Publications by authors named "Markus M Lerch"

317 Publications

[Pancreatitis].

Internist (Berl) 2021 Oct 29;62(10):1005-1006. Epub 2021 Sep 29.

Medizinische Fakultät, Universität Leipzig, Liebigstraße 36, 04103, Leipzig, Deutschland.

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http://dx.doi.org/10.1007/s00108-021-01168-wDOI Listing
October 2021

Lived Experience of Hereditary Chronic Pancreatitis - A Qualitative Interview Study.

Chronic Illn 2021 Sep 24:17423953211039774. Epub 2021 Sep 24.

Institute of Ethics, 88782History and Philosophy of Medicine, Hannover Medical School, Hannover, Germany.

Objectives: Hereditary chronic pancreatitis is a rare condition characterized by intermittent acute episodes of pancreatitis and long-term impairment of pancreatic functions. However, the subjective perspective of individuals affected by hereditary chronic pancreatitis has been little studied. This qualitative study investigates the experience of hereditary chronic pancreatitis patients and their relatives because the awareness of the needs of those affected is an essential component of a patient-centered management of chronic conditions.

Methods: Semi-structured qualitative interviews were conducted with hereditary chronic pancreatitis patients and their relatives. Data were analysed using qualitative content analysis. The concepts of 'biographical contingency,' 'biographical disruption' and the 'shifting perspectives model' served as theoretical frameworks.

Results: A total of 24 participants (17 patients, 7 relatives) were interviewed individually. Four main themes were identified: (1) The unpredictable clinical course of hereditary chronic pancreatitis; (2) hereditary chronic pancreatitis as a devastating experience; (3) hereditary chronic pancreatitis as part of a normal life; and (4) being reduced to hereditary chronic pancreatitis.

Discussion: The 'shifting perspectives model' of chronic illness covers the four dimensions adequately and can serve as a theoretical model to explain hereditary chronic pancreatitis patients' experience. A better understanding of the patients and their families' experience and the shifting character of hereditary chronic pancreatitis can help healthcare professionals to tailor the care to meet the needs of those affected.
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http://dx.doi.org/10.1177/17423953211039774DOI Listing
September 2021

Excess Body Weight and Pancreatic Disease.

Visc Med 2021 Aug 9;37(4):281-286. Epub 2021 Jul 9.

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

Background: Excess body weight (EBW) is a risk factor for various acute and chronic conditions. Conversely, the "obesity paradox" suggests a protective effect of higher body weight on some disease outcomes. This article discusses the role of EBW along the disease continuum of pancreatitis and pancreatic cancer (PC) in terms of incidence and outcome.

Summary: Comparison of findings is hampered by the use of different methods to assess EBW. Nevertheless, in acute pancreatitis (AP) and PC, EBW, especially visceral obesity, presents a distinct risk factor and predictor of a negative outcome. Findings of a protective effect likely result from nonconsideration of fat distribution or other confounders. Regarding chronic pancreatitis (CP), few studies indicate lower incidence and a better outcome with higher body mass. However, there is insufficient evidence to confirm the existence of an obesity paradox. The precise mechanisms of how EBW affects the disease continuum require further elucidation but both common and disease-specific effects seem involved.

Key Messages: EBW is associated with higher incidence and a negative outcome in AP and PC. The association with CP is less conclusive. Thus, maintaining normal weight is advisable at any stage of the disease continuum.
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http://dx.doi.org/10.1159/000517147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406348PMC
August 2021

Higher Trimethylamine--Oxide Plasma Levels with Increasing Age Are Mediated by Diet and Trimethylamine-Forming Bacteria.

mSystems 2021 Sep 14:e0094521. Epub 2021 Sep 14.

Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Researchgrid.7490.a, Braunschweig, Germany.

