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1.
Nutrients ; 13(7)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34371983

RESUMO

The worldwide prevalence of metabolic diseases such as obesity, metabolic syndrome and type 2 diabetes shows an upward trend in recent decades. A characteristic feature of these diseases is hyperglycemia which can be associated with hyperphagia. Absorption of glucose in the small intestine physiologically contributes to the regulation of blood glucose levels, and hence, appears as a putative target for treatment of hyperglycemia. In fact, recent progress in understanding the molecular and cellular mechanisms of glucose absorption in the gut and its reabsorption in the kidney helped to develop a new strategy of diabetes treatment. Changes in blood glucose levels are also involved in regulation of appetite, suggesting that glucose absorption may be relevant to hyperphagia in metabolic diseases. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. The key role of SGLT1 transporter in intestinal glucose absorption in both physiological conditions and in diabetes was clearly established. We conclude that although inhibition of small intestinal glucose absorption represents a valuable target for the treatment of hyperglycemia, it is not always suitable for the treatment of hyperphagia. In fact, independent regulation of glucose absorption and appetite requires a more complex approach for the treatment of metabolic diseases.


Assuntos
Regulação do Apetite , Glucose/metabolismo , Hiperglicemia/metabolismo , Absorção Intestinal/fisiologia , Doenças Metabólicas/metabolismo , Humanos , Hiperglicemia/etiologia , Intestino Delgado/metabolismo , Doenças Metabólicas/complicações , Transportador 1 de Glucose-Sódio/metabolismo
2.
Science ; 373(6553)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34437091

RESUMO

The biogenesis of high-density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most of the HDL in the blood, HDL synthesis also occurs in the small intestine. Here, we show that intestine-derived HDL traverses the portal vein in the HDL3 subspecies form, in complex with lipopolysaccharide (LPS)-binding protein (LBP). HDL3, but not HDL2 or low-density lipoprotein, prevented LPS binding to and inflammatory activation of liver macrophages and instead supported extracellular inactivation of LPS. In mouse models involving surgical, dietary, or alcoholic intestinal insult, loss of intestine-derived HDL worsened liver injury, whereas outcomes were improved by therapeutics that elevated and depended upon raising intestinal HDL. Thus, protection of the liver from injury in response to gut-derived LPS is a major function of intestinally synthesized HDL.


Assuntos
Intestino Delgado/metabolismo , Lipoproteínas HDL3/metabolismo , Hepatopatias/prevenção & controle , Fígado/metabolismo , Veia Porta/metabolismo , Proteínas de Fase Aguda/metabolismo , Adulto , Animais , Proteínas de Transporte/metabolismo , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Enterócitos/metabolismo , Humanos , Intestino Delgado/cirurgia , Macrófagos do Fígado/imunologia , Macrófagos do Fígado/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/metabolismo , Lipoproteínas HDL3/sangue , Fígado/patologia , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Hepatopatias/patologia , Receptores X do Fígado/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
3.
Nutrients ; 13(7)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34371835

RESUMO

The small intestine is key in the digestion and absorption of macro and micronutrients. The large intestine is essential for the absorption of water, to allow adequate defecation, and to harbor intestinal microbiota, for which their nutritional role is as important as it is unknown. This article will describe the causes and consequences of malnutrition in patients with inflammatory bowel diseases, the importance of screening and replacement of micronutrient deficits, and the main indications for enteral and parenteral nutrition in these patients. We will also discuss the causes of short bowel syndrome, a complex entity due to anatomical or functional loss of part of the small bowel, which can cause insufficient absorption of liquid, electrolytes, and nutrients and lead to complex management. Finally, we will review the causes, consequences, and management of malnutrition in patients with malignant and benign digestive tumors, including neuroendocrine tumors (present not only in the intestine but also in the pancreas).


