RESUMEN
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.
Asunto(s)
Pancreatitis Crónica , Linfocitos T Reguladores , Animales , Fibrosis , Factores de Transcripción Forkhead/metabolismo , Inmunidad Innata , Subunidad alfa del Receptor de Interleucina-2/inmunología , Linfocitos/metabolismo , Ratones , Ratones Transgénicos , Pancreatitis Crónica/metabolismoRESUMEN
Microbial metabolites measured using NMR may serve as markers for physiological or pathological host-microbe interactions and possibly mediate the beneficial effects of microbiome diversity. Yet, comprehensive analyses of gut microbiome data and the urine NMR metabolome from large general population cohorts are missing. Here, we report the associations between gut microbiota abundances or metrics of alpha diversity, quantified from stool samples using 16S rRNA gene sequencing, with targeted urine NMR metabolites measures from 951 participants of the Study of Health in Pomerania (SHIP). We detected significant genus-metabolite associations for hippurate, succinate, indoxyl sulfate, and formate. Moreover, while replicating the previously reported association between hippurate and measures of alpha diversity, we identified formate and 4-hydroxyphenylacetate as novel markers of gut microbiome alpha diversity. Next, we predicted the urinary concentrations of each metabolite using genus abundances via an elastic net regression methodology. We found profound associations of the microbiome-based hippurate prediction score with markers of liver injury, inflammation, and metabolic health. Moreover, the microbiome-based prediction score for hippurate completely mediated the clinical association pattern of microbial diversity, hinting at a role of benzoate metabolism underlying the positive associations between high alpha diversity and healthy states. In conclusion, large-scale NMR urine metabolomics delivered novel insights into metabolic host-microbiome interactions, identifying pathways of benzoate metabolism as relevant candidates mediating the beneficial health effects of high microbial alpha diversity.
RESUMEN
BACKGROUND: The human body is inhabited by diverse microorganisms. Together, this so-called microbiome exerts important metabolic functions and contributes to the maintenance of health. At the same time, shifts in the microbiome composition may lead to disease. OBJECTIVES: Review of the current literature about the role of the microbiome in diseases of the pancreas. MATERIALS AND METHODS: Literature search in PubMed and Embase. RESULTS: The exocrine pancreas is a major factor determining the composition and stability of the intestinal microbiome even in healthy people without pancreatic disease. Inflammatory diseases of the pancreas such as acute or chronic pancreatitis lead to reduced microbial diversity, loss of gut barrier stabilizing bacteria and an increase in facultative pathogens like Escherichia or Enterococcus. Even pancreatic cancer tissue harbours microbiota and mice models have shown that the growth of pancreatic cancer can be inhibited by microbiota ablation. CONCLUSIONS: Inflammatory diseases of the pancreas lead to gut microbiome dysbiosis and tumor microbiota probably play a role in the development of pancreatic cancer. Until now, however, there is no proof that therapeutic microbiota modulation in individuals with pancreatic disease can improve mortality or quality of life. At this point, the analysis of the microbiome in pancreatic disease should only be performed in scientific studies.
Asunto(s)
Microbioma Gastrointestinal , Microbiota , Animales , Disbiosis , Humanos , Ratones , Páncreas , Calidad de VidaRESUMEN
Uncovering potential new targets involved in pancreatitis may permit the development of new therapies and improvement of patient's outcome. Acute pancreatitis is a primarily sterile disease characterized by a severe systemic inflammatory response associated with extensive necrosis and a mortality rate of up to 24%. Considering that one of the reported disease mechanisms comprises the endoplasmic reticulum (ER) stress response and that the immunoproteasome is a key regulator to prevent proteotoxic stress in an inflammatory context, we investigated its role in acute pancreatitis. In this study, we demonstrate that immunoproteasome deficiency by deletion of the ß5i/LMP7-subunit leads to persistent pancreatic damage. Interestingly, immunoproteasome-deficient mice unveil increased activity of pancreatic enzymes in the acute disease phase as well as higher secretion of Interleukin-6 and transcript expression of the Interleukin IL-1ß, IFN-ß cytokines and the CXCL-10 chemokine. Cell death was increased in immunoproteasome-deficient mice, which appears to be due to the increased accumulation of ubiquitin-protein conjugates and prolonged unfolded protein response. Accordingly, our findings suggest that the immunoproteasome plays a protective role in acute pancreatitis via its role in the clearance of damaged proteins and the balance of ER stress responses in pancreatic acini and in macrophages cytokine production.
