The global obesity epidemic constitutes a major cause of morbidity and mortality challenging public health care systems worldwide. Thus, a better understanding of its pathophysiology and the ...development of novel therapeutic options are urgently needed. Recently, alterations of the intestinal microbiome in the obese have been discussed as a promoting factor in the pathophysiology of obesity and as a contributing factor to related diseases such as type 2 diabetes and metabolic syndrome. The present pilot study investigated the effect of a structured weight loss program on fecal microbiota in obese type 2 diabetics. Twelve study subjects received a low-calorie formula diet for six weeks, followed by a nine week food reintroduction and stabilization period. Fecal microbiota were determined by 16S rRNA gene sequencing of stool samples at baseline, after six weeks and at the end of the study after fifteen weeks. All study subjects lost weight continuously throughout the program. Changes in fecal microbiota were most pronounced after six weeks of low-calorie formula diet, but reverted partially until the end of the study. However, the gut microbiota phylogenetic diversity increased persistently. The abundance of Collinsella, which has previously been associated with atherosclerosis, decreased significantly during the weight loss program. This study underlines the impact of dietary changes on the intestinal microbiome and further demonstrates the beneficial effects of weight loss on gut microbiota. Trial registration: ClinicalTrials.gov NCT02970838.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Among health care personnel working regular hours or rotating shifts can affect parameters of general health and nutrition. We have investigated physical activity, sleep quality, metabolic activity ...and stress levels in health care workers from both groups.
We prospectively recruited 46 volunteer participants from the workforce of a University Medical Department of which 23 worked in rotating shifts (all nursing) and 21 non-shift regular hours (10 nursing, 13 clerical staff). All were investigated over 7 days by multisensory accelerometer (SenseWear Bodymedia® armband) and kept a detailed food diary. Physical activity and resting energy expenditure (REE) were measured in metabolic equivalents of task (METs). Quality of sleep was assessed as Pittsburgh Sleeping Quality Index and stress load using the Trier Inventory for Chronic Stress questionnaire (TICS).
No significant differences were found for overall physical activity, steps per minute, time of exceeding the 3 METs level or sleep quality. A significant difference for physical activity during working hours was found between shift-workers vs. non-shift-workers (p<0.01) and for shift-working nurses (median = 2.1 METs SE = 0.1) vs. non-shift-working clerical personnel (median = 1.5 METs SE = 0.07, p<0.05). Non-shift-working nurses had a significantly lower REE than the other groups (p<0.05). The proportion of fat in the diet was significantly higher (p<0.05) in the office worker group (median = 42% SE = 1.2) whereas shift-working nurses consumed significantly more carbohydrates (median = 46% SE = 1.4) than clerical staff (median = 41% SE = 1.7). Stress assessment by TICS confirmed a significantly higher level of social overload in the shift working group (p<0.05).
In this prospective cohort study shift-working had no influence on overall physical activity. Lower physical activity during working hours appears to be compensated for during off-hours. Differences in nutritional habits and stress load warrant larger scale trials to determine the effect on implicit health-associated conditions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cathepsin C (CatC, syn. Dipeptidyl peptidase I) is a lysosomal cysteine proteinase expressed in several tissues including inflammatory cells. This enzyme is important for maintaining multiple ...cellular functions and for processing immune cell-derived proteases. While mutations in the CatC gene were reported in Papillon-Lefèvre syndrome, a rare autosomal recessive disorder featuring hyperkeratosis and periodontitis, evidence from clinical and preclinical studies points toward pro-inflammatory effects of CatC in various disease processes that are mainly mediated by the activation of neutrophil serine proteinases. Moreover, tumor-promoting effects were ascribed to CatC. The aim of this review is to highlight current knowledge of the CatC as a potential therapeutic target in inflammatory disorders.
Abstract
Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identify Treg cells as central ...regulators of the fibroinflammatory reaction by a selective depletion of FOXP3-positive cells in a transgenic mouse model (DEREG-mice) of experimental CP. In Treg-depleted DEREG-mice, the induction of CP results in a significantly increased stroma deposition, the development of exocrine insufficiency and significant weight loss starting from day 14 after disease onset. In CP, FOXP3
+
CD25
+
Treg cells suppress the type-2 immune response by a repression of GATA3
+
T helper cells (Th2), GATA3
+
innate lymphoid cells type 2 (ILC2) and CD206
+
M2-macrophages. A suspected pathomechanism behind the fibrotic tissue replacement may involve an observed dysbalance of Activin A expression in macrophages and of its counter regulator follistatin. Our study identified Treg cells as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg/Th2 axis could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue.