Assuntos
Neoplasias do Sistema Digestório/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Intestino Grosso/metabolismo , Intestino Delgado/metabolismo , Desnutrição/etiologia , Síndrome do Intestino Curto/metabolismo , Digestão , Neoplasias do Sistema Digestório/complicações , Absorção Gastrointestinal , Humanos , Doenças Inflamatórias Intestinais/complicações , Apoio Nutricional , Síndrome do Intestino Curto/complicações
4.
Nat Commun ; 12(1): 4462, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294718

RESUMO

RORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Intestino Delgado/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Diferenciação Celular , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/deficiência , Proteínas de Grupo de Alta Mobilidade/genética , Homeostase/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Masculino , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Organoides , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Subpopulações de Linfócitos T/citologia , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo
5.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298894

RESUMO

(1) The high-fat diet (HFD) of western countries has dramatic effect on the health of several organs, including the digestive tract, leading to the accumulation of fats that can also trigger a chronic inflammatory process, such as that which occurs in non-alcohol steatohepatitis. The effects of a HFD on the small intestine, the organ involved in the absorption of this class of nutrients, are still poorly investigated. (2) To address this aspect, we administered a combined HFD with sucrose (HFD w/Suc, fat: 58% Kcal) regimen (18 months) to mice and investigated the morphological and molecular changes that occurred in the wall of proximal tract of the small intestine compared to the intestine of mice fed with a standard diet (SD) (fat: 18% Kcal). (3) We found an accumulation of lipid droplets in the mucosa of HFD w/Suc-fed mice that led to a disarrangement of mucosa architecture. Furthermore, we assessed the expression of several key players involved in lipid metabolism and inflammation, such as perilipin, leptin, leptin receptor, PI3K, p-mTOR, p-Akt, and TNF-α. All these molecules were increased in HFD mice compared to the SD group. We also evaluated anti-inflammatory molecules like adiponectin, adiponectin receptor, and PPAR-γ, and observed their significant reduction in the HFD w/Suc group compared to the control. Our data are in line with the knowledge that improper eating habits present a primary harmful assault on the bowel and the entire body's health. (4) These results represent a promising starting point for future studies, helping to better understand the complex and not fully elucidated spectrum of intestinal alterations induced by the overconsumption of fat.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/administração & dosagem , Sacarose na Dieta/efeitos adversos , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Adiponectina/metabolismo , Animais , Comportamento Alimentar/fisiologia , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/patologia , PPAR gama/metabolismo , Receptores para Leptina/metabolismo
6.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206340

RESUMO

Intestinal organoids are used to analyze the differentiation of enteroendocrine cells (EECs) and to manipulate their density for treating type 2 diabetes. EEC differentiation is a continuous process tightly regulated in the gut by a complex regulatory network. However, the effect of chronic hyperglycemia, in the modulation of regulatory networks controlling identity and differentiation of EECs, has not been analyzed. This study aimed to investigate the effect of glucotoxicity on EEC differentiation in small intestinal organoid platforms. Mouse intestinal organoids were cultured in the presence/absence of high glucose concentrations (35 mM) for 48 h to mimic glucotoxicity. Chronic hyperglycemia impaired the expression of markers related to the differentiation of EEC progenitors (Ngn3) and L-cells (NeuroD1), and it also reduced the expression of Gcg and GLP-1 positive cell number. In addition, the expression of intestinal stem cell markers was reduced in organoids exposed to high glucose concentrations. Our data indicate that glucotoxicity impairs L-cell differentiation, which could be associated with decreased intestinal stem cell proliferative capacity. This study provides the identification of new targets involved in new molecular signaling mechanisms impaired by glucotoxicity that could be a useful tool for the treatment of type 2 diabetes.


Assuntos
Diferenciação Celular , Células Enteroendócrinas/metabolismo , Hiperglicemia/complicações , Intestino Delgado/metabolismo , Organoides , Animais , Diabetes Mellitus Tipo 2/complicações , Células Enteroendócrinas/efeitos dos fármacos , Células Enteroendócrinas/fisiologia , Glucose/metabolismo , Glucose/toxicidade , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/fisiopatologia , Células L , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
7.
Clin Transl Gastroenterol ; 12(6): e00367, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34092778

RESUMO

Severe acute respiratory syndrome coronavirus 2 infection has been associated with both endotoxemia and thrombosis of small and large vessels, but the relationship between these 2 phenomena has not been pursued. Oliva et al. in this issue of Clinical and Translational Gastroenterology demonstrate an association between the 2 findings and suggest that increased intestinal permeability is a possible mechanism to explain the endotoxemia. Although the evidence to support this hypothesis is only suggestive, the role of the small intestine in the illness produced by the virus needs to be further explored.