Asunto(s)
Cisteína Endopeptidasas/genética , Pancreatitis/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Animales , Muerte Celular , Células Cultivadas , Quimiocina CXCL10/metabolismo , Cisteína Endopeptidasas/metabolismo , Femenino , Eliminación de Gen , Interferón beta/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Páncreas/metabolismo , UbiquitinaciónRESUMEN
Gallstone disease affects up to twenty percent of the population in western countries and is a significant contributor to morbidity and health care expenditure. Intestinal microbiota have variously been implicated as either contributing to gallstone formation or to be affected by cholecystectomy. We conducted a large-scale investigation on 404 gallstone carriers, 580 individuals post-cholecystectomy and 984 healthy controls with similar distributions of age, sex, body mass index, smoking habits, and food-frequency-score. All 1968 subjects were recruited from the population-based Study-of-Health-in-Pomerania (SHIP), which includes transabdominal gallbladder ultrasound. Fecal microbiota profiles were determined by 16S rRNA gene sequencing. No significant differences in microbiota composition were detected between gallstone carriers and controls. Individuals post-cholecystectomy exhibited reduced microbiota diversity, a decrease in the potentially beneficial genus Faecalibacterium and an increase in the opportunistic pathogen Escherichia/Shigella. The absence of an association between the gut microbiota and the presence of gallbladder stones suggests that there is no intestinal microbial risk profile increasing the likelihood of gallstone formation. Cholecystectomy, on the other hand, is associated with distinct microbiota changes that have previously been implicated in unfavorable health effects and may not only contribute to gastrointestinal infection but also to the increased colon cancer risk of cholecystectomized patients.
Asunto(s)
Enfermedades Asintomáticas , Colecistectomía/efectos adversos , Disbiosis/etiología , Cálculos Biliares/diagnóstico , Cálculos Biliares/cirugía , Microbioma Gastrointestinal , Anciano , Estudios de Casos y Controles , Colecistectomía/métodos , Heces/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , UltrasonografíaRESUMEN
OBJECTIVE: Chronic pancreatitis (CP) is a fibroinflammatory syndrome leading to organ dysfunction, chronic pain, an increased risk for pancreatic cancer and considerable morbidity. Due to a lack of specific biomarkers, diagnosis is based on symptoms and specific but insensitive imaging features, preventing an early diagnosis and appropriate management. DESIGN: We conducted a type 3 study for multivariable prediction for individual prognosis according to the TRIPOD guidelines. A signature to distinguish CP from controls (n=160) was identified using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry on ethylenediaminetetraacetic acid (EDTA)-plasma and validated in independent cohorts. RESULTS: A Naive Bayes algorithm identified eight metabolites of six ontology classes. After algorithm training and computation of optimal cut-offs, classification according to the metabolic signature detected CP with an area under the curve (AUC) of 0.85 ((95% CI 0.79 to 0.91). External validation in two independent cohorts (total n=502) resulted in similar accuracy for detection of CP compared with non-pancreatic controls in EDTA-plasma (AUC 0.85 (95% CI 0.81 to 0.89)) and serum (AUC 0.87 (95% CI 0.81 to 0.95)). CONCLUSIONS: This is the first study that identifies and independently validates a metabolomic signature in plasma and serum for the diagnosis of CP in large, prospective cohorts. The results could provide the basis for the development of the first routine laboratory test for CP.