The gut microbiota-dependent metabolite trimethylamine--oxide (TMAO) is linked to an increased risk for cardiovascular diseases. Trimethylamine (TMA), which is subsequently oxidized to TMAO in the liver, is formed by intestinal bacteria via distinct biochemical routes from dietary precursors that are enriched in animal product-based foods. To get a full picture of the entire process of the diet > gut microbiota > TMAO axis, we quantified potential TMA-forming gut bacteria and plasma metabolites using gene-targeted assays and targeted metabolomics on a subsample ( = 425) of a German population-based cohort study. We specifically compared persons reporting daily meat intake with those that rarely or never consume meat. While meat intake did not predict TMAO plasma levels in our study, two major bacterial TMA-forming pathways were linked to the metabolite's concentration. Furthermore, advancing age was strongly associated with TMAO. Construction of a structural equation model allowed us to disentangle the different routes that promote higher TMAO levels with increasing age, demonstrating, for the first time, a functional role of gut microbiota in the process, where specific food items augmented abundances of TMA-forming bacteria that were associated with higher TMAO plasma concentrations. Analyses stratified by age showed an association between carotid intima-media thickness and TMAO only in individuals >65 of age, indicating that this group is particularly affected by the metabolite. Many cohort studies have investigated the link between diet and plasma TMAO levels, reporting incongruent results, while gut microbiota were only recently included into analyses. In these studies, taxonomic data were recorded that are not a good proxy for TMA formation, as specific members of various taxa exhibit genes catalyzing this reaction, demanding function-based technologies for accurate quantification of TMA-synthesizing bacteria. Using this approach, we demonstrated that abundances of the main components leading to TMAO formation, i.e., TMA precursors and TMA-forming bacteria, are uncoupled and not governed by the same (dietary) factors. Results emphasize that all levels leading to TMA(O) formation should be considered for accurate risk assessment, rejecting the simple view that diets rich in TMA precursors directly lead to increased plasma levels of this hazardous compound. The results can assist in developing strategies to reduce TMAO levels, specifically in the elderly, who are prone to TMAO-associated diseases.
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http://dx.doi.org/10.1128/mSystems.00945-21DOI Listing
September 2021

Early weight loss is an independent risk factor for shorter survival and increased side effects in patients with metastatic colorectal cancer undergoing first-line treatment within the randomized Phase III trial FIRE-3 (AIO KRK-0306).

Int J Cancer 2021 Aug 25. Epub 2021 Aug 25.

Comprehensive Cancer Center, University Hospital, LMU Munich, Munich, Germany.

Body weight loss is frequently regarded as negatively related to outcomes in patients with malignancies. This retrospective analysis of the FIRE-3 study evaluated the evolution of body weight in patients with metastatic colorectal cancer (mCRC). FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab or bevacizumab in mCRC patients with RAS-WT tumors (ie, wild-type in KRAS and NRAS exons 2-4). The prognostic and predictive relevance of early weight loss (EWL) regarding patient outcomes and treatment side effects were evaluated. Retrospective data on body weight during first 6 months of treatment were evaluated (N = 326). To correlate with efficacy endpoints and treatment side effects, patients were grouped according to clinically significant EWL ≥5% and <5% at Month 3. Age constituted the only significant predictor of EWL following a linear relationship with the corresponding log odds ratio (P = .016). EWL was significantly associated with the incident frequencies of diarrhea, edema, fatigue, nausea and vomiting. Further, a multivariate analysis revealed EWL to be an independent negative prognostic factor for overall survival (32.4 vs 21.1 months; hazard ratio [HR]: 1.64; 95% confidence interval [CI] = 1.13-2.38; P = .0098) and progression-free survival (11.8 vs 9.0 months; HR: 1.72; 95% CI = 1.18-2.5; P = .0048). In conclusion, EWL during systemic treatment against mCRC is significantly associated with patient age. Patients exhibiting EWL had worse survival and higher frequencies of adverse events. Early preventative measures targeted at weight maintenance should be evaluated, especially in elderly patients being at highest risk of EWL.
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http://dx.doi.org/10.1002/ijc.33775DOI Listing
August 2021

Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma.

