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1.
Cell ; 186(13): 2823-2838.e20, 2023 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-37236193

RESUMEN

Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-ß2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.


Asunto(s)
Sistema Nervioso Entérico , Enfermedades Inflamatorias del Intestino , Humanos , Glucocorticoides/farmacología , Inflamación , Sistema Nervioso Entérico/fisiología , Estrés Psicológico
2.
Nat Immunol ; 24(1): 42-54, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36050414

RESUMEN

Innate lymphoid cells (ILCs) are well-characterized immune cells that play key roles in host defense and tissue homeostasis. Yet, how the three-dimensional (3D) genome organization underlies the development and functions of ILCs is unknown. Herein, we carried out an integrative analysis of the 3D genome structure, chromatin accessibility and gene expression in mature ILCs. Our results revealed that the local 3D configuration of the genome is rewired specifically at loci associated with ILC biology to promote their development and functional differentiation. Importantly, we demonstrated that the ontogenesis of ILC2s and the progression of allergic airway inflammation are determined by a unique local 3D configuration of the region containing the ILC-lineage-defining factor Id2, which is characterized by multiple interactions between the Id2 promoter and distal regulatory elements bound by the transcription factors GATA-3 and RORα, unveiling the mechanism whereby the Id2 expression is specifically controlled in group 2 ILCs.


Asunto(s)
Inmunidad Innata , Linfocitos , Humanos , Inflamación/genética , Inflamación/metabolismo , Linaje de la Célula , Regiones Promotoras Genéticas
3.
Trends Immunol ; 42(5): 375-388, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33849777

RESUMEN

The mammalian immune system has crucial homeostatic functions in different adipose depots. However, white adipose tissue (WAT) inflammation is a hallmark of obesity and can contribute to type 2 diabetes mellitus (T2DM). Recently, mesenchymal cells were identified as highly heterogenous populations displaying specialized immune functions in immune cell migration, activation, survival, and overall lymphoid tissue organization in several tissues. How they regulate the inflammatory milieu within different adipose depots remains unknown. Using recently published single-cell RNA-sequencing (scRNAseq) data sets, we analyze cytokine and chemokine expression of mouse WAT mesenchymal cell subpopulations to highlight potential immunological heterogeneity and specialization, hypothesizing on their immunological functions. This new perspective on immune-mesenchymal cell interactions in adipose tissue may promote studies that heighten our understanding of immune cell processes within WAT during health and obesity. We hope that these studies redefine our knowledge of the roles of mesenchymal cells in regulating adipose tissue inflammation and physiology.


Asunto(s)
Diabetes Mellitus Tipo 2 , Tejido Adiposo , Tejido Adiposo Blanco , Animales , Inflamación , Ratones , Obesidad
4.
PLoS Genet ; 14(6): e1007449, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29902209

RESUMEN

Threespine stickleback fish offer a powerful system to dissect the genetic basis of morphological evolution in nature. Marine sticklebacks have repeatedly invaded and adapted to numerous freshwater environments throughout the Northern hemisphere. In response to new diets in freshwater habitats, changes in craniofacial morphology, including heritable increases in tooth number, have evolved in derived freshwater populations. Using a combination of quantitative genetics and genome resequencing, here we fine-mapped a quantitative trait locus (QTL) regulating evolved tooth gain to a cluster of ten QTL-associated single nucleotide variants, all within intron four of Bone Morphogenetic Protein 6 (Bmp6). Transgenic reporter assays revealed this intronic region contains a tooth enhancer. We induced mutations in Bmp6, revealing required roles for survival, growth, and tooth patterning. Transcriptional profiling of Bmp6 mutant dental tissues identified significant downregulation of a set of genes whose orthologs were previously shown to be expressed in quiescent mouse hair stem cells. Collectively these data support a model where mutations within a Bmp6 intronic tooth enhancer contribute to evolved tooth gain, and suggest that ancient shared genetic circuitry regulates the regeneration of diverse vertebrate epithelial appendages including mammalian hair and fish teeth.


Asunto(s)
Proteína Morfogenética Ósea 6/genética , Smegmamorpha/genética , Animales , Evolución Biológica , Proteína Morfogenética Ósea 6/fisiología , Mapeo Cromosómico , Elementos de Facilitación Genéticos/genética , Evolución Molecular , Agua Dulce , Regulación del Desarrollo de la Expresión Génica/genética , Ligamiento Genético , Genotipo , Intrones/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo , Diente/embriología
5.
Proc Natl Acad Sci U S A ; 111(38): 13912-7, 2014 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-25205810

