RESUMO
Rotavirus (RV) encounters intestinal epithelial cells amidst diverse microbiota, opening possibilities of microbes influencing RV infection. Although RV clearance typically requires adaptive immunity, we unintentionally generated RV-resistant immunodeficient mice, which, we hypothesized, reflected select microbes protecting against RV. Accordingly, such RV resistance was transferred by co-housing and fecal transplant. RV-protecting microbiota were interrogated by heat, filtration, and antimicrobial agents, followed by limiting dilution transplant to germ-free mice and microbiome analysis. This approach revealed that segmented filamentous bacteria (SFB) were sufficient to protect mice against RV infection and associated diarrhea. Such protection was independent of previously defined RV-impeding factors, including interferon, IL-17, and IL-22. Colonization of the ileum by SFB induced changes in host gene expression and accelerated epithelial cell turnover. Incubation of RV with SFB-containing feces reduced infectivity in vitro, suggesting direct neutralization of RV. Thus, independent of immune cells, SFB confer protection against certain enteric viral infections and associated diarrheal disease.
Assuntos
Imunidade Adaptativa/genética , Diarreia/microbiologia , Mucosa Intestinal/microbiologia , Infecções por Rotavirus/microbiologia , Animais , Anti-Infecciosos/farmacologia , Bactérias/genética , Bactérias/metabolismo , Diarreia/prevenção & controle , Diarreia/virologia , Fezes/microbiologia , Regulação da Expressão Gênica/genética , Humanos , Íleo/microbiologia , Íleo/patologia , Íleo/virologia , Interferons/genética , Interleucina-17/genética , Interleucinas/genética , Mucosa Intestinal/patologia , Mucosa Intestinal/virologia , Camundongos , Microbiota/genética , Rotavirus/patogenicidade , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/virologia , Interleucina 22RESUMO
Dietary soluble fibers are fermented by gut bacteria into short-chain fatty acids (SCFA), which are considered broadly health-promoting. Accordingly, consumption of such fibers ameliorates metabolic syndrome. However, incorporating soluble fiber inulin, but not insoluble fiber, into a compositionally defined diet, induced icteric hepatocellular carcinoma (HCC). Such HCC was microbiota-dependent and observed in multiple strains of dysbiotic mice but not in germ-free nor antibiotics-treated mice. Furthermore, consumption of an inulin-enriched high-fat diet induced both dysbiosis and HCC in wild-type (WT) mice. Inulin-induced HCC progressed via early onset of cholestasis, hepatocyte death, followed by neutrophilic inflammation in liver. Pharmacologic inhibition of fermentation or depletion of fermenting bacteria markedly reduced intestinal SCFA and prevented HCC. Intervening with cholestyramine to prevent reabsorption of bile acids also conferred protection against such HCC. Thus, its benefits notwithstanding, enrichment of foods with fermentable fiber should be approached with great caution as it may increase risk of HCC.
Assuntos
Carcinoma Hepatocelular/etiologia , Colestase/complicações , Fibras na Dieta/metabolismo , Disbiose/complicações , Fermentação , Microbioma Gastrointestinal , Neoplasias Hepáticas/etiologia , Animais , Carcinoma Hepatocelular/microbiologia , Linhagem Celular Tumoral , Colestase/microbiologia , Dieta Hiperlipídica/efeitos adversos , Disbiose/microbiologia , Inulina/efeitos adversos , Neoplasias Hepáticas/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Dietary emulsifiers, including carboxymethylcellulose (CMC) and polysorbate 80 (P80), perturb gut microbiota composition and gene expression, resulting in a microbiota with enhanced capacity to activate host pro-inflammatory gene expression and invade the intestine's inner mucus layer. Such microbiota alterations promote intestinal inflammation, which can have a variety of phenotypic consequences including increased adiposity. Bacterial flagellin is a key mediator of emulsifiers' impact in that this molecule enables motility and is itself a pro-inflammatory agonist. Hence, we reasoned that training the adaptive mucosal immune system to exclude microbes that express flagellin might protect against emulsifiers. Investigating this notion found that immunizing mice with flagellin elicited an increase in mucosal anti-flagellin IgA and IgA-coated microbiota that would have otherwise developed in response to CMC and P80 consumption. Yet, eliciting these responses in advance via flagellin immunization prevented CMC/P80-induced increases in microbiota expression of pro-inflammatory agonists including LPS and flagellin. Furthermore, such immunization prevented CMC/P80-induced microbiota encroachment and deleterious pro-inflammatory consequences associated therewith, including colon shortening and increased adiposity. Hence, eliciting mucosal immune responses to pathobiont surface components, including flagellin, may be a means of combatting the array of inflammatory diseases that are promoted by emulsifiers and perhaps other modern microbiota stressors.