Cells 2021 07 19;10(7). Epub 2021 Jul 19.

Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Developing biomarkers for early detection and chemotherapeutic response prediction is crucial to improve the dismal prognosis of PDAC patients. However, molecular cancer signatures based on transcriptome analysis do not reflect intratumoral heterogeneity. To explore a more accurate stratification of PDAC phenotypes in an easily accessible matrix, plasma metabolome analysis using MxP Global Profiling and MxP Lipidomics was performed in 361 PDAC patients. We identified three metabolic PDAC subtypes associated with distinct complex lipid patterns. Subtype 1 was associated with reduced ceramide levels and a strong enrichment of triacylglycerols. Subtype 2 demonstrated increased abundance of ceramides, sphingomyelin and other complex sphingolipids, whereas subtype 3 showed decreased levels of sphingolipid metabolites in plasma. Pathway enrichment analysis revealed that sphingolipid-related pathways differ most among subtypes. Weighted correlation network analysis (WGCNA) implied PDAC subtypes differed in their metabolic programs. Interestingly, a reduced expression among related pathway genes in tumor tissue was associated with the lowest survival rate. However, our metabolic PDAC subtypes did not show any correlation to the described molecular PDAC subtypes. Our findings pave the way for further studies investigating sphingolipids metabolisms in PDAC.
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http://dx.doi.org/10.3390/cells10071821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305839PMC
July 2021

Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration.

Adv Sci (Weinh) 2021 07 13;8(14):2100626. Epub 2021 May 13.

Department of Internal Medicine I University Hospital Ulm Albert-Einstein Allee 23 89081 Ulm Germany.

Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, -null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5 liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical-Wnt-signaling in -null animals. This results in reduced expression of the Hedgehog repressor and increased Hedgehog-signaling activity upon loss. Collectively, these data reveal as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical-Wnt-, and Hedgehog-signaling.
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http://dx.doi.org/10.1002/advs.202100626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292873PMC
July 2021

[Update 2021: COVID-19 from the perspective of gastroenterology].

Dtsch Med Wochenschr 2021 Jul 13;146(13-14):891-893. Epub 2021 Jul 13.

During COVID 19 pandemic patients typically present with respiratory symptoms. However, in a significant number of patients the gastrointestinal tract is also involved in the disease. Up to 20 % of patients suffering from gastrointestinal symptoms. New insights in pathophysiological aspects might open new therapeutic concepts. This up-date includes current data regarding epidemiology of gastrointestinal symptoms in COVID 19, its role for prognosis and specific risks in relation to immunosuppressive therapies and underlying diseases.
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http://dx.doi.org/10.1055/a-1449-4054DOI Listing
July 2021

Association of hepatic steatosis derived from ultrasound and quantitative MRI with prediabetes in the general population.

Sci Rep 2021 06 24;11(1):13276. Epub 2021 Jun 24.

Institute for Community Medicine, University Medicine Greifswald, Walther Rathenau Str. 48, 17475, Greifswald, Germany.

The aim of our study was to investigate the association of hepatic steatosis derived from quantitative ultrasound and magnetic resonance imaging (MRI) with prediabetes in a large population-based study conducted in Northeast Germany. Hepatic steatosis was assessed through transabdominal ultrasound and quantitative MRI. For analysis we included 1622 subjects with MRI who participated in an oral glucose tolerance test and reported no known type 2 diabetes mellitus (T2DM). We classified participants as proposed by the American Diabetes Association: isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT), and undiagnosed T2DM. Regression models were adjusted for age, sex body mass index and alcohol consumption. We observed positive associations of hepatic steatosis with glycated hemoglobin, fasting glucose and insulin, 2-h glucose and insulin, as well as homeostasis model assessment-insulin resistance index. Similarly, individuals having hepatic steatosis as defined by MRI had a higher relative risk ratio (RR) to be in the prediabetes groups i-IFG (RR = 1.6; 95% confidence interval (CI) 1.2; 2.2), i-IGT (RR = 3.3, 95% CI 2.0; 5.6) and IFG + IGT (RR = 2.5, 95% CI 1.6; 3.9) or to have undiagnosed T2DM (RR = 4.8, 95% CI 2.6; 9.0). All associations were attenuated when defining hepatic steatosis by ultrasound. Hepatic steatosis is associated with prediabetes and undiagnosed T2DM in the general population. Quantitative liver MRI revealed stronger associations with prediabetes and undiagnosed T2DM compared to ultrasound, which indicates the higher sensitivity and specificity of MRI to determine hepatic steatosis.
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http://dx.doi.org/10.1038/s41598-021-92681-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225774PMC
June 2021

