptivní imunita MeSH
• aktivace lymfocytů MeSH
• antibakteriální látky farmakologie   MeSH
• autoantigeny imunologie   MeSH
• autoimunitní nemoci chemicky indukované   imunologie   mikrobiologie   MeSH
• bakteriální nálož účinky léků   MeSH
• gnotobiologické modely MeSH
• interferon gama biosyntéza   MeSH
• interleukin-17 biosyntéza   MeSH
• makrofágy imunologie   MeSH
• mikrobiota * imunologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• oči imunologie   patologie   MeSH
• oční proteiny imunologie   MeSH
• proteiny vázající retinol imunologie   MeSH
• průtoková cytometrie MeSH
• regulační T-lymfocyty imunologie   MeSH
• retina imunologie   MeSH
• retinitida chemicky indukované   etiologie   imunologie   mikrobiologie   MeSH
• uveitida chemicky indukované   imunologie   mikrobiologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• Názvy látek
• antibakteriální látky MeSH
• autoantigeny MeSH
• interferon gama MeSH
• interleukin-17 MeSH
• interstitial retinol-binding protein MeSH Prohlížeč
• oční proteiny MeSH
• proteiny vázající retinol MeSH

BACKGROUND: Disturbances in the intestinal microbial community (i.e. dysbiosis) or presence of the microbes with deleterious effects on colonic mucosa has been linked to the pathogenesis of inflammatory bowel diseases. However the role of microbiota in induction and progression of ulcerative colitis (UC) has not yet been fully elucidated. METHODS: Three lines of human microbiota-associated (HMA) mice were established by gavage of colon biopsy from three patients with active UC. The shift in microbial community during its transferring from humans to mice was analyzed by next-generation sequencing using Illumina MiSeq sequencer. Spontaneous or dextran sulfate sodium (DSS)-induced colitis and microbiota composition profiling in germ-free mice and HMA mice over 3-4 generations were assessed to decipher the features of the distinctive and crucial events occurring during microbial colonization and animal reproduction. RESULTS: None of the HMA mice developed colitis spontaneously. When treated with DSS, mice in F4 generation of one line of colonized mice (aHMA) developed colitis. Compared to the DSS-resistant earlier generations of aHMA mice, the F4 generation have increased abundance of Clostridium difficile and decrease abundance of C. symbiosum in their cecum contents measured by denaturing gradient gel electrophoresis and DNA sequencing. CONCLUSION: In our study, mucosa-associated microbes of UC patients were not able to induce spontaneous colitis in gnotobiotic BALB/c mice but they were able to increase the susceptibility to DSS-induced colitis, once the potentially deleterious microbes found a suitable niche.

• Klíčová slova
• Dysbiosis, Germ-free mice, Microbiota, Ulcerative colitis,
• Publikační typ
• časopisecké články 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
• azoxymethan toxicita   MeSH
• cytokiny genetika   metabolismus   MeSH
• gastrointestinální trakt mikrobiologie   MeSH
• karcinogeny toxicita   MeSH
• kinázy asociované s receptory interleukinu-1 fyziologie   MeSH
• kolitida chemicky indukované   komplikace   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• messenger RNA genetika   MeSH
• metagenom * MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• nádory tračníku etiologie   metabolismus   patologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• průtoková cytometrie MeSH
• receptory interleukinu-1 metabolismus   MeSH
• regulační T-lymfocyty imunologie   metabolismus   patologie   MeSH
• signální transdukce MeSH
• síran dextranu toxicita   MeSH
• toll-like receptory genetika   metabolismus   MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• azoxymethan MeSH
• cytokiny MeSH
• Irak3 protein, mouse MeSH Prohlížeč
• karcinogeny MeSH
• kinázy asociované s receptory interleukinu-1 MeSH
• messenger RNA MeSH
• receptory interleukinu-1 MeSH
• síran dextranu MeSH
• toll-like receptory 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
• autoimunitní nemoci etiologie   mikrobiologie   MeSH
• gastrointestinální trakt mikrobiologie   MeSH
• gnotobiologické modely * MeSH
• imunita MeSH
• lidé MeSH
• metagenom imunologie   MeSH
• modely nemocí na zvířatech MeSH
• nádory etiologie   mikrobiologie   MeSH
• sliznice imunologie   MeSH
• zánět etiologie   mikrobiologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Commensal bacteria have been shown to modulate the host mucosal immune system. Here, we report that oral treatment of BALB/c mice with components from the commensal, Parabacteroides distasonis, significantly reduces the severity of intestinal inflammation in murine models of acute and chronic colitis induced by dextran sulphate sodium (DSS). The membranous fraction of P. distasonis (mPd) prevented DSS-induced increases in several proinflammatory cytokines, increased mPd-specific serum antibodies and stabilized the intestinal microbial ecology. The anti-colitic effect of oral mPd was not observed in severe combined immunodeficient mice and probably involved induction of specific antibody responses and stabilization of the intestinal microbiota. Our results suggest that specific bacterial components derived from the commensal bacterium, P. distasonis, may be useful in the development of new therapeutic strategies for chronic inflammatory disorders such as inflammatory bowel disease.

• MeSH
• akutní nemoc MeSH
• antigeny bakteriální aplikace a dávkování   imunologie   MeSH
• aplikace orální MeSH
• Bacteroides imunologie   MeSH
• chronická nemoc MeSH
• cytokiny krev   imunologie   MeSH
• kolitida terapie   MeSH
• metagenom imunologie   MeSH
• myši inbrední BALB C MeSH
• myši SCID MeSH
• myši MeSH
• protilátky bakteriální krev   imunologie   MeSH
• střevní sliznice imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny bakteriální MeSH
• cytokiny MeSH
• protilátky bakteriální MeSH