Assuntos
Microbiota , Vacinação , Animais , Camundongos , Imunização , Dieta , Obesidade , Flagelina , Polissorbatos/farmacologia , Imunoglobulina ARESUMO
BACKGROUND: Emulsifiers are widely used food additives in industrially processed foods to improve texture and enhance shelf-life. Experimental research suggests deleterious effects of emulsifiers on the intestinal microbiota and the metabolome, leading to chronic inflammation and increasing susceptibility to carcinogenesis. However, human epidemiological evidence investigating their association with cancer is nonexistent. This study aimed to assess associations between food additive emulsifiers and cancer risk in a large population-based prospective cohort. METHODS AND FINDINGS: This study included 92,000 adults of the French NutriNet-Santé cohort without prevalent cancer at enrolment (44.5 y [SD: 14.5], 78.8% female, 2009 to 2021). They were followed for an average of 6.7 years [SD: 2.2]. Food additive emulsifier intakes were estimated for participants who provided at least 3 repeated 24-h dietary records linked to comprehensive, brand-specific food composition databases on food additives. Multivariable Cox regressions were conducted to estimate associations between emulsifiers and cancer incidence. Overall, 2,604 incident cancer cases were diagnosed during follow-up (including 750 breast, 322 prostate, and 207 colorectal cancers). Higher intakes of mono- and diglycerides of fatty acids (FAs) (E471) were associated with higher risks of overall cancer (HR high vs. low category = 1.15; 95% CI [1.04, 1.27], p-trend = 0.01), breast cancer (HR = 1.24; 95% CI [1.03, 1.51], p-trend = 0.04), and prostate cancer (HR = 1.46; 95% CI [1.09, 1.97], p-trend = 0.02). In addition, associations with breast cancer risk were observed for higher intakes of total carrageenans (E407 and E407a) (HR = 1.32; 95% CI [1.09, 1.60], p-trend = 0.009) and carrageenan (E407) (HR = 1.28; 95% CI [1.06, 1.56], p-trend = 0.01). No association was detected between any of the emulsifiers and colorectal cancer risk. Several associations with other emulsifiers were observed but were not robust throughout sensitivity analyses. Main limitations include possible exposure measurement errors in emulsifiers intake and potential residual confounding linked to the observational design. CONCLUSIONS: In this large prospective cohort, we observed associations between higher intakes of carrageenans and mono- and diglycerides of fatty acids with overall, breast and prostate cancer risk. These results need replication in other populations. They provide new epidemiological evidence on the role of emulsifiers in cancer risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT03335644.
Assuntos
Neoplasias da Mama , Neoplasias da Próstata , Adulto , Masculino , Humanos , Dieta , Fatores de Risco , Estudos Prospectivos , Aditivos Alimentares/efeitos adversos , Diglicerídeos , Ácidos GraxosRESUMO
There is increasing evidence that probiotic and commensal bacteria play a role in substrate metabolism, energy harvesting and intestinal homeostasis, and may exert immunomodulatory activities on human health. In addition, recent research suggests that these microorganisms interact with vitamins and minerals, promoting intestinal and metabolic well-being while producing vital microbial metabolites such as short-chain fatty acids (SCFAs). In this regard, there is a flourishing field exploring the intricate dynamics between vitamins, minerals, SCFAs, and commensal/probiotic interactions. In this review, we summarize some of the major hypotheses beyond the mechanisms by which commensals/probiotics impact gut health and their additional effects on the absorption and metabolism of vitamins, minerals, and SCFAs. Our analysis includes comprehensive review of existing evidence from preclinical and clinical studies, with particular focus on the potential interaction between commensals/probiotics and micronutrients. Finally, we highlight knowledge gaps and outline directions for future research in this evolving field.