Gut microbial pathways for bile acid metabolism.

Hepatobiliary Surg Nutr 2021 Jun;10(3):379-381

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

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http://dx.doi.org/10.21037/hbsn-21-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188139PMC
June 2021

Immunoproteasome impairment via β5i/LMP7-deletion leads to sustained pancreatic injury from experimental pancreatitis.

J Cell Mol Med 2021 07 15;25(14):6786-6799. Epub 2021 Jun 15.

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

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 β5i/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-1β, IFN-β 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.
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http://dx.doi.org/10.1111/jcmm.16682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278072PMC
July 2021

Tumor-Specific Delivery of 5-Fluorouracil-Incorporated Epidermal Growth Factor Receptor-Targeted Aptamers as an Efficient Treatment in Pancreatic Ductal Adenocarcinoma Models.

Gastroenterology 2021 Sep 25;161(3):996-1010.e1. Epub 2021 Jun 25.

Department of Medicine II, University Hospital, LMU Munich, Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. Electronic address:

Backgrounds & Aims: Fluoropyrimidine c (5-fluorouracil [5FU]) increasingly represents the chemotherapeutic backbone for neoadjuvant, adjuvant, and palliative treatment of pancreatic ductal adenocarcinoma (PDAC). Even in combination with other agents, 5FU efficacy remains transient and limited. One explanation for the inadequate response is insufficient and nonspecific delivery of 5FU to the tumor.

Methods: We designed, generated, and characterized 5FU-incorporated systematic evolution of ligands by exponential enrichment (SELEX)-selected epidermal growth factor receptor (EGFR)-targeted aptamers for tumor-specific delivery of 5FU to PDAC cells and tested their therapeutic efficacy in vitro and in vivo.

Results: 5FU-EGFR aptamers reduced proliferation in a concentration-dependent manner in mouse and human pancreatic cancer cell lines. Time-lapsed live imaging showed EGFR-specific uptake of aptamers via clathrin-dependent endocytosis. The 5FU-aptamer treatment was equally effective in 5FU-sensitive and 5FU-refractory PDAC cell lines. Biweekly treatment with 5FU-EGFR aptamers reduced tumor burden in a syngeneic orthotopic transplantation model of PDAC, in an autochthonously growing genetically engineered PDAC model (LSL-Kras;LSL-Trp53;Ptf1a-Cre [KPC]), in an orthotopic cell line-derived xenograft model using human PDAC cells in athymic mice (CDX; Crl:NU-Foxn1), and in patient-derived organoids. Tumor growth was significantly attenuated during 5FU-EGFR aptamer treatment in the course of follow-up.

Conclusions: Tumor-specific targeted delivery of 5FU using EGFR aptamers as the carrier achieved high target specificity; overcame 5FU resistance; and proved to be effective in a syngeneic orthotopic transplantation model, in KPC mice, in a CDX model, and in patient-derived organoids and, therefore, represents a promising backbone for pancreatic cancer chemotherapy in patients. Furthermore, our approach has the potential to target virtually any cancer entity sensitive to 5FU treatment by incorporating 5FU into cancer cell-targeting aptamers as the delivery platform.
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http://dx.doi.org/10.1053/j.gastro.2021.05.055DOI Listing
September 2021

A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies.