Assuntos
COVID-19 , Endotoxemia , Intestino Delgado , SARS-CoV-2 , Trombose , COVID-19/sangue , COVID-19/complicações , COVID-19/fisiopatologia , Correlação de Dados , Endotoxemia/diagnóstico , Endotoxemia/metabolismo , Endotoxemia/virologia , Humanos , Intestino Delgado/metabolismo , Intestino Delgado/virologia , Permeabilidade , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Trombose/sangue , Trombose/diagnóstico , Trombose/etiologia
8.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070501

RESUMO

Our goal was to analyze postmortem tissues of an adult patient with late-onset thymidine kinase 2 (TK2) deficiency who died of respiratory failure. Compared with control tissues, we found a low mtDNA content in the patient's skeletal muscle, liver, kidney, small intestine, and particularly in the diaphragm, whereas heart and brain tissue showed normal mtDNA levels. mtDNA deletions were present in skeletal muscle and diaphragm. All tissues showed a low content of OXPHOS subunits, and this was especially evident in diaphragm, which also exhibited an abnormal protein profile, expression of non-muscular ß-actin and loss of GAPDH and α-actin. MALDI-TOF/TOF mass spectrometry analysis demonstrated the loss of the enzyme fructose-bisphosphate aldolase, and enrichment for serum albumin in the patient's diaphragm tissue. The TK2-deficient patient's diaphragm showed a more profound loss of OXPHOS proteins, with lower levels of catalase, peroxiredoxin 6, cytosolic superoxide dismutase, p62 and the catalytic subunits of proteasome than diaphragms of ventilated controls. Strong overexpression of TK1 was observed in all tissues of the patient with diaphragm showing the highest levels. TK2 deficiency induces a more profound dysfunction of the diaphragm than of other tissues, which manifests as loss of OXPHOS and glycolytic proteins, sarcomeric components, antioxidants and overactivation of the TK1 salvage pathway that is not attributed to mechanical ventilation.


Assuntos
DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Diafragma/metabolismo , Mitocôndrias/metabolismo , Insuficiência Respiratória/metabolismo , Timidina Quinase/deficiência , Timidina Quinase/genética , Actinas/metabolismo , Adulto , Autopsia , Encéfalo/metabolismo , Catalase/metabolismo , Diafragma/enzimologia , Feminino , Frutose-Bifosfato Aldolase/metabolismo , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Humanos , Intestino Delgado/metabolismo , Rim/metabolismo , Fígado/metabolismo , Espectrometria de Massas , Mitocôndrias/enzimologia , Mitocôndrias/genética , Músculo Esquelético/metabolismo , Fosforilação Oxidativa , Peroxirredoxina VI/metabolismo , Complexo de Endopeptidases do Proteassoma , Proteoma/genética , Proteoma/metabolismo , Insuficiência Respiratória/genética , Insuficiência Respiratória/mortalidade , Superóxido Dismutase/metabolismo , Timidina Quinase/metabolismo , Regulação para Cima
9.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074061

RESUMO

BACKGROUND: Erythritol, a sugar alcohol, is widely used as a substitute for sugar in diets for patients with diabetes or obesity. METHODS: In this study, we aimed to investigate the effects of erythritol on metabolic disorders induced by a high-fat diet in C57BL/6J mice, while focusing on changes in innate immunity. RESULTS: Mice that were fed a high-fat diet and administered water containing 5% erythritol (Ery group) had markedly lower body weight, improved glucose tolerance, and markedly higher energy expenditure than the control mice (Ctrl group) (n = 6). Furthermore, compared with the Ctrl group, the Ery group had lesser fat deposition in the liver, smaller adipocytes, and significantly better inflammatory findings in the small intestine. The concentrations of short-chain fatty acids (SCFAs), such as acetic acid, propanoic acid, and butanoic acid, in the serum, feces, and white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. In flow cytometry experiments, group 3 innate lymphoid cell (ILC3) counts in the lamina propria of the small intestine and ILC2 counts in the white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. Quantitative real-time reverse transcription polymerase chain reaction analyses showed that the Il-22 expression in the small intestine of the Ery group was markedly higher than that in the Ctrl group. CONCLUSIONS: Erythritol markedly decreased metabolic disorders such as diet-induced obesity, glucose intolerance, dyslipidemia, and fat accumulation in the mouse liver by increasing SCFAs and modulating innate immunity.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Eritritol/farmacologia , Intolerância à Glucose/dietoterapia , Imunidade Inata/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Metabolismo Energético/efeitos dos fármacos , Eritritol/administração & dosagem , Ácidos Graxos Voláteis/sangue , Ácidos Graxos Voláteis/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Intolerância à Glucose/metabolismo , Imunidade Inata/genética , Inflamação/dietoterapia , Inflamação/genética , Inflamação/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Obesidade/genética , Obesidade/metabolismo
10.
Nat Commun ; 12(1): 3318, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083536