Assuntos
Bactérias , Ácidos Graxos Voláteis , Microbioma Gastrointestinal , Minerais , Probióticos , Vitaminas , Probióticos/metabolismo , Humanos , Vitaminas/metabolismo , Minerais/metabolismo , Ácidos Graxos Voláteis/metabolismo , Bactérias/metabolismo , Simbiose , AnimaisRESUMO
Alterations in enteric microbiota are associated with several highly prevalent immune-mediated and metabolic diseases1-3, and experiments involving faecal transplants have indicated that such alterations have a causal role in at least some such conditions4-6. The postnatal period is particularly critical for the development of microbiota composition, host-microbe interactions and immune homeostasis7-9. However, the underlying molecular mechanisms of this neonatal priming period have not been defined. Here we report the identification of a host-mediated regulatory circuit of bacterial colonization that acts solely during the early neonatal period but influences life-long microbiota composition. We demonstrate age-dependent expression of the flagellin receptor Toll-like receptor 5 (TLR5) in the gut epithelium of neonate mice. Using competitive colonization experiments, we demonstrate that epithelial TLR5-mediated REG3γ production is critical for the counter-selection of colonizing flagellated bacteria. Comparative microbiota transfer experiments in neonate and adult wild-type and Tlr5-deficient germ-free mice reveal that neonatal TLR5 expression strongly influences the composition of the microbiota throughout life. Thus, the beneficial microbiota in the adult host is shaped during early infancy. This might explain why environmental factors that disturb the establishment of the microbiota during early life can affect immune homeostasis and health in adulthood.
Assuntos
Envelhecimento/imunologia , Animais Recém-Nascidos/imunologia , Microbioma Gastrointestinal/imunologia , Receptor 5 Toll-Like/imunologia , Envelhecimento/genética , Animais , Animais Recém-Nascidos/genética , Cruzamentos Genéticos , Meio Ambiente , Feminino , Flagelina/imunologia , Flagelina/metabolismo , Microbioma Gastrointestinal/genética , Homeostase , Interações entre Hospedeiro e Microrganismos , Abrigo para Animais , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Receptor 5 Toll-Like/genéticaRESUMO
In Fig. 1d of this Letter, the third group along should have been labelled 'WT' rather than 'Tlr5'. This has been corrected online.
RESUMO
BACKGROUND: Accumulating evidence indicates that some non-absorbed food additives, including emulsifiers carboxymethylcellulose (CMC) and polysorbate 80 (P80), can negatively impact intestinal microbiota, leading to microbiota encroachment, chronic low-grade intestinal inflammation and, subsequently, promotion of metabolic dysregulations. Detrimental impacts of emulsifier consumption on gut microbiota include depletion of the health-associated mucus-fortifying bacteria, Akkermansia muciniphila. OBJECTIVE: Investigate, in mice, the potential of administration of exogenous A. muciniphila as a means to protect against detrimental impacts of emulsifiers. RESULTS: Daily oral administration of A. muciniphila prevented phenotypic consequences of consumption of both CMC and P80, including hyperphagia, weight gain and dysglycaemia. A. muciniphila administration also counteracted the low-grade intestinal inflammation-induced CMC and P80. Furthermore, A. muciniphila supplementation prevented the proximal impacts of CMC and P80 on gut microbiota that are thought to drive low-grade chronic inflammation and metabolic dysregulations. Specifically, A. muciniphila prevented alterations in species composition and encroachment of gut microbiota that were otherwise induced by CMC and P80. Remarkably, we finally report that CMC and P80 altered the colonic transcriptome, while A. muciniphila largely protected against these alterations. CONCLUSION: Daily administration of A. muciniphila protects against the detrimental impact of emulsifiers on both the microbiota and host. These results support the notion that use of A. muciniphila as a probiotic can help maintain intestinal and metabolic health amidst the broad array of modern stresses that can promote chronic inflammatory diseases.
