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1.
PLoS Pathog ; 14(3): e1006925, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29522566

RESUMEN

Effector molecules translocated by the Salmonella pathogenicity island (SPI)1-encoded type 3 secretion system (T3SS) critically contribute to the pathogenesis of human Salmonella infection. They facilitate internalization by non-phagocytic enterocytes rendering the intestinal epithelium an entry site for infection. Their function in vivo has remained ill-defined due to the lack of a suitable animal model that allows visualization of intraepithelial Salmonella. Here, we took advantage of our novel neonatal mouse model and analyzed various bacterial mutants and reporter strains as well as gene deficient mice. Our results demonstrate the critical but redundant role of SopE2 and SipA for enterocyte invasion, prerequisite for transcriptional stimulation and mucosal translocation in vivo. In contrast, the generation of a replicative intraepithelial endosomal compartment required the cooperative action of SipA and SopE2 or SipA and SopB but was independent of SopA or host MyD88 signaling. Intraepithelial growth had no critical influence on systemic spread. Our results define the role of SPI1-T3SS effector molecules during enterocyte invasion and intraepithelial proliferation in vivo providing novel insight in the early course of Salmonella infection.


Asunto(s)
Proteínas Bacterianas/metabolismo , Enterocitos/microbiología , Mucosa Intestinal/microbiología , Factor 88 de Diferenciación Mieloide/fisiología , Infecciones por Salmonella/microbiología , Salmonella typhimurium/patogenicidad , Sistemas de Secreción Tipo III/metabolismo , Animales , Proteínas Bacterianas/genética , Proliferación Celular , Enterocitos/metabolismo , Enterocitos/patología , Prueba de Complementación Genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Salmonella/metabolismo , Transducción de Señal , Sistemas de Secreción Tipo III/genética
2.
Brain Behav Immun ; 80: 452-463, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30981713

RESUMEN

Early life stress is known to impair intestinal barrier through induction of intestinal hyperpermeability, low-grade inflammation and microbiota dysbiosis in young adult rodents. Interestingly, those features are also observed in metabolic disorders (obesity and type 2 diabetes) that appear with ageing. Based on the concept of Developmental Origins of Health and Diseases, our study aimed to investigate whether early life stress can trigger metabolic disorders in ageing mice. Maternal separation (MS) is a well-established model of early life stress in rodent. In this study, MS increased fasted blood glycemia, induced glucose intolerance and decreased insulin sensitivity in post-natal day 350 wild type C3H/HeN male mice fed a standard diet without affecting body weight. MS also triggered fecal dysbiosis favoring pathobionts and significantly decreased IL-17 and IL-22 secretion in response to anti-CD3/CD28 stimulation in small intestine lamina propria. Finally, IL-17 secretion in response to anti-CD3/CD28 stimulation was also diminished at systemic level (spleen). For the first time, we demonstrate that early life stress is a risk factor for metabolic disorders development in ageing wild type mice under normal diet.


Asunto(s)
Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/metabolismo , Estrés Psicológico/fisiopatología , Animales , Diabetes Mellitus Tipo 2/complicaciones , Disbiosis/metabolismo , Femenino , Microbioma Gastrointestinal/fisiología , Intolerancia a la Glucosa/fisiopatología , Inflamación/metabolismo , Resistencia a la Insulina/fisiología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Intestinos/microbiología , Masculino , Privación Materna , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Microbiota/fisiología , Obesidad/metabolismo
3.
Gastroenterology ; 153(6): 1594-1606.e2, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28865734

RESUMEN

BACKGROUND & AIMS: Separation of newborn rats from their mothers induces visceral hypersensitivity and impaired epithelial secretory cell lineages when they are adults. Little is known about the mechanisms by which maternal separation causes visceral hypersensitivity or its relationship with defects in epithelial secretory cell lineages. METHODS: We performed studies with C3H/HeN mice separated from their mothers as newborns and mice genetically engineered (Sox9flox/flox-vil-cre on C57BL/6 background) to have deficiencies in Paneth cells. Paneth cell deficiency was assessed by lysozyme staining of ileum tissues and lysozyme activity in fecal samples. When mice were 50 days old, their abdominal response to colorectal distension was assessed by electromyography. Fecal samples were collected and microbiota were analyzed using Gut Low-Density Array quantitative polymerase chain reaction. RESULTS: Mice with maternal separation developed visceral hypersensitivity and defects in Paneth cells, as reported from rats, compared with mice without maternal separation. Sox9flox/flox-vil-Cre mice also had increased visceral hypersensitivity compared with control littermate Sox9flox/flox mice. Fecal samples from mice with maternal separation and from Sox9flox/flox-vil-cre mice had evidence for intestinal dysbiosis of the microbiota, characterized by expansion of Escherichia coli. Daily gavage of conventional C3H/HeN adult mice with 109 commensal E coli induced visceral hypersensitivity. Conversely, daily oral administration of lysozyme prevented expansion of E coli during maternal separation and visceral hypersensitivity. CONCLUSIONS: Mice with defects in Paneth cells (induced by maternal separation or genetically engineered) have intestinal expansion of E coli leading to visceral hypersensitivity. These findings provide evidence that Paneth cell function and intestinal dysbiosis are involved in visceral sensitivity.


Asunto(s)
Ansiedad de Separación/complicaciones , Escherichia coli/crecimiento & desarrollo , Microbioma Gastrointestinal , Hiperalgesia/etiología , Células de Paneth/microbiología , Dolor Visceral/etiología , Factores de Edad , Animales , Animales Recién Nacidos , Ansiedad de Separación/metabolismo , Ansiedad de Separación/microbiología , Ansiedad de Separación/fisiopatología , Modelos Animales de Enfermedad , Disbiosis , Heces/microbiología , Femenino , Predisposición Genética a la Enfermedad , Hiperalgesia/metabolismo , Hiperalgesia/microbiología , Hiperalgesia/fisiopatología , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Muramidasa/administración & dosificación , Muramidasa/metabolismo , Células de Paneth/metabolismo , Fenotipo , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Dolor Visceral/metabolismo , Dolor Visceral/microbiología , Dolor Visceral/fisiopatología
4.
Sci Transl Med ; 12(565)2020 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-33055245

RESUMEN

Although infection with the human enteropathogen Giardia lamblia causes self-limited diarrhea in adults, infant populations in endemic areas experience persistent pathogen carriage in the absence of diarrhea. The persistence of this protozoan parasite in infants has been associated with reduced weight gain and linear growth (height-for-age). The mechanisms that support persistent infection and determine the different disease outcomes in the infant host are incompletely understood. Using a neonatal mouse model of persistent G. lamblia infection, we demonstrate that G. lamblia induced bile secretion and used the bile constituent phosphatidylcholine as a substrate for parasite growth. In addition, we show that G. lamblia infection altered the enteric microbiota composition, leading to enhanced bile acid deconjugation and increased expression of fibroblast growth factor 15. This resulted in elevated energy expenditure and dysregulated lipid metabolism with reduced adipose tissue, body weight gain, and growth in the infected mice. Our results indicate that this enteropathogen's modulation of bile acid metabolism and lipid metabolism in the neonatal mouse host led to an altered body composition, suggesting how G. lamblia infection could contribute to growth restriction in infants in endemic areas.


Asunto(s)
Microbioma Gastrointestinal , Giardiasis , Animales , Bilis , Giardia , Homeostasis , Ratones
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