RESUMO

Dormancy, a reversible quiescent cellular state characterized by greatly reduced metabolic activity, protects from genetic damage, prolongs survival and is crucial for tissue homeostasis and cellular response to injury or transplantation. Dormant cells have been characterized in many tissues, but their identification, isolation and characterization irrespective of tissue of origin remains elusive. Here, we develop a live cell ratiometric fluorescent Optical Stem Cell Activity Reporter (OSCAR) based on the observation that phosphorylation of RNA Polymerase II (RNApII), a hallmark of active mRNA transcription elongation, is largely absent in dormant stem cells from multiple lineages. Using the small intestinal crypt as a model, OSCAR reveals in real time the dynamics of dormancy induction and cellular differentiation in vitro, and allows the identification and isolation of several populations of transcriptionally diverse OSCARhigh and OSCARlow intestinal epithelial cell states in vivo. In particular, this reporter is able to identify a dormant OSCARhigh cell population in the small intestine. OSCAR therefore provides a tool for a better understanding of dormant stem cell biology.


Assuntos
RNA Polimerase II/metabolismo , Fase de Repouso do Ciclo Celular/fisiologia , Animais , Separação Celular , Quinase 9 Dependente de Ciclina/metabolismo , Citometria de Fluxo , Corantes Fluorescentes/metabolismo , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Transcrição Genética
11.
Nat Commun ; 12(1): 3371, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099671

RESUMO

The role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such as Tritrichomonas muris and Nippostrongylus brasiliensis. Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca2+ influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity.


Assuntos
Imunidade Inata/imunologia , Intestinos/imunologia , Nippostrongylus/imunologia , Doenças Parasitárias/imunologia , Tritrichomonas/imunologia , Proteína Supressora de Tumor p53/imunologia , Animais , Linhagem Celular Tumoral , Eosinófilos/imunologia , Eosinófilos/parasitologia , Regulação da Expressão Gênica , Células Caliciformes/imunologia , Células Caliciformes/parasitologia , Interações Hospedeiro-Parasita/imunologia , Humanos , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Intestino Delgado/parasitologia , Intestinos/parasitologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nippostrongylus/fisiologia , Doenças Parasitárias/metabolismo , Doenças Parasitárias/parasitologia , Tritrichomonas/fisiologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
12.
Nat Commun ; 12(1): 3339, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099655

RESUMO

The intestinal epithelium is a complex structure that integrates digestive, immunological, neuroendocrine, and regenerative functions. Epithelial homeostasis is maintained by a coordinated cross-talk of different epithelial cell types. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here we show that the intestine-enriched miR-802 is a central regulator of intestinal epithelial cell proliferation, Paneth cell function, and enterocyte differentiation. Genetic ablation of mir-802 in the small intestine of mice leads to decreased glucose uptake, impaired enterocyte differentiation, increased Paneth cell function and intestinal epithelial proliferation. These effects are mediated in part through derepression of the miR-802 target Tmed9, a modulator of Wnt and lysozyme/defensin secretion in Paneth cells, and the downstream Wnt signaling components Fzd5 and Tcf4. Mutant Tmed9 mice harboring mutations in miR-802 binding sites partially recapitulate the augmented Paneth cell function of mice lacking miR-802. Our study demonstrates a broad miR-802 network that is important for the integration of signaling pathways of different cell types controlling epithelial homeostasis in the small intestine.


Assuntos
Diferenciação Celular/fisiologia , Enterócitos/metabolismo , Intestino Delgado/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Celulas de Paneth/metabolismo , Animais , Proliferação de Células , Feminino , Receptores Frizzled/metabolismo , Expressão Gênica , Células HEK293 , Homeostase/fisiologia , Humanos , Mucosa Intestinal/metabolismo , Intestinos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Salmonella typhimurium , Fator de Transcrição 4/metabolismo , Transcriptoma , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Via de Sinalização Wnt
13.
Food Chem ; 362: 130233, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34090043