Assuntos
Microbioma Gastrointestinal , Microbiota , Animais , Camundongos , Dieta , Inflamação/metabolismo , VerrucomicrobiaRESUMO
BACKGROUND & AIMS: Epidemiologic and murine studies suggest that dietary emulsifiers promote development of diseases associated with microbiota dysbiosis. Although the detrimental impact of these compounds on the intestinal microbiota and intestinal health have been demonstrated in animal and in vitro models, impact of these food additives in healthy humans remains poorly characterized. METHODS: To examine this notion in humans, we performed a double-blind controlled-feeding study of the ubiquitous synthetic emulsifier carboxymethylcellulose (CMC) in which healthy adults consumed only emulsifier-free diets (n = 9) or an identical diet enriched with 15 g per day of CMC (n = 7) for 11 days. RESULTS: Relative to control subjects, CMC consumption modestly increased postprandial abdominal discomfort and perturbed gut microbiota composition in a way that reduced its diversity. Moreover, CMC-fed subjects exhibited changes in the fecal metabolome, particularly reductions in short-chain fatty acids and free amino acids. Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition. CONCLUSIONS: These results support the notion that the broad use of CMC in processed foods may be contributing to increased prevalence of an array of chronic inflammatory diseases by altering the gut microbiome and metabolome (ClinicalTrials.gov, number NCT03440229).
Assuntos
Carboximetilcelulose Sódica/efeitos adversos , Dieta/efeitos adversos , Emulsificantes/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Animais , Método Duplo-Cego , Disbiose/etiologia , Fezes , Feminino , Voluntários Saudáveis , Humanos , Masculino , CamundongosRESUMO
Connections between the microbiome and health are rapidly emerging in a wide range of diseases. However, a detailed mechanistic understanding of how different microbial communities are influencing their hosts is often lacking. One method researchers have used to understand these effects are germ-free (GF) mouse models. Differences found within the organ systems of these model organisms may highlight generalizable mechanisms that microbiome dysbioses have throughout the host. Here, we applied multiplexed, quantitative proteomics on the brains, spleens, hearts, small intestines, and colons of conventionally raised and GF mice, identifying associations to colonization state in over 7000 proteins. Highly ranked associations were constructed into protein-protein interaction networks and visualized onto an interactive 3D mouse model for user-guided exploration. These results act as a resource for microbiome researchers hoping to identify host effects of microbiome colonization on a given organ of interest. Our results include validation of previously reported effects in xenobiotic metabolism, the innate immune system, and glutamate-associated proteins while simultaneously providing organism-wide context. We highlight organism-wide differences in mitochondrial proteins including consistent increases in NNT, a mitochondrial protein with essential roles in influencing levels of NADH and NADPH, in all analyzed organs of conventional mice. Our networks also reveal new associations for further exploration, including protease responses in the spleen, high-density lipoproteins in the heart, and glutamatergic signaling in the brain. In total, our study provides a resource for microbiome researchers through detailed tables and visualization of the protein-level effects of microbial colonization on several organ systems.
Assuntos
Disbiose/genética , Microbioma Gastrointestinal/genética , Interações Hospedeiro-Patógeno/genética , Proteômica , Animais , Encéfalo/metabolismo , Encéfalo/microbiologia , Colo/metabolismo , Colo/microbiologia , Disbiose/microbiologia , Coração/microbiologia , Humanos , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Fígado/metabolismo , Fígado/microbiologia , Camundongos , Baço/metabolismo , Baço/microbiologiaRESUMO
Systems biological analysis of immunity to the trivalent inactivated influenza vaccine (TIV) in humans revealed a correlation between early expression of TLR5 and the magnitude of the antibody response. Vaccination of Trl5(-/-) mice resulted in reduced antibody titers and lower frequencies of plasma cells, demonstrating a role for TLR5 in immunity to TIV. This was due to a failure to sense host microbiota. Thus, antibody responses in germ-free or antibiotic-treated mice were impaired, but restored by oral reconstitution with a flagellated, but not aflagellated, strain of E. coli. TLR5-mediated sensing of flagellin promoted plasma cell differentiation directly and by stimulating lymph node macrophages to produce plasma cell growth factors. Finally, TLR5-mediated sensing of the microbiota also impacted antibody responses to the inactivated polio vaccine, but not to adjuvanted vaccines or the live-attenuated yellow fever vaccine. These results reveal an unappreciated role for gut microbiota in promoting immunity to vaccination.
