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Gut Jul 2023In acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death....
OBJECTIVE
In acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death. Understanding how immunological host defence mechanisms fail to protect the intestinal barrier is of great importance in reducing the mortality risk of the disease. Here, we studied the role of the T/Th17 balance for maintaining the intestinal barrier function in a mouse model of severe AP.
DESIGN
AP was induced by partial duct ligation in C57Bl/6 or DEREG mice, in which regulatory T-cells (T) were depleted by intraperitoneal injection of diphtheria toxin. By flow cytometry, functional suppression assays and transcriptional profiling we analysed T activation and characterised T-cells of the lamina propria as well as intraepithelial lymphocytes (IELs) regarding their activation and differentiation. Microbiota composition was examined in intestinal samples as well as in murine and human pancreatic necrosis by 16S rRNA gene sequencing.
RESULTS
The prophylactic Tdepletion enhanced the proinflammatory response in an experimental mouse model of AP but stabilised the intestinal immunological barrier function of Th17 cells and CD8/γδTCR IELs. T depleted animals developed less bacterial translocation to the pancreas. Duodenal overgrowth of the facultative pathogenic taxa which associates with severe disease and infected necrosis was diminished in T depleted animals.
CONCLUSION
T play a crucial role in the counterbalance against systemic inflammatory response syndrome. In AP, T-activation disturbs the duodenal barrier function and permits translocation of commensal bacteria into pancreatic necrosis. Targeting T in AP may help to ameliorate the disease course.
Topics: Mice; Humans; Animals; T-Lymphocytes, Regulatory; Pancreatitis, Acute Necrotizing; Acute Disease; Bacterial Translocation; RNA, Ribosomal, 16S; Mice, Inbred C57BL
PubMed: 36631247
DOI: 10.1136/gutjnl-2022-327448 -
Nature Communications Feb 2024The development of vascular networks in microfluidic chips is crucial for the long-term culture of three-dimensional cell aggregates such as spheroids, organoids,...
The development of vascular networks in microfluidic chips is crucial for the long-term culture of three-dimensional cell aggregates such as spheroids, organoids, tumoroids, or tissue explants. Despite rapid advancement in microvascular network systems and organoid technologies, vascularizing organoids-on-chips remains a challenge in tissue engineering. Most existing microfluidic devices poorly reflect the complexity of in vivo flows and require complex technical set-ups. Considering these constraints, we develop a platform to establish and monitor the formation of endothelial networks around mesenchymal and pancreatic islet spheroids, as well as blood vessel organoids generated from pluripotent stem cells, cultured for up to 30 days on-chip. We show that these networks establish functional connections with the endothelium-rich spheroids and vascular organoids, as they successfully provide intravascular perfusion to these structures. We find that organoid growth, maturation, and function are enhanced when cultured on-chip using our vascularization method. This microphysiological system represents a viable organ-on-chip model to vascularize diverse biological 3D tissues and sets the stage to establish organoid perfusions using advanced microfluidics.
Topics: Microfluidics; Organoids; Tissue Engineering; Endothelium; Islets of Langerhans
PubMed: 38365780
DOI: 10.1038/s41467-024-45710-4 -
Endocrine Reviews Mar 2024Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute and chronic COVID-19... (Review)
Review
Obesity, diabetes mellitus (mostly type 2), and COVID-19 show mutual interactions because they are not only risk factors for both acute and chronic COVID-19 manifestations, but also because COVID-19 alters energy metabolism. Such metabolic alterations can lead to dysglycemia and long-lasting effects. Thus, the COVID-19 pandemic has the potential for a further rise of the diabetes pandemic. This review outlines how preexisting metabolic alterations spanning from excess visceral adipose tissue to hyperglycemia and overt diabetes may exacerbate COVID-19 severity. We also summarize the different effects of SARS-CoV-2 infection on the key organs and tissues orchestrating energy metabolism, including adipose tissue, liver, skeletal muscle, and pancreas. Last, we provide an integrative view of the metabolic derangements that occur during COVID-19. Altogether, this review allows for better understanding of the metabolic derangements occurring when a fire starts from a small flame, and thereby help reducing the impact of the COVID-19 pandemic.