RESUMO

The present study aimed to investigate the bioavailability of soybean polysaccharides and their metabolites on gut microbiota in the simulator of the human intestinal microbial ecosystem (SHIME). The effects of soybean polysaccharides on probiotics and pathogenic bacteria were investigated in vitro. Our results showed that soybean polysaccharides were only partially degraded in the oral, gastric, and small intestinal compartments of the SHIME. Moreover, the polysaccharides could be mainly broken down and utilized by the gut microbiota in the colon of the SHIME. Soybean polysaccharides could significantly reduce the ratio of Firmicutes to Bacteroidetes at the phylum level. Therefore, the number of beneficial bacteria were noticeably enhanced, and the pathogenic bacteria were inhibited. Furthermore, soybean polysaccharides promoted the growth of probiotics and improved the ability of these probiotics to inhibit pathogenic bacteria. Therefore, soybean polysaccharides could potentially be functional food to prevent disease by promoting gut health.


Assuntos
Bactérias/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Polissacarídeos/farmacologia , Probióticos , Soja/química , Bactérias/metabolismo , Disponibilidade Biológica , Colo/metabolismo , Colo/microbiologia , Ecossistema , Humanos , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Polissacarídeos/metabolismo
14.
Am J Physiol Gastrointest Liver Physiol ; 321(1): G41-G51, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33949197

RESUMO

Assessing intestinal development and host-microbe interactions in healthy human infants requires noninvasive approaches. We have shown that the transcriptome of exfoliated epithelial cells in feces can differentiate breast-fed and formula-fed infants and term and preterm infants. However, it is not fully understood which regions of the intestine that the exfoliated cells represent. Herein, the transcriptional profiles of exfoliated cells with that of the ileal and colonic mucosa were compared. We hypothesized that exfoliated cells in the distal colon would reflect mucosal signatures of more proximal regions of the gut. Two-day-old piglets (n = 8) were fed formulas for 20 days. Luminal contents and mucosa were collected from ileum (IL), ascending colon (AC), and descending (DC) colon, and mRNA was extracted and sequenced. On average, ∼13,000 genes were mapped in mucosal tissues and ∼10,000 in luminal contents. The intersection of detected genes between three mucosa regions and DC exfoliome indicated an approximately 99% overlap. On average, 49% of the genes in IL, AC, and DC mucosa were present in the AC and DC exfoliome. Genes expressed predominantly in specific anatomic sites (stomach, pancreas, small intestine, colon) were detectable in exfoliated cells. In addition, gene markers for all intestinal epithelial cell types were expressed in the exfoliome representing a diverse array of cell types arising from both the small and large intestine. Genes were mapped to nutrient absorption and transport and immune function. Thus, the exfoliome represents a robust reservoir of information in which to assess intestinal development and responses to dietary interventions.NEW & NOTEWORTHY The transcriptome of exfoliated epithelial cells in stool contain gene signatures from both small and large intestinal mucosa affording a noninvasive approach to assess gut health and function.


Assuntos
Células Epiteliais/metabolismo , Intestino Grosso/metabolismo , Intestino Delgado/metabolismo , Transcriptoma/fisiologia , Animais , Colo/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Mucosa Intestinal/metabolismo , Suínos
15.
Am J Physiol Gastrointest Liver Physiol ; 321(1): G75-G86, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34009042

RESUMO

The absorptive cells of the small intestine, namely, enterocytes, contribute to postprandial blood lipid levels by secreting dietary triacylglycerol in chylomicrons. The rate and amount of dietary triacylglycerol absorbed vary along the length of the small intestine. Excess dietary triacylglycerol not immediately secreted in chylomicrons can be temporarily stored in cytoplasmic lipid droplets (CLDs) and repackaged in chylomicrons at later times. The characteristics of CLDs, including their size, number per cell, and associated proteins, may influence CLD metabolism and reflect differences in lipid processing or storage in each intestinal region. However, it is unknown whether the characteristics or proteomes of CLDs differ in enterocytes of each intestine region in response to dietary fat. Furthermore, it is unclear if obesity influences the characteristics or proteomes of CLDs in each intestine region. To address this, we used transmission electron microscopy and shotgun liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis to assess the characteristics and proteome of CLDs in the proximal, middle, and distal regions of the small intestine of lean and diet-induced obese (DIO) mice 2 h after an oil gavage. We identified differences in lipid storage along the length of the small intestine and between lean and DIO mice, as well as distinct CLD proteomes reflecting potentially unique roles of CLDs in each region. This study reveals differences in lipid processing along the length of the small intestine in response to dietary fat in lean and DIO mice and reflects distinct features of the proximal, middle, distal region of the small intestine.NEW & NOTEWORTHY This study reflects the dynamics of fat absorption along the length of the small intestine in lean and obese mice in the physiological response to dietary fat. We identified unique features of cytoplasmic lipid droplets (CLDs) in the proximal, middle, and distal regions of the small intestine of lean and obese mice that may contribute to regional differences in dietary fat processing, absorption, or CLD metabolism.