Assuntos
Formação de Anticorpos/imunologia , Vacinas contra Influenza/imunologia , Intestinos/microbiologia , Microbiota/imunologia , Receptor 5 Toll-Like/imunologia , Animais , Anticorpos Antivirais/sangue , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Escherichia coli/imunologia , Flagelina/imunologia , Humanos , Memória Imunológica/imunologia , Influenza Humana/prevenção & controle , Intestinos/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmócitos/imunologia , Plasmócitos/metabolismo , Vacina Antipólio de Vírus Inativado/imunologia , Transdução de Sinais/imunologia , Receptor 5 Toll-Like/biossíntese , Receptor 5 Toll-Like/genética , Vacina contra Febre Amarela/imunologiaRESUMO
BACKGROUND: Edible gold (Au) is commonly used as a food additive (E175 in EU) for confectionery and cake decorations, coatings and in beverages. Food-grade gold is most often composed of thin Au sheets or flakes exhibiting micro- and nanometric dimensions in their thickness. Concerns about the impact of mineral particles used as food additives on human health are increasing with respect to the particular physico-chemical properties of nanosized particles, which enable them to cross biological barriers and interact with various body cell compartments. In this study, male and female mice were exposed daily to E175 or an Au nanomaterial (Ref-Au) incorporated into food at relevant human dose for 90 days in order to determine the potential toxicity of edible gold. RESULTS: E175 or Ref-Au exposure in mice did not induce any histomorphological damage of the liver, spleen or intestine, nor any genotoxic effects in the colon and liver despite an apparent higher intestinal absorption level of Au particles in mice exposed to Ref-Au compared to the E175 food additive. No changes in the intestinal microbiota were reported after treatment with Ref-Au, regardless of sex. In contrast, after E175 exposure, an increase in the Firmicutes/Bacteroidetes ratio and in the abundance of Proteobacteria were observed in females, while a decrease in the production of short-chain fatty acids occurred in both sexes. Moreover, increased production of IL-6, TNFα and IL-1ß was observed in the colon of female mice at the end of the 90-day exposure to E175, whereas, decreased IL-6, IL-1ß, IL-17 and TGFß levels were found in the male colon. CONCLUSIONS: These results revealed that a 90-day exposure to E175 added to the diet alters the gut microbiota and intestinal immune response in a sex-dependent manner in mice. Within the dose range of human exposure to E175, these alterations remained low in both sexes and mostly appeared to be nontoxic. However, at the higher dose, the observed gut dysbiosis and the intestinal low-grade inflammation in female mice could favour the occurrence of metabolic disorders supporting the establishment of toxic reference values for the safe use of gold as food additive.