Topics: Humans; COVID-19; Pandemics; SARS-CoV-2; Diabetes Mellitus; Energy Metabolism
PubMed: 37934800
DOI: 10.1210/endrev/bnad032 -
Biomolecules Dec 2023Acute pancreatitis (AP) is a common acute abdomen disease characterized by the pathological activation of digestive enzymes and the self-digestion of pancreatic acinar... (Review)
Review
Acute pancreatitis (AP) is a common acute abdomen disease characterized by the pathological activation of digestive enzymes and the self-digestion of pancreatic acinar cells. Secondary infection and sepsis are independent prognosticators for AP progression and increased mortality. Accumulating anatomical and epidemiological evidence suggests that the dysbiosis of gut microbiota affects the etiology and severity of AP through intestinal barrier disruption, local or systemic inflammatory response, bacterial translocation, and the regulatory role of microbial metabolites in AP patients and animal models. Recent studies discussing the interactions between gut microbiota and the pancreas have opened new scopes for AP, and new therapeutic interventions that target the bacteria community have received substantial attention. This review concentrates on the alterations of gut microbiota and its roles in modulating gut-pancreas axis in AP. The potential therapies of targeting microbes as well as the major challenges of applying those interventions are explored. We expect to understand the roles of microbes in AP diagnosis and treatment.
Topics: Animals; Humans; Pancreatitis; Acute Disease; Pancreas; Microbiota; Gastrointestinal Microbiome
PubMed: 38254659
DOI: 10.3390/biom14010059 -
Best Practice & Research. Clinical... Jul 2023The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease 2019 (COVID-19) can infect multiple tissues, including endocrine organs,... (Review)
Review
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease 2019 (COVID-19) can infect multiple tissues, including endocrine organs, such as the pancreas, adrenal, thyroid, and adipose tissue. The main receptor for SARS-CoV-2, ACE2, is ubiquitously expressed in the cells of the endocrine organs and accordingly, the virus has been detected in various amounts in all endocrine tissues in post-mortem samples from COVID-19 patients. The infection with SARS-CoV-2 may directly lead to organ damage or dysfunction, such as hyperglycaemia or in rare cases, new-onset diabetes. Furthermore, an infection with SARS-CoV-2 may have indirect effects affecting the endocrine system. The exact mechanisms are not yet completely understood and have to be further investigated. Conversely, endocrine diseases may affect the severity of COVID-19 and emphasis has to be laid on reducing the prevalence, or enhance the treatment, of these often non-communicable diseases in the future.
Topics: Humans; COVID-19; SARS-CoV-2; Peptidyl-Dipeptidase A; Angiotensin-Converting Enzyme 2; Endocrine Glands
PubMed: 36907787
DOI: 10.1016/j.beem.2023.101761 -
Molecular Cancer Sep 2023Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC...
Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately high immune reactivity that are characteristic of microsatellite instable tumors. Most CGS6 tumors are positive for Epstein Barr virus and show extremely high levels of methylation and high immune reactivity. In a systematic analysis of genomic and proteomic data, we estimated the potential response rate of each consensus subtype to standard and experimental treatments such as radiation therapy, targeted therapy, and immunotherapy. Interestingly, CGS3 was significantly associated with a benefit from chemoradiation therapy owing to its high basal level of ferroptosis. In addition, we also identified potential therapeutic targets for each consensus subtype. Thus, the consensus subtypes produced a robust classification and provide for additional characterizations for subtype-based customized interventions.
Topics: Humans; Proteomics; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Genomics; Adenocarcinoma; Stomach Neoplasms
PubMed: 37674200
DOI: 10.1186/s12943-023-01796-w