Asunto(s)
Metabolómica , Pancreatitis Crónica/sangre , Plasma , Teorema de Bayes , Biomarcadores/sangre , Estudios de Casos y Controles , Cromatografía de Gases , Cromatografía Liquida , Femenino , Humanos , Masculino , Espectrometría de Masas , Valor Predictivo de las Pruebas , Pronóstico , Prueba de Estudio ConceptualRESUMEN
Acute pancreatitis (AP) is one of the most common gastroenterological indications for emergency admittance and hospitalization. Gallstones, alcohol consumption or the presence of additional initiating factors give rise to a disease with a diverse clinical appearance and a hard-to predict course of progression. One major challenge in the treatment of AP patients is the early identification of patients at risk for the development of systemic complications and organ failure. In addition, 20%-30% of patients with a first episode of AP later experience progress to recurrent or chronic disease. Complex gene-environment interactions have been identified to play a role in the pathogenesis of pancreatitis, but so far no predictive genetic biomarkers could be implemented into the routine clinical care of AP patients. The current review explains common and rare etiologies of acute pancreatitis with emphasis on underlying genetic aberrations and ensuing clinical management.
RESUMEN
PURPOSE: Exocrine pancreatic function is critically involved in regulating the gut microbiota composition. At the same time, its impairment acutely affects human metabolism. How these 2 roles are connected is unknown. We studied how the exocrine pancreas contributes to metabolism via modulation of gut microbiota. DESIGN: Fecal samples were collected in 2226 participants of the population-based Study of Health in Pomerania (SHIP/SHIP-TREND) to determine exocrine pancreatic function (pancreatic elastase enzyme-linked immunosorbent assay) and intestinal microbiota profiles (16S ribosomal ribonucleic acid gene sequencing). Plasma metabolite levels were determined by mass spectrometry. RESULTS: Exocrine pancreatic function was associated with changes in the abundance of 28 taxa and, simultaneously, with those of 16 plasma metabolites. Mediation pathway analysis revealed that a significant component of how exocrine pancreatic function affects the blood metabolome is mediated via gut microbiota abundance changes, most prominently, circulating serotonin and lysophosphatidylcholines. CONCLUSION: These results imply that the effect of exocrine pancreatic function on intestinal microbiota composition alters the availability of microbial-derived metabolites in the blood and thus directly contributes to the host metabolic changes associated with exocrine pancreatic dysfunction.
Asunto(s)
Microbioma Gastrointestinal/fisiología , Metaboloma , Páncreas Exocrino/fisiología , Adulto , Anciano , Análisis Químico de la Sangre , Proteínas Sanguíneas/metabolismo , Estudios de Cohortes , Femenino , Microbioma Gastrointestinal/genética , Alemania , Humanos , Masculino , Persona de Mediana Edad , ARN Ribosómico 16S/análisis , ARN Ribosómico 16S/genéticaRESUMEN
OBJECTIVE: The intestinal microbiome affects the prevalence and pathophysiology of a variety of diseases ranging from inflammation to cancer. A reduced taxonomic or functional diversity of the microbiome was often observed in association with poorer health outcomes or disease in general. Conversely, factors or manifest diseases that determine the long-term stability or instability of the microbiome are largely unknown. We aimed to identify disease-relevant phenotypes associated with faecal microbiota (in-)stability. DESIGN: A total of 2564 paired faecal samples from 1282 participants of the population-based Study of Health in Pomerania (SHIP) were collected at a 5-year (median) interval and microbiota profiles determined by 16S rRNA gene sequencing. The changes in faecal microbiota over time were associated with highly standardised and comprehensive phenotypic data to determine factors related to microbiota (in-)stability. RESULTS: The overall microbiome landscape remained remarkably stable over time. The greatest microbiome instability was associated with factors contributing to metabolic syndrome such as fatty liver disease and diabetes mellitus. These, in turn, were associated with an increase in facultative pathogens such as Enterobacteriaceae or Escherichia/Shigella. Greatest stability of the microbiome was determined by higher initial alpha diversity, female sex, high household income and preserved exocrine pancreatic function. Participants who newly developed fatty liver disease or diabetes during the 5-year follow-up already displayed significant microbiota changes at study entry when the diseases were absent. CONCLUSION: This study identifies distinct components of metabolic liver disease to be associated with instability of the intestinal microbiome, increased abundance of facultative pathogens and thus greater susceptibility toward dysbiosis-associated diseases.