Assuntos
Microbioma Gastrointestinal , Humanos , Camundongos , Masculino , Feminino , Animais , Ouro , Interleucina-6 , Sistema Imunitário , Aditivos Alimentares/toxicidadeRESUMO
Oral antibiotic treatment is often applied in animal studies in order to allow establishment of an introduced antibiotic-resistant bacterium in the gut. Here, we compared the application of streptomycin dosed orally in microcontainers to dosage through drinking water. The selective effect on a resistant bacterial strain, as well as the effects on fecal, luminal, and mucosal microbiota composition, were investigated. Three groups of rats (n = 10 per group) were orally dosed with microcontainers daily for 3 days. One of these groups (STR-M) received streptomycin-loaded microcontainers designed for release in the distal ileum, while the other two groups (controls [CTR] and STR-W) received empty microcontainers. The STR-W group was additionally dosed with streptomycin through the drinking water. A streptomycin-resistant Escherichia coli strain was orally inoculated into all animals. Three days after inoculation, the resistant E. coli was found only in the cecum and colon of animals receiving streptomycin in microcontainers but in all intestinal compartments of animals receiving streptomycin in the drinking water. 16S rRNA amplicon sequencing revealed significant changes in the fecal microbiota of both groups of streptomycin-treated animals. Investigation of the inner colonic mucus layer by confocal laser scanning microscopy and laser capture microdissection revealed no significant effect of streptomycin treatment on the mucus-inhabiting microbiota or on E. coli encroachment into the inner mucus. Streptomycin-loaded microcontainers thus enhanced proliferation of an introduced streptomycin-resistant E. coli in the cecum and colon without affecting the small intestine environment. While improvements of the drug delivery system are needed to facilitate optimal local concentration and release of streptomycin, the application of microcontainers provides new prospects for antibiotic treatment. IMPORTANCE Delivery of antibiotics in microcontainer devices designed for release at specific sites of the gut represents a novel approach which might reduce the amount of antibiotic needed to obtain a local selective effect. We propose that the application of microcontainers may have the potential to open novel opportunities for antibiotic treatment of humans and animals with fewer side effects on nontarget bacterial populations. In the current study, we therefore elucidated the effects of streptomycin, delivered in microcontainers coated with pH-sensitive lids, on the selective effect on a resistant bacterium, as well as on the surrounding intestinal microbiota in rats.
Assuntos
Água Potável , Estreptomicina , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias/genética , Colo , Escherichia coli/genética , Humanos , Mucosa Intestinal/microbiologia , RNA Ribossômico 16S , Ratos , Estreptomicina/farmacologiaRESUMO
The Western diet, rich in lipids and in n-6 polyunsaturated fatty acids (PUFAs), favors gut dysbiosis observed in Crohn's disease (CD). The aim of this study was to assess the effects of rebalancing the n-6/n-3 PUFA ratio in CEABAC10 transgenic mice that mimic CD. Mice in individual cages with running wheels were randomized in three diet groups for 12 weeks: high-fat diet (HFD), HFD + linseed oil (HFD-LS-O) and HFD + extruded linseed (HFD-LS-E). Then, they were orally challenged once with the Adherent-Invasive Escherichia coli (AIEC) LF82 pathobiont. After 12 weeks of diet, total energy intake, body composition, and intestinal permeability were not different between groups. After the AIEC-induced intestinal inflammation, fecal lipocalin-2 concentration was lower at day 6 in n-3 PUFAs supplementation groups (HFD-LS-O and HFD-LS-E) compared to HFD. Analysis of the mucosa-associated microbiota showed that the abundance of Prevotella, Paraprevotella, Ruminococcus, and Clostridiales was higher in the HFD-LS-E group. Butyrate levels were higher in the HFD-LS-E group and correlated with the Firmicutes/Proteobacteria ratio. This study demonstrates that extruded linseed supplementation had a beneficial health effect in a physically active mouse model of CD susceptibility. Additional studies are required to better decipher the matrix influence in the linseed supplementation effect.