J Inflamm Res 2021 21;14:2111-2119. Epub 2021 May 21.

Institute of Biochemistry, University of Greifswald, Greifswald, Germany.

Purpose: Although strongly related, the pathophysiological effect of the N34S mutation in the serine protease inhibitor Kazal type 1 (SPINK1) in chronic pancreatitis is still unknown. In this study, we investigate the conformational space of the human cationic trypsin-serine protease inhibitor complex.

Methods: Simulations with molecular dynamics, replica exchange, and transition pathway methods are used.

Results: Two main binding states of the inhibitor to the complex were found, which explicitly relate the influence of the mutation site to conformational changes in the active site of trypsin.

Conclusion: Based on our result, a hypothesis is formulated that explains the development of chronic pancreatitis through accelerated digestion of the mutant by trypsin.
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http://dx.doi.org/10.2147/JIR.S304787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157096PMC
May 2021

Carrying asymptomatic gallstones is not associated with changes in intestinal microbiota composition and diversity but cholecystectomy with significant dysbiosis.

Sci Rep 2021 03 23;11(1):6677. Epub 2021 Mar 23.

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

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.
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http://dx.doi.org/10.1038/s41598-021-86247-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988160PMC
March 2021

[German Terminology of the Revised Atlanta Classification of Acute Pancreatitis: Glossary Based on the New German S3 Guideline on Acute, Chronic, and Autoimmune Pancreatitis].

Rofo 2021 Aug 18;193(8):909-918. Epub 2021 Mar 18.

Imaging and Prevention Center, Conradia Radiology Munich, Germany.

The Atlanta classification published in 1992 was supposed to classify the severity and complications in acute pancreatitis with the goal of providing uniform terminology for clinicians and researchers. After continuous evolution, the revised Atlanta classification was published in 2012. In this updated classification, imaging aspects were better integrated and unclear terms were better defined. To date, this terminology for disease grading, severity, and local complications has been solely available in English. This prevented wide acceptance of the classification by the German-speaking medical community. Therefore, an expert team of the German Radiological Society translated the terms based on German medical literature. This translation was approved by consensus in the new S3 guideline meeting in February 2020 with an approval rate of 97.3 %. This manuscript explains the translated and approved German terminology of the revised Atlanta classification and offers additional imaging examples. KEY POINTS::   · The revised Atlanta classification allows correct definition of the grading and complication assessment of acute pancreatitis.. · An expert group translated the terms into the German language. The translation was approved by the S3 guideline committee for pancreatitis.. · Based on the new German S3 guideline for pancreatitis, the translated terms should be employed consistently.. CITATION FORMAT: · Schreyer AG, Seidensticker M, Mayerle J et al. German Terminology of the Revised Atlanta Classification of Acute Pancreatitis: Glossary Based on the New German S3 Guideline on Acute, Chronic, and Autoimmune Pancreatitis. Fortschr Röntgenstr 2021; 193: 909 - 918.
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http://dx.doi.org/10.1055/a-1388-8316DOI Listing
August 2021

Hepatic steatosis and hepatic iron overload modify the association of iron markers with glucose metabolism disorders and metabolic syndrome.

Liver Int 2021 08 22;41(8):1841-1852. Epub 2021 Mar 22.

Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

Background: Iron status has been linked with impaired glucose metabolism (IGM), type 2 diabetes mellitus (T2DM) and the metabolic syndrome (MetS), but the role of hepatic steatosis or iron overload on these associations remains uncertain.

Methods: We analysed data from 2310 participants without known T2DM of the population-based Study of Health in Pomerania (SHIP-TREND, Germany) through logistic regression models. We tested additive and multiplicative interactions between ferritin and hepatic steatosis or iron overload.

