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1.
Immunity ; 56(5): 1115-1131.e9, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-36917985

RESUMO

Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.


Assuntos
Estresse do Retículo Endoplasmático , Mucosa Intestinal , Células Th17 , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Diferenciação Celular , Humanos , Animais , Camundongos , Camundongos Transgênicos , Antibacterianos/farmacologia
2.
Immunity ; 53(6): 1296-1314.e9, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33296687

RESUMO

Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is needed for understanding skewed immune responses and defining predictors of outcome. Here, we performed a longitudinal multi-omics study using a two-center cohort of 14 patients. We analyzed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of interferon-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling. Megakaryocyte- and erythroid-cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond adaptive immune cells and provides an entry point toward developing biomarkers and targeted treatments of patients with COVID-19.


Assuntos
COVID-19/metabolismo , Células Eritroides/patologia , Megacariócitos/fisiologia , Plasmócitos/fisiologia , SARS-CoV-2/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Circulação Sanguínea , COVID-19/imunologia , Células Cultivadas , Estudos de Coortes , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteômica , Análise de Sequência de RNA , Índice de Gravidade de Doença , Análise de Célula Única
3.
Cell Metab ; 33(12): 2355-2366.e8, 2021 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-34847376

RESUMO

Hexokinases (HK) catalyze the first step of glycolysis limiting its pace. HK2 is highly expressed in gut epithelium, contributes to immune responses, and is upregulated during inflammation. We examined the microbial regulation of HK2 and its impact on inflammation using mice lacking HK2 in intestinal epithelial cells (Hk2ΔIEC). Hk2ΔIEC mice were less susceptible to acute colitis. Analyzing the epithelial transcriptome from Hk2ΔIEC mice during colitis and using HK2-deficient intestinal organoids and Caco-2 cells revealed reduced mitochondrial respiration and epithelial cell death in the absence of HK2. The microbiota strongly regulated HK2 expression and activity. The microbially derived short-chain fatty acid (SCFA) butyrate repressed HK2 expression via histone deacetylase 8 (HDAC8) and reduced mitochondrial respiration in wild-type but not in HK2-deficient Caco-2 cells. Butyrate supplementation protected wild-type but not Hk2ΔIEC mice from colitis. Our findings define a mechanism how butyrate promotes intestinal homeostasis and suggest targeted HK2-inhibition as therapeutic avenue for inflammation.


Assuntos
Colite , Hexoquinase , Animais , Células CACO-2 , Morte Celular/fisiologia , Colite/metabolismo , Colite/microbiologia , Células Epiteliais/metabolismo , Hexoquinase/metabolismo , Histona Desacetilases/metabolismo , Humanos , Camundongos , Mitocôndrias/metabolismo , Proteínas Repressoras/metabolismo
4.
Nutrients ; 12(10)2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33022941

RESUMO

Homeostatic interactions with the microbiome are central for a healthy human physiology and nutrition is the main driving force shaping the microbiome. In the past decade, a wealth of preclinical studies mainly using gnotobiotic animal models demonstrated that malnutrition and chronic inflammation stress these homeostatic interactions and various microbial species and their metabolites or metabolic activities have been associated with disease. For example, the dysregulation of the bacterial metabolism of dietary tryptophan promotes an inflammatory environment and susceptibility to pathogenic infection. Clinical studies have now begun to evaluate the therapeutic potential of nutritional and probiotic interventions in malnutrition and chronic inflammation to ameliorate disease symptoms or even prevent pathogenesis. Here, we therefore summarize the recent progress in this field and propose to move further towards the nutritional targeting of the microbiome for malnutrition and chronic inflammation.


Assuntos
Dieta/efeitos adversos , Inflamação/microbiologia , Desnutrição/microbiologia , Microbiota/fisiologia , Terapia Nutricional/métodos , Animais , Doença Crônica , Disbiose/metabolismo , Disbiose/terapia , Humanos , Inflamação/etiologia , Desnutrição/etiologia , Probióticos/uso terapêutico
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