Assuntos
Gorduras na Dieta/metabolismo , Intestino Delgado/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/fisiologia , Animais , Citosol/metabolismo , Enterócitos/metabolismo , Intestinos , Camundongos , Triglicerídeos/metabolismo
16.
Biochem Biophys Res Commun ; 559: 135-140, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33940384

RESUMO

Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor (GEF) for Cdc42. In humans, homozygous or compound heterozygous deletions in DOCK8 cause a combined immunodeficiency characterized by various allergic diseases including food allergies. Although group 2 innate lymphoid cells (ILC2s) contribute to the development of allergic inflammation by producing interleukin (IL)-5 and IL-13, the role of ILC2s in DOCK8 deficiency has not been fully explored. With the use of cytometry by time-of-flight (CyTOF), we performed high-dimensional phenotyping of intestinal immune cells and found that DOCK8-deficient (Dock8-/-) mice exhibited expansion of ILC2s and other leukocytes associated with type 2 immunity in the small intestine. Moreover, IL-5- and IL-13-producing cells markedly increased in Dock8-/- mice, and the majority of them were lineage-negative cells, most likely ILC2s. Intestinal ILC2s expanded when DOCK8 expression was selectively deleted in hematopoietic cells. Importantly, intestinal ILC2 expansion was also observed in Dock8VAGR mice having mutations in the catalytic center of DOCK8, thereby failing to activate Cdc42. Our findings indicate that DOCK8 is a negative regulator of intestinal ILC2s to inhibit their expansion via Cdc42 activation, and that deletion of DOCK8 causes a skewing to type 2 immunity in the gut.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/imunologia , Imunidade Inata , Intestino Delgado/imunologia , Linfócitos/imunologia , Animais , Deleção de Genes , Fatores de Troca do Nucleotídeo Guanina/genética , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Linfócitos/citologia , Camundongos Endogâmicos C57BL
17.
Environ Toxicol Pharmacol ; 86: 103672, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33989784

RESUMO

Clinical studies have shown that Intrahepatic cholestasis is closely related to intestinal injury. The gut-liver axis theory suggests that the intestine and liver are closely related, and that bile acids are important mediators linking the intestine and liver. We compared two cholestasis models: a single injection model that received a single subcutaneous ANIT injection (75 mg/kg), and a multiple subcutaneous injection model that received an injection of ANIT (50 mg/kg) every other day for 2 weeks. We used Transmetil (ademetionine 1,4-butanedisulfonate) to relieve intrahepatic cholestasis in the multiple injection group. In the multiple injection group, we found increased hepatic bile duct hyperplasia, increased fibrosis of the liver, increased small intestine inflammation and oxidative damage, increased harmful bile acids, decreased bile acids transporter levels. After treatment with Transmetil, the liver and gut injuries were relieved. These results suggest that intrahepatic cholestasis can cause disorders of the gut-liver axis.


Assuntos
1-Naftilisotiocianato , Colestase Intra-Hepática/induzido quimicamente , Enteropatias/induzido quimicamente , Cirrose Hepática/induzido quimicamente , Animais , Ácidos e Sais Biliares/análise , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/patologia , Citocinas/genética , Fezes/química , Enteropatias/genética , Enteropatias/patologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL
18.
Diabetes Res Clin Pract ; 176: 108818, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33932493