RESUMEN

Developmental genetic studies of evolved differences in morphology have led to the hypothesis that cis-regulatory changes often underlie morphological evolution. However, because most of these studies focus on evolved loss of traits, the genetic architecture and possible association with cis-regulatory changes of gain traits are less understood. Here we show that a derived benthic freshwater stickleback population has evolved an approximate twofold gain in ventral pharyngeal tooth number compared with their ancestral marine counterparts. Comparing laboratory-reared developmental time courses of a low-toothed marine population and this high-toothed benthic population reveals that increases in tooth number and tooth plate area and decreases in tooth spacing arise at late juvenile stages. Genome-wide linkage mapping identifies largely separate sets of quantitative trait loci affecting different aspects of dental patterning. One large-effect quantitative trait locus controlling tooth number fine-maps to a genomic region containing an excellent candidate gene, Bone morphogenetic protein 6 (Bmp6). Stickleback Bmp6 is expressed in developing teeth, and no coding changes are found between the high- and low-toothed populations. However, quantitative allele-specific expression assays of Bmp6 in developing teeth in F1 hybrids show that cis-regulatory changes have elevated the relative expression level of the freshwater benthic Bmp6 allele at late, but not early, stages of stickleback development. Collectively, our data support a model where a late-acting cis-regulatory up-regulation of Bmp6 expression underlies a significant increase in tooth number in derived benthic sticklebacks.


Asunto(s)
Alelos , Proteína Morfogenética Ósea 6 , Evolución Molecular , Proteínas de Peces , Elementos Reguladores de la Transcripción , Smegmamorpha , Diente/crecimiento & desarrollo , Animales , Secuencia de Bases , Proteína Morfogenética Ósea 6/genética , Proteína Morfogenética Ósea 6/metabolismo , Mapeo Cromosómico , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Ligamiento Genético , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Datos de Secuencia Molecular , Smegmamorpha/genética , Smegmamorpha/metabolismo
6.
Sci Rep ; 14(1): 9998, 2024 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-38693196

RESUMEN

It is estimated that more than half of the world population has been infected with Helicobacter pylori. Most newly acquired H. pylori infections occur in children before 10 years of age. We hypothesized that early life H. pylori infection could influence the composition of the microbiome at mucosal sites distant to the stomach. To test this hypothesis, we utilized the infant rhesus macaque monkey as an animal model of natural H. pylori colonization to determine the impact of infection on the lung and oral microbiome during a window of postnatal development. From a cohort of 4-7 month-old monkeys, gastric biopsy cultures identified 44% of animals infected by H. pylori. 16S ribosomal RNA gene sequencing of lung washes and buccal swabs from animals showed distinct profiles for the lung and oral microbiome, independent of H. pylori infection. In order of relative abundance, the lung microbiome was dominated by the phyla Proteobacteria, Firmicutes, Bacteroidota, Fusobacteriota, Campilobacterota and Actinobacteriota while the oral microbiome was dominated by Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota. In comparison to the oral cavity, the lung was composed of more genera and species that significantly differed by H. pylori status, with a total of 6 genera and species that were increased in H. pylori negative infant monkey lungs. Lung, but not plasma IL-8 concentration was also associated with gastric H. pylori load and lung microbial composition. We found the infant rhesus macaque monkey lung harbors a microbiome signature that is distinct from that of the oral cavity during postnatal development. Gastric H. pylori colonization and IL-8 protein were linked to the composition of microbial communities in the lung and oral cavity. Collectively, these findings provide insight into how H. pylori infection might contribute to the gut-lung axis during early childhood and modulate future respiratory health.


Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Pulmón , Macaca mulatta , Microbiota , Boca , ARN Ribosómico 16S , Animales , Macaca mulatta/microbiología , Pulmón/microbiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Boca/microbiología , ARN Ribosómico 16S/genética , Masculino , Modelos Animales de Enfermedad
7.
Res Sq ; 2023 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-37609264

RESUMEN

Background: It is estimated that more than half of the world population has been infected with Helicobacter pylori. Most newly acquired H. pylori infections occur in children before 10 years of age. We hypothesized that early life H. pylori infection could influence the composition of the microbiome at mucosal sites distant to the stomach. To test this hypothesis, we utilized the infant rhesus macaque monkey as an animal model of natural H. pylori colonization to determine the impact of infection on the lung and oral microbiome during a window of postnatal development. Results: From a cohort of 4-7-month-old monkeys, gastric biopsy cultures identified 44% of animals infected by H. pylori. 16S ribosomal RNA gene sequencing of lung washes and buccal swabs from animals showed distinct profiles for the lung and oral microbiome, independent of H. pylori infection. In relative order of abundance, the lung microbiome was dominated by the phyla Proteobacteria, Firmicutes, Bacteroidota, Fusobacteriota, Campilobacterota and Actinobacteriota while the oral microbiome was dominated by Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota. Relative to the oral cavity, the lung was composed of more genera and species that significantly differed by H. pylori status, with a total of 6 genera and species that were increased in H. pylori negative infant monkey lungs. Lung, but not plasma IL-8 concentration was also associated with gastric H. pylori load and lung microbial composition. Conclusions: We found the infant rhesus macaque monkey lung harbors a microbiome signature that is distinct from that of the oral cavity during postnatal development. Gastric H. pylori colonization and IL-8 protein were linked to the composition of microbial communities in the lung and oral cavity. Collectively, these findings provide insight into how H. pylori infection might contribute to the gut-lung axis during early childhood and modulate future respiratory health.