Asunto(s)
Diabetes Mellitus/metabolismo , Disbiosis/complicaciones , Insuficiencia Pancreática Exocrina/fisiopatología , Microbioma Gastrointestinal , Hepatopatías/metabolismo , Adulto , Anciano , Biodiversidad , Heces/microbiología , Femenino , Microbioma Gastrointestinal/genética , Alemania , Humanos , Renta/estadística & datos numéricos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Fenotipo , ARN Ribosómico 16S/análisis , Factores de Riesgo , Factores SexualesRESUMEN
INTRODUCTION: Exocrine pancreatic function is a critical host factor in determining the intestinal microbiota composition. Diseases affecting the exocrine pancreas could therefore influence the gut microbiome. We investigated the changes in gut microbiota of patients with chronic pancreatitis (CP). METHODS: Patients with clinical and imaging evidence of CP (n = 51) were prospectively recruited and compared with twice the number of nonpancreatic disease controls matched for distribution in age, sex, body mass index, smoking, diabetes mellitus, and exocrine pancreatic function (stool elastase). From stool samples of these 153 subjects, DNA was extracted, and intestinal microbiota composition was determined by bacterial 16S ribosomal RNA gene sequencing. RESULTS: Patients with CP exhibited severely reduced microbial diversity (Shannon diversity index and Simpson diversity number, P < 0.001) with an increased abundance of facultative pathogenic organisms (P < 0.001) such as Enterococcus (q < 0.001), Streptococcus (q < 0.001), and Escherichia.Shigella (q = 0.002). The CP-associated changes were independent of exocrine pancreatic insufficiency. Short-chain fatty acid producers, considered protective for epithelia such as Faecalibacterium (q < 0.001), showed reduced abundance in patients with CP. Of 4 additional patients with CP previously treated with antibiotics (ceftriaxone and metronidazole), 3 patients were characterized by distinct Enterococcus overgrowth. DISCUSSION: CP is associated with marked gut microbiota dysbiosis, greatly reduced diversity, and increased abundance of opportunistic pathogens, specifically those previously isolated from infected pancreatic necrosis. Taxa with a potentially beneficial role in intestinal barrier function are depleted. These changes can increase the probability of complications from pancreatitis such as infected fluid collections or small intestinal bacterial overgrowth (see Graphical Abstract, Supplementary Digital Content 1, http://links.lww.com/CTG/A383).