RESUMO

OBJECTIVE: Gestational diabetes mellitus (GDM) is a common complication of pregnancy. The purpose of this study was to compare the incidence of small intestinal bacterial overgrowth (SIBO) in patients with GDM and the control group by methane and hydrogen lactulose breath test (LBT), and to explore its relationship with inflammation, vitamins, and the outcomes of maternal and child. METHODS: LBT was detected in 220 GDM patients, 160 pregnancy control patients and 160 pre-pregnancy control patients. The fasting blood glucose, white blood cells, vitamin A, D, E, neonatal weight, neonatal blood glucose and so on were compared and analyzed. RESULTS: There was no statistical significance in the general data of the three groups. The proportion of abdominal distension in the GDM group was higher than that in the other two groups (P < 0.001). The positive rates of SIBO + in GDM group, gestational control group and pre-pregnancy control group were 54.55%, 27.50% and 14.38%, respectively. The average abundance of hydrogen and methane in GDM group was significantly higher than that in control group at each time point. In the GDM group, SIBO + subjects had higher levels of fasting blood glucose, glycoglycated hemoglobin, C-reactive protein, neonatal weight, and lower levels of vitamin D and neonatal blood glucose (P < 0.001). CONCLUSION: Patients with GDM have a high incidence of SIBO, and SIBO may further increase their blood glucose by affecting inflammatory response and vitamin level, and even affect the outcome of mother and child.


Assuntos
Diabetes Gestacional/diagnóstico , Disbiose/diagnóstico , Microbioma Gastrointestinal/fisiologia , Hidrogênio/análise , Metano/análise , Adulto , Glicemia/análise , Glicemia/metabolismo , Testes Respiratórios/métodos , Estudos de Casos e Controles , Diabetes Gestacional/metabolismo , Diabetes Gestacional/microbiologia , Disbiose/complicações , Disbiose/metabolismo , Feminino , Humanos , Hidrogênio/metabolismo , Recém-Nascido , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Lactulose/análise , Lactulose/metabolismo , Metano/metabolismo , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/metabolismo , Complicações na Gravidez/microbiologia , Respiração
19.
Nat Commun ; 12(1): 3074, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031373

RESUMO

Single-cell RNA sequencing combined with spatial information on landmark genes enables reconstruction of spatially-resolved tissue cell atlases. However, such approaches are challenging for rare cell types, since their mRNA contents are diluted in the spatial transcriptomics bulk measurements used for landmark gene detection. In the small intestine, enterocytes, the most common cell type, exhibit zonated expression programs along the crypt-villus axis, but zonation patterns of rare cell types such as goblet and tuft cells remain uncharacterized. Here, we present ClumpSeq, an approach for sequencing small clumps of attached cells. By inferring the crypt-villus location of each clump from enterocyte landmark genes, we establish spatial atlases for all epithelial cell types in the small intestine. We identify elevated expression of immune-modulatory genes in villus tip goblet and tuft cells and heterogeneous migration patterns of enteroendocrine cells. ClumpSeq can be applied for reconstructing spatial atlases of rare cell types in other tissues and tumors.


Assuntos
Transporte Biológico/genética , Transporte Biológico/fisiologia , Biologia Computacional/métodos , Intestinos/fisiologia , Animais , Diferenciação Celular , Enterócitos/metabolismo , Células Enteroendócrinas/metabolismo , Células Epiteliais/metabolismo , Epitélio , Expressão Gênica , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Análise de Sequência de RNA
20.
Toxicol Appl Pharmacol ; 423: 115570, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33965372

RESUMO

The expression of transporters on the apical and basal membranes of renal proximal tubular cells are down- or upregulated to various extents under cisplatin (CDDP)-induced acute kidney injury (AKI). However, little is known about the changes in transporters in tissues other than the kidney under CDDP-induced AKI. This study aimed to investigate the modulation of the expression/function of intestinal efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), in CDDP-induced AKI rats. On day 3 after the intraperitoneal administration of CDDP (5 mg/kg) to rats, the expression levels of P-gp and Bcrp were compared with those of normal rats. Further, the absorption of three P-gp substrates (6α-methylprednisolone, rhodamine 123, and gatifloxacin) was evaluated in both groups using conventional loop techniques. In the CDDP-induced AKI rats, P-gp expression in the ileum was markedly decreased to approximately 38% of that in the normal rats. However, no significant changes in Bcrp expression were observed in the AKI rats. In contrast with the reduction in P-gp expression in the AKI rats, the absorption of the three P-gp substrates remained almost the same or decreased in the AKI group. The addition of verapamil (a potent P-gp inhibitor) increased the absorption of the three P-gp substrates to the values obtained from the normal rats. In conclusion, our results suggested that P-gp expression is downregulated in rats with CDDP-induced AKI but that P-gp maintains its potency as a "gatekeeper" against the absorption of xenobiotics by amplifying its individual transport capacity under these conditions.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Cisplatino/toxicidade , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Injúria Renal Aguda/genética , Animais , Antineoplásicos/toxicidade , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Expressão Gênica , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley
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