Assuntos
Doença de Crohn , Linho , Microbiota , Animais , Doença de Crohn/tratamento farmacológico , Doença de Crohn/microbiologia , Dieta Hiperlipídica , Suplementos Nutricionais , Modelos Animais de Doenças , Escherichia coli , Mucosa Intestinal/microbiologia , Óleo de Semente do Linho/farmacologia , Camundongos , Camundongos TransgênicosRESUMO
BACKGROUND: Bacterial flagellin is a major target of innate and adaptive immunity, both of which can promote and/or compensate for deficiencies in each other's function. METHODS: To investigate the role of innate immune detection of flagellin irrespective of adaptive immunity, we examined the consequences of loss of Toll-like receptor 5 (T5) and/or Nod-like receptor 4 (N4) upon a Rag1-deficient background. RESULTS: Mice lacking Toll-like receptor 5 and Rag1 (T5/Rag-DKO) exhibited frequent lethal Pasteurellaceae-containing abscesses that prevented breeding of these mice. Mice lacking Toll-like receptor 5, Nod-like receptor 4, and Rag1 (T5/N4/Rag-TKO) also resulted in sporadic lethal abdominal abscesses caused by similar Pasteurellaceae. In the absence of such infections, relative to Rag1-KO, T5/N4/Rag-TKO mice exhibited microbiota encroachment, low-grade inflammation, microbiota dysbiosis, and, moreover were highly prone to Citrobacter infection and developed severe colitis when adoptively transferred with colitogenic T cells. Relative proneness of T5/N4/Rag-TKO mice to T-cell colitis was ablated by antibiotics while fecal microbiota transplant from T5/N4/Rag-TKO mice to wild-type mice transferred proneness to Citrobacter infection, indicating that dysbiosis in T5/N4/Rag-TKO mice contributed to these phenotypes. CONCLUSIONS: These results demonstrate a critical role for innate immune detection of flagellin, especially in the intestinal tract and particularly in hosts deficient in adaptive immunity.
Assuntos
Colite , Flagelina/imunologia , Proteínas de Homeodomínio , Imunidade Inata , Proteínas NLR , Receptor 5 Toll-Like , Imunidade Adaptativa , Animais , Disbiose , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas NLR/genética , Receptor 5 Toll-Like/genéticaRESUMO
Selecting the most relevant control diet is of critical importance for metabolic and intestinal studies in animal models. Chow and LF-purified diet differentially impact metabolic and gut microbiome outcomes resulting in major changes in intestinal integrity in LF-fed animals which contributes to altering metabolic homeostasis. Dietary fat and low fiber both contribute to the deleterious metabolic effect of purified HF diets through both selective and overlapping mechanisms.
Assuntos
Dieta , Gorduras na Dieta , Fibras na Dieta , Trato Gastrointestinal/metabolismo , Fígado/metabolismo , Obesidade/metabolismo , Ração Animal , Animais , Ácidos e Sais Biliares/metabolismo , Microbioma Gastrointestinal/fisiologia , Resistência à Insulina/fisiologia , Masculino , CamundongosRESUMO
The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota-host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine. Thus, agents that disrupt mucus-bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro, might be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century. Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host-microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.
Assuntos
Colite/induzido quimicamente , Colite/microbiologia , Dieta/efeitos adversos , Emulsificantes/efeitos adversos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/microbiologia , Adiposidade/efeitos dos fármacos , Animais , Carboximetilcelulose Sódica/administração & dosagem , Carboximetilcelulose Sódica/efeitos adversos , Colite/patologia , Emulsificantes/administração & dosagem , Fezes/microbiologia , Feminino , Trato Gastrointestinal/patologia , Vida Livre de Germes , Inflamação/induzido quimicamente , Inflamação/microbiologia , Inflamação/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Síndrome Metabólica/patologia , Camundongos , Microbiota/efeitos dos fármacos , Obesidade/induzido quimicamente , Obesidade/microbiologia , Obesidade/patologia , Polissorbatos/administração & dosagem , Polissorbatos/efeitos adversosRESUMO
Consumption of refined high-fat, low-fiber diets promotes development of obesity and its associated consequences. Although genetics play an important role in dictating susceptibility to such obesogenic diets, mice with nearly uniform genetics exhibit marked heterogeneity in their extent of obesity in response to such diets. This suggests non-genetic determinants play a role in diet-induced obesity. Hence, we sought to identify parameters that predict, and/or correlate with, development of obesity in response to an obesogenic diet. We assayed behavior, metabolic parameters, inflammatory markers/cytokines, microbiota composition, and the fecal metaproteome, in a cohort of mice (n = 50) prior to, and the 8 weeks following, administration of an obesogenic high-fat low-fiber diet. Neither behavioral testing nor quantitation of inflammatory markers broadly predicted severity of diet-induced obesity. Although, the small subset of mice that exhibited basal elevations in serum IL-6 (n = 5) were among the more obese mice in the cohort. While fecal microbiota composition changed markedly in response to the obesogenic diet, it lacked the ability to predict which mice were relative prone or resistant to obesity. In contrast, fecal metaproteome analysis revealed functional and taxonomic differences among the proteins associated with proneness to obesity. Targeted interrogation of microbiota composition data successfully validated the taxonomic differences seen in the metaproteome. Although future work will be needed to determine the breadth of applicability of these associations to other cohorts of animals and humans, this study nonetheless highlights the potential power of gut microbial proteins to predict and perhaps impact development of obesity.