Asunto(s)
Disbiosis/diagnóstico , Insuficiencia Pancreática Exocrina/microbiología , Microbioma Gastrointestinal/fisiología , Pancreatitis Crónica/complicaciones , Adulto , Anciano , ADN Bacteriano/aislamiento & purificación , Disbiosis/microbiología , Enterococcus/genética , Enterococcus/aislamiento & purificación , Escherichia/genética , Escherichia/aislamiento & purificación , Insuficiencia Pancreática Exocrina/fisiopatología , Faecalibacterium/genética , Faecalibacterium/aislamiento & purificación , Heces/microbiología , Femenino , Humanos , Mucosa Intestinal/microbiología , Masculino , Persona de Mediana Edad , Pancreatitis Crónica/microbiología , Estudios Prospectivos , ARN Ribosómico 16S/genética , Shigella/genética , Shigella/aislamiento & purificación , Streptococcus/genética , Streptococcus/aislamiento & purificaciónRESUMEN
BACKGROUND: Acute pancreatitis is a gastrointestinal disorder of high incidence resulting in life threatening complications in up to 20% of patients. Its severe form is characterized by an extensive and systemic immune response. We investigated the role of the adaptive immune response in two experimental models of pancreatitis. METHODS: In C57BI/6-mice mild pancreatitis was induced by 8-hourly injections of caerulein and severe pancreatitis by additional, partial pancreatic duct ligation. T-cell-activation was determined by flow-cytometry of CD25/CD69, T-cell-differentiation by nuclear staining of the transcription-factors Tbet, Gata3 and Foxp3. In vivo CD4+ T-cells were depleted using anti-CD4 antibody. Disease severity was determined by histology, serum amylase and lipase activities, lung MPO and serum cytokine levels (IL-6, TNFα, IL-10). RESULTS: In both models T-cells were activated. Th1-differentiation (Tbet) was absent during pancreatitis but we detected a pronounced Th2/Treg (Gata3/Foxp3) response which paralleled disease severity in both models. The complete depletion of CD4+ T-cells via anti-CD4 antibody, surprisingly, reduced disease severity significantly, as well as granulocyte infiltration and pro- and anti-inflammatory cytokine levels. Co-incubation of acini and T-cells did not lead to T-cell-activation by acinar cells but to acinar damage by T-cells. During pancreatitis no significant T-cell-infiltration into the pancreas was observed. CONCLUSION: T cells orchestrate the early local as well as the systemic immune responses in pancreatitis and are directly involved in organ damage. The Th2 response appears to increase disease severity, rather than conferring an immunological protection.
Asunto(s)
Inmunidad Adaptativa , Diferenciación Celular , Pancreatitis , Linfocitos T Reguladores , Células Th2 , Animales , Citocinas , Modelos Animales de Enfermedad , Activación de Linfocitos , Ratones , Pancreatitis/inmunologíaRESUMEN
PURPOSE OF REVIEW: Pancreatitis remains an intractable disease because no causative treatment is yet available. Recent studies have uncovered some of its underlying pathophysiology, a requirement for identifying potential treatment targets. These advancements were achieved by human genetic studies and by introducing genetic mechanisms into experimental pancreatitis models. RECENT FINDINGS: Cationic trypsin mutations are the most prominent genetic risk factor for pancreatitis. Investigators have now introduced genetically modified trypsin variants into transgenic animals. In this manner they characterized the role of cellular defense mechanisms, for example degradation of active trypsin by chymotrypsin-C, but also found that increased autoactivation or decreased degradation, not only boost disease severity but also drive progression to chonic pancreatitis. Other studies found that harmful trypsin effects are not restricted to acinar cells, that other digestive enzymes, notably pancreatic elastase, can also induce cellular injury and that endoplasmic-reticulum-stress is an important mechanism when mutations induce protein misfolding. SUMMARY: Identifying genetic subsceptibility factors for a disease never completely uncovers its underlying pathogenesis or potential treatment targets. This requires studying the mechanisms suggested by genetic findings in experimentel disease models. Pancreatitis is a field, in which much progress has now been achieved by adopting this approach.
Asunto(s)
Páncreas , Pancreatitis , Animales , Estrés del Retículo Endoplásmico , Humanos , Mutación , Pancreatitis/genética , Tripsina/genéticaRESUMEN
Helicobacter (H.) pylori is the most important cause for peptic ulcer disease and a risk factor for gastric carcinoma. How colonization with H. pylori affects the intestinal microbiota composition in humans is unknown. We investigated the association of H. pylori infection with intestinal microbiota composition in the population-based cohort Study-of-Health-in-Pomerania (SHIP)-TREND. Anti-H. pylori serology and H. pylori stool antigen tests were used to determine the H. pylori infection status. The fecal microbiota composition of 212 H. pylori positive subjects and 212 matched negative control individuals was assessed using 16S rRNA gene sequencing. H. pylori infection was found to be significantly associated with fecal microbiota alterations and a general increase in fecal microbial diversity. In infected individuals, the H. pylori stool antigen load determined a larger portion of the microbial variation than age or sex. The highest H. pylori stool antigen loads were associated with a putatively harmful microbiota composition. This study demonstrates profound alterations in human fecal microbiota of H. pylori infected individuals. While the increased microbiota diversity associated with H. pylori infection as well as changes in abundance of specific genera could be considered to be beneficial, others may be associated with adverse health effects, reflecting the complex relationship between H. pylori and its human host.