Acute pancreatitis is a complex disorder involving both premature intracellular protease activation and inflammatory cell invasion. An initiating event is the intracellular activation of trypsinogen ...by cathepsin B (CTSB), which can be induced directly via G protein–coupled receptors on acinar cells or through inflammatory cells. Here, we studied CTSB regulation by another lysosomal hydrolase, cathepsin D (CTSD), using mice with a complete (CTSD−/−) or pancreas-specific conditional CTSD knockout (KO) (CTSDf/f/p48Cre/+). We induced acute pancreatitis by repeated caerulein injections and isolated acinar and bone marrow cells for ex vivo studies. Supramaximal caerulein stimulation induced subcellular redistribution of CTSD from the lysosomal to the zymogen-containing subcellular compartment of acinar cells and activation of CTSD, CTSB, and trypsinogen. Of note, the CTSD KO greatly reduced CTSB and trypsinogen activation in acinar cells, and CTSD directly activated CTSB but not trypsinogen in vitro. During pancreatitis in pancreas-specific CTSDf/f/p48Cre/+ animals, markers of severity were reduced only at 1 h, whereas in the complete KO, this effect also included the late disease phase (8 h), indicating an important effect of extra-acinar CTSD on course of the disease. CTSD−/− leukocytes exhibited reduced cytokine release after lipopolysaccharide (LPS) stimulation, and CTSD KO also reduced caspase-3 activation and apoptosis in acinar cells stimulated with the intestinal hormone cholecystokinin. In summary, CTSD is expressed in pancreatic acinar and inflammatory cells, undergoes subcellular redistribution and activation during experimental pancreatitis, and regulates disease severity by potently activating CTSB. Its impact is only minimal and transient in the early, acinar cell–dependent phase of pancreatitis and much greater in the later, inflammatory cell–dependent phase of the disease.
Liver cirrhosis is frequently accompanied by disease-related malnutrition (DRM) and sarcopenia, defined as loss of skeletal muscle mass and function. DRM and sarcopenia often coexist in cirrhotic ...patients and are associated with increased morbidity and mortality. The clinical manifestation of both comorbidities are triggered by multifactorial mechanisms including reduced nutrient and energy intake caused by dietary restrictions, anorexia, neuroendocrine deregulation, olfactory and gustatory deficits. Maldigestion and malabsorption due to small intestinal bacterial overgrowth, pancreatic insufficiency or cholestasis may also contribute to DRM and sarcopenia. Decreased protein synthesis and increased protein degradation is the cornerstone mechanism to muscle loss, among others mediated by disease- and inflammation-mediated metabolic changes, hyperammonemia, increased myostatin and reduced human growth hormone. The concise pathophysiological mechanisms and interactions of DRM and sarcopenia in liver cirrhosis are not completely understood. Furthermore, most knowledge in this field are based on experimental models, but only few data in humans exist. This review summarizes known and proposed molecular mechanisms contributing to malnutrition and sarcopenia in liver cirrhosis and highlights remaining knowledge gaps. Since, in the prevention and treatment of DRM and sarcopenia in cirrhotic patients, more research is needed to identify potential biomarkers for diagnosis and development of targeted therapeutic strategies.
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.
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.
The prophylactic T
depletion 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.
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.
Changes in intestinal microbiome composition are associated with inflammatory, metabolic, and malignant disorders. We studied how exocrine pancreatic function affects intestinal microbiota.
We ...performed 16S ribosomal RNA gene sequencing analysis of stool samples from 1795 volunteers from the population-based Study of Health in Pomerania who had no history of pancreatic disease. We also measured fecal pancreatic elastase by enzyme-linked immunosorbent assay and performed quantitative imaging of secretin-stimulated pancreatic fluid secretion. Associations of exocrine pancreatic function with microbial diversity or individual genera were calculated by permutational analysis of variance or linear regression, respectively.
Differences in pancreatic elastase levels associated with significantly (P < .0001) greater changes in microbiota diversity than with participant age, body mass index, sex, smoking, alcohol consumption, or dietary factors. Significant changes in the abundance of 30 taxa, such as an increase in Prevotella (q < .0001) and a decrease of Bacteroides (q < .0001), indicated a shift from a type-1 to a type-2 enterotype. Changes in pancreatic fluid secretion alone were also associated with changes in microbial diversity (P = .0002), although to a lesser degree.
In an analysis of fecal samples from 1795 volunteers, pancreatic acinar cell, rather than duct cell, function is presently the single most significant host factor to be associated with changes in intestinal microbiota composition.
Malnutrition is a common complication of chronic pancreatitis (CP) and liver cirrhosis (LC). Inadequate food intake is considered a relevant driver of malnutrition in both entities. However, the ...contribution of habitual diet to impaired nutritional status is unclear. In a prospective, multicenter cross-sectional study, we recruited patients with confirmed CP or LC and healthy volunteers as a control group. Malnutrition was diagnosed according to the Global Leadership Initiative on Malnutrition criteria. We comprehensively investigated habitual dietary intake on nutrient, food group, and dietary pattern level applying two validated food frequency questionnaires. We included 144 patients (CP: n = 66; LC: n = 78) and 94 control subjects. Malnutrition was prevalent in 64% and 62% of patients with CP or LC, respectively. In both CP and LC, despite slightly altered food group consumption in malnourished and non-malnourished patients there were no differences in energy or nutrient intake as well as dietary quality. Compared to controls patients showed distinct dietary food group habits. Patients consumed less alcohol but also lower quantities of fruits and vegetables as well as whole grain products (p < 0.001, respectively). Nevertheless, overall dietary quality was comparable between patients and healthy controls. Nutritional status in CP and LC patients is rather related to disease than habitual dietary intake supporting the relevance of other etiologic factors for malnutrition such as malassimilation or chronic inflammation. Despite distinct disease-related differences, overall dietary quality in patients with CP or LC was comparable to healthy subjects, which suggests susceptibility to dietary counselling and the benefits of nutrition therapy in these entities.
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