8.
J Exp Med ; 219(12)2022 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-36074090

RESUMEN

The intestinal epithelium is a key physical interface that integrates dietary and microbial signals to regulate nutrient uptake and mucosal immune cell function. The transcriptional programs that regulate intestinal epithelial cell (IEC) quiescence, proliferation, and differentiation have been well characterized. However, how gene expression networks critical for IECs are posttranscriptionally regulated during homeostasis or inflammatory disease remains poorly understood. Herein, we show that a conserved family of microRNAs, miR-181, is significantly downregulated in IECs from patients with inflammatory bowel disease and mice with chemical-induced colitis. Strikingly, we showed that miR-181 expression within IECs, but not the hematopoietic system, is required for protection against severe colonic inflammation in response to epithelial injury in mice. Mechanistically, we showed that miR-181 expression increases the proliferative capacity of IECs, likely through the regulation of Wnt signaling, independently of the gut microbiota composition. As epithelial reconstitution is crucial to restore intestinal homeostasis after injury, the miR-181 family represents a potential therapeutic target against severe intestinal inflammation.


Asunto(s)
Colitis , MicroARNs , Animales , Colitis/inducido químicamente , Colitis/genética , Células Epiteliales/metabolismo , Inflamación/genética , Inflamación/metabolismo , Mucosa Intestinal , Ratones , MicroARNs/genética , MicroARNs/metabolismo
9.
Sci Transl Med ; 11(496)2019 06 12.
Artículo en Inglés | MEDLINE | ID: mdl-31189717

RESUMEN

The gut microbiota is a key environmental determinant of mammalian metabolism. Regulation of white adipose tissue (WAT) by the gut microbiota is a process critical to maintaining metabolic fitness, and gut dysbiosis can contribute to the development of obesity and insulin resistance (IR). However, how the gut microbiota regulates WAT function remains largely unknown. Here, we show that tryptophan-derived metabolites produced by the gut microbiota controlled the expression of the miR-181 family in white adipocytes in mice to regulate energy expenditure and insulin sensitivity. Moreover, dysregulation of the gut microbiota-miR-181 axis was required for the development of obesity, IR, and WAT inflammation in mice. Our results indicate that regulation of miR-181 in WAT by gut microbiota-derived metabolites is a central mechanism by which host metabolism is tuned in response to dietary and environmental changes. As we also found that MIR-181 expression in WAT and the plasma abundance of tryptophan-derived metabolites were dysregulated in a cohort of obese human children, the MIR-181 family may represent a potential therapeutic target to modulate WAT function in the context of obesity.


Asunto(s)
Microbioma Gastrointestinal/fisiología , Inflamación/metabolismo , Obesidad/metabolismo , Adipocitos/metabolismo , Animales , Metabolismo Energético/genética , Metabolismo Energético/fisiología , Microbioma Gastrointestinal/genética , Inflamación/genética , Resistencia a la Insulina/genética , Resistencia a la Insulina/fisiología , Masculino , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Obesidad/genética , Triptófano/metabolismo
10.
PLoS One ; 12(8): e0183324, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28813514

RESUMEN

Epidemiologic studies have reported an inverse relationship between childhood Helicobacter pylori infection and development of allergic asthma. Because lung epithelium plays an important role in allergic asthma pathogenesis, we hypothesized that H. pylori may directly influence airway epithelial cell innate immune function, particularly in early childhood. To test our hypothesis, we established an in vitro H. pylori infection model using primary tracheobronchial epithelial cell cultures derived from infant, juvenile and adult rhesus monkeys. Airway epithelial cell cultures were infected with wild-type or cag pathogenicity island mutant H. pylori strains, followed by evaluation of IL-8 and IL-6 protein synthesis. We found that H. pylori primarily increased IL-8 synthesis in a MOI and age-dependent fashion, with a greater than 4-fold induction in infant versus adult cultures. H. pylori-induced IL-8 synthesis in infant and juvenile cultures was significantly reduced by cag pathogenicity island mutants, indicating a requirement for the type IV secretion system. Although peptidoglycan recognition of nucleotide binding oligomerization domain-containing protein 1 (NOD1) and NF-kappaB have been implicated as key cytokine signaling molecules for H. pylori infection in gastric epithelium, NOD1 (ML130) or NF-kappaB (JSH-23) inhibitors minimally affected IL-8 synthesis in airway epithelial cell cultures following H. pylori infection. In contrast, inhibition of the p38 MAP kinase pathway (SB203580) resulted in almost complete suppression of H. pylori-induced IL-8 synthesis. Collectively, these results indicate that H. pylori can preferentially elicit IL-8 synthesis in a model of pediatric airway epithelium using the type IV secretion system via p38 MAP kinase.


Asunto(s)
Helicobacter pylori/fisiología , Interleucina-8/metabolismo , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/microbiología , Sistemas de Secreción Tipo IV/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Proteínas Bacterianas/metabolismo , Línea Celular , Infecciones por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , Humanos , Técnicas In Vitro , Interleucina-6/metabolismo , Primates , Mucosa Respiratoria/enzimología , Transducción de Señal/fisiología
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