Asunto(s)
Biodiversidad , Heces/microbiología , Microbioma Gastrointestinal , Infecciones por Helicobacter/microbiología , Helicobacter pylori , Estudios de Casos y Controles , Susceptibilidad a Enfermedades , Femenino , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Interacciones Huésped-Patógeno , Humanos , Masculino , Factores de RiesgoRESUMEN
Niemann-Pick Type C (NP-C) is a rare disorder of lipid metabolism caused by mutations within the NPC1 and NPC2 genes. NP-C is a neurovisceral disease leading to a heterogeneous, multisystemic spectrum of symptoms in those affected. Until now, there is no investigative tool to demonstrate the significance of single variants within the NPC genes. Hence, the aim of the study was to establish a test that allows for an objective assessment of the pathological potential of NPC1 gene variants. Chinese hamster ovary cells defective in the NPC1 gene accumulate cholesterol in lysosomal storage organelles. The cells were transfected with NPC1-GFP plasmid vectors carrying distinct sequence variants. Filipin staining was used to test for complementation of the phenotype. The known variant p.Ile1061Thr showed a significantly impaired cholesterol clearance after 12 and 24 h compared to the wild type. Among the investigated variants, p.Ser954Leu and p.Glu1273Lys showed decelerated cholesterol clearance as well. The remaining variants p.Gln60His, p.Val494Met, and p.Ile787Val showed a cholesterol clearance indistinguishable from wild type. Further, p.Ile1061Thr acquired an enhanced clearance ability upon 25-hydroxycholesterol treatment. We conclude that the variants that caused an abnormal clearance phenotype are highly likely to be of clinical relevance. Moreover, we present a system that can be utilized to screen for new drugs.
Asunto(s)
Prueba de Complementación Genética , Variación Genética , Péptidos y Proteínas de Señalización Intracelular/genética , Alelos , Secuencia de Aminoácidos , Animales , Células CHO , Células Cultivadas , Colesterol/metabolismo , Mapeo Cromosómico , Cricetulus , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Modelos Moleculares , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/diagnóstico , Enfermedad de Niemann-Pick Tipo C/genética , Enfermedad de Niemann-Pick Tipo C/metabolismo , Fenotipo , Conformación Proteica , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Actinobacteria/fisiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/microbiología , Microbioma Gastrointestinal , Obesidad/complicaciones , Obesidad/microbiología , Filogenia , Biodiversidad , Índice de Masa Corporal , Heces/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Componente Principal , Programas de Reducción de PesoRESUMEN
OBJECTIVES: The aim of this study was to investigate if pancreatic steatosis measured by proton density fat fraction (PDFF) is associated with exocrine pancreatic function defined by fecal elastase concentrations. MATERIALS AND METHODS: A total of 1458 volunteers (777 women; age range, 21-88 years) underwent magnetic resonance imaging of the pancreas, and organ fat content was quantified by using confounder corrected PDFF. Exocrine pancreatic function was categorized by fecal elastase levels using defined cutoffs: greater than 200 µg/g normal function (n = 1319) and 200 µg/g or less impaired function (n = 139). Statistical analysis to correlate pancreatic fat content with fecal elastase included linear regression, and analyses were adjusted for known confounders for pancreatic steatosis, such as age, sex, and body mass index. RESULTS: Overall mean (±standard deviation) of pancreatic fat content was 7.50% ± 3.78%. Pancreatic fat content was significantly higher in subjects with impaired pancreatic exocrine function (9.36% ± 4.95%) compared with subjects with normal function (7.30% ± 3.59%; P < 0.01). Linear regression analyses showed an inverse correlation between pancreatic fat and fecal elastase levels over the whole study population (beta, -7.19 [standard error, 1.39]; P < 0.01) as well as in the subgroup of subjects with normal function (-4.26 [1.32]; P < 0.01). Among subjects with impaired pancreatic exocrine function, a trend toward an inverse relation was detected (-1.28 [0.84]; P < 0.13). CONCLUSIONS: An inverse correlation between PDFF of the pancreas and fecal elastase suggests an association between pancreatic steatosis and impaired pancreatic exocrine function.