Assuntos
Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Obesidade/etiologia , Proteoma/metabolismo , Animais , Composição Corporal , Dieta Hiperlipídica/efeitos adversos , Dieta Ocidental/efeitos adversos , Feminino , Flagelina/metabolismo , Microbioma Gastrointestinal/genética , Imunoglobulina A/sangue , Mediadores da Inflamação/metabolismo , Lipocalina-2/metabolismo , Síndrome Metabólica/etiologia , Síndrome Metabólica/microbiologia , Camundongos Endogâmicos C57BL , Obesidade/microbiologia , Proteoma/análise , RNA Ribossômico 16SRESUMO
Inflammation is a well-characterized critical driver of gastrointestinal cancers. Previous findings have shown that intestinal low-grade inflammation can be promoted by the consumption of select dietary emulsifiers, ubiquitous component of processed foods which alter the composition and function of the gut microbiota. Using a model of colitis-associated cancer, we previously reported that consumption of the dietary emulsifiers carboxymethylcellulose or polysorbate-80 exacerbated colonic tumor development. Here, we investigate the impact of dietary emulsifiers consumption on cancer initiation and progression in a genetical model of intestinal adenomas. In APCmin mice, we observed that dietary emulsifiers consumption enhanced small-intestine tumor development in a way that appeared to be independent of chronic intestinal inflammation but rather associated with emulsifiers' impact on the proliferative status of the intestinal epithelium as well as on intestinal microbiota composition in both male and female mice. Overall, our findings further support the hypothesis that emulsifier consumption may be a new modifiable risk factor for colorectal cancer (CRC) and that alterations in host-microbiota interactions can favor gastrointestinal carcinogenesis in individuals with a genetical predisposition to such disorders.
Assuntos
Adenoma/induzido quimicamente , Neoplasias Colorretais/induzido quimicamente , Dieta/efeitos adversos , Emulsificantes/efeitos adversos , Trato Gastrointestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Animais , Carboximetilcelulose Sódica/química , Carcinogênese/induzido quimicamente , Proliferação de Células/efeitos dos fármacos , Feminino , Aditivos Alimentares/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/induzido quimicamente , Mucosa Intestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polissorbatos/químicaRESUMO
Natural mineral water (NMWs) intake has been traditionally used in the treatment of various gastrointestinal diseases. We investigated the effect of two French NMWs, one a calcium and magnesium sulphate, sodium chloride, carbonic, and ferruginous water (NMW1), the other a mainly bicarbonate water (NMW2) on the prevention of intestinal inflammation. Intestinal epithelial cells stimulated with heat inactivated Escherichia coli or H2O2 were treated with NMWs to evaluate the anti-inflammatory effects. Moderate colitis was induced by 1% dextran sulfate sodium (DSS) in Balbc/J mice drinking NMW1, NWW2, or control water. General signs and histological features of colitis, fecal lipocalin-2 and pro-inflammatory KC cytokine levels, global mucosa-associated microbiota, were analyzed. We demonstrated that both NMW1 and NMW2 exhibited anti-inflammatory effects using intestinal cells. In induced-colitis mice, NMW1 was effective in dampening intestinal inflammation, with significant reductions in disease activity scores, fecal lipocalin-2 levels, pro-inflammatory KC cytokine release, and intestinal epithelial lesion sizes. Moreover, NMW1 was sufficient to prevent alterations in the mucosa-associated microbiota. These observations, through mechanisms involving modulation of the mucosa-associated microbiota, emphasize the need of investigation of the potential clinical efficiency of such NMWs to contribute, in human beings, to a state of low inflammation in inflammatory bowel disease.