Asunto(s)
Tejido Adiposo/diagnóstico por imagen , Insuficiencia Pancreática Exocrina/diagnóstico , Imagen por Resonancia Magnética/métodos , Enfermedades Pancreáticas/diagnóstico por imagen , Enfermedades Pancreáticas/patología , Tejido Adiposo/patología , Tejido Adiposo/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Insuficiencia Pancreática Exocrina/enzimología , Insuficiencia Pancreática Exocrina/fisiopatología , Heces/enzimología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Páncreas/diagnóstico por imagen , Páncreas/patología , Páncreas/fisiopatología , Enfermedades Pancreáticas/fisiopatología , Elastasa Pancreática/análisis , Adulto JovenAsunto(s)
Hipersensibilidad , Síndrome del Colon Irritable , Microbiota , Dolor Abdominal , Heces , HumanosRESUMEN
BACKGROUND & AIMS: Changes in intestinal microbiome composition are associated with inflammatory, metabolic, and malignant disorders. We studied how exocrine pancreatic function affects intestinal microbiota. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Asunto(s)
Bacterias/aislamiento & purificación , Insuficiencia Pancreática Exocrina/fisiopatología , Heces/enzimología , Microbioma Gastrointestinal , Páncreas/fisiopatología , Elastasa Pancreática/metabolismo , Células Acinares/fisiología , Bacteroides/aislamiento & purificación , Biodiversidad , Interacciones Microbiota-Huesped , Humanos , Páncreas/citología , Pruebas de Función Pancreática , Prevotella/aislamiento & purificación , ARN Ribosómico 16S/análisisRESUMEN
BACKGROUND: Irritable bowel syndrome (IBS) is associated with reduced quality of life and high healthcare costs. This study aimed to assess the prevalence and risk factors for IBS in a general adult population. METHODS: The Study of Health in Pomerania (SHIP) is a population-based cohort study in northeastern Germany. SHIP-Trend-0 participants enrolled from 2008 to 2012 were grouped according to Rome III criteria (main criteria: abdominal discomfort or crampy or bloating pain for at least six months plus 2/3 additional criteria). Factors associated with IBS were assessed using survey-weighted backward stepwise logistic regression. KEY RESULTS: The final data set included 4194 records. IBS prevalence was 3.5% (3.0%-4.2%). Unemployment (OR: 2.02, 1.26-3.21), headaches (OR: 2.37, 1.59-3.52), mental quality of life (OR: 0.95 per unit increase, 0.93-0.97), and interactions between gender and physical quality of life (P = 0.004) and gender and alexithymia (P = 0.002) predicted IBS probability. The model resulted in a good discrimination (area under the curve = 75.4%) and model fit (F = 0.72, P = 0.69). History of depression (OR: 2.77, 1.94-3.95), back pain (OR: 2.38, 1.69-3.35), early trauma (OR: 1.03, 1.02-1.04), and duration of inpatient treatment within the last twelve months (OR: 1.02, 1.01-1.04) lost their significance in multivariable analysis. CONCLUSIONS & INFERENCES: IBS prevalence was relatively low compared to other studies. Factors predicting IBS were of biological, psychological, and social nature. The association between IBS and pain in different areas of the body indicates a potential underlying complex somatic symptom disorder.