Results: Serum ferritin was positively associated with IGM (OR per 100 µg/L: 1.11 [1.01, 1.23]), T2DM (OR per 100 µg/L: 1.20 [1.06, 1.36]) and MetS (OR per 100 µg/L: 1.11 [1.02, 1.20]) in the total population as well as in participants without hepatic iron overload. However, the synergistic effect of higher ferritin concentrations and hepatic iron overload showed stronger associations with IGM and T2DM. Similarly, while ferritin was positively associated with T2DM and MetS even in the absence of hepatic steatosis, the synergistic effect of higher ferritin concentrations and hepatic steatosis showed stronger associations with IGM, T2DM and MetS. Transferrin was associated with isolated impaired glucose tolerance but not with T2DM and MetS.

Conclusions: Our study suggests that ferritin may be associated with glucose metabolism disorders and MetS even in people without hepatic steatosis or iron overload. However, in individuals with higher ferritin concentrations, the presence of hepatic steatosis may indicate stronger risk for glucose metabolism disorders and MetS, while the presence of hepatic iron overload may indicate stronger risk only for glucose metabolism disorders.
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http://dx.doi.org/10.1111/liv.14868DOI Listing
August 2021

Pancreatitis severity in mice with impaired CFTR function but pancreatic sufficiency is mediated via ductal and inflammatory cells-Not acinar cells.

J Cell Mol Med 2021 05 8;25(10):4658-4670. Epub 2021 Mar 8.

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) are an established risk factor for cystic fibrosis (CF) and chronic pancreatitis. Whereas patients with CF usually develop complete exocrine pancreatic insufficiency, pancreatitis patients with CFTR mutations have mostly preserved exocrine pancreatic function. We therefore used a strain of transgenic mice with significant residual CFTR function (CFTR ) to induce pancreatitis experimentally by serial caerulein injections. Protease activation and necrosis were investigated in isolated acini, disease severity over 24h, pancreatic function by MRI, isolated duct stimulation and faecal chymotrypsin, and leucocyte function by ex vivo lipopolysaccharide (LPS) stimulation. Pancreatic and lung injury were more severe in CFTR but intrapancreatic trypsin and serum enzyme activities higher than in wild-type controls only at 8h, a time interval previously attributed to leucocyte infiltration. CCK-induced trypsin activation and necrosis in acini from CFTR did not differ from controls. Fluid and bicarbonate secretion were greatly impaired, whereas faecal chymotrypsin remained unchanged. LPS stimulation of splenocytes from CFTR resulted in increased INF-γ and IL-6, but decreased IL-10 secretion. CFTR mutations that preserve residual pancreatic function significantly increase the severity of experimental pancreatitis-mostly via impairing duct cell function and a shift towards a pro-inflammatory phenotype, not by rendering acinar cells more susceptible to pathological stimuli.
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http://dx.doi.org/10.1111/jcmm.16404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107082PMC
May 2021

Efficiency of a 15-Week Weight-Loss Program, Including a Low-Calorie Formula Diet, on Glycemic Control in Patients with Type 2 Diabetes Mellitus and Overweight or Obesity.

Obes Facts 2021 Feb 18:1-11. Epub 2021 Feb 18.

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

Introduction: Patients who are overweight or obese have an increased risk of developing type 2 diabetes mellitus (T2DM). Weight loss can have a positive effect on glycemic control.

Objective: We aimed to investigate glycemic control in patients with T2DM and overweight or obesity during a structured weight-loss program.

Methods: This was a prospective, interventional study. We recruited 36 patients (14 men and 22 women) with a median age of 58.5 years and median body mass index (BMI) of 34.1, to a 15-week structured weight-loss program with a low-calorie (800 kcal) formula diet for 6 weeks. The primary end point, HbA1c level, and secondary end points, anthropometric data, medication, and safety, were assessed weekly. Laboratory values and quality of life were assessed at baseline and after 15 weeks.

Results: HbA1c decreased from 7.3% at baseline to 6.5% at 15 weeks (p < 0.001), median body weight by 11.9 kg (p < 0.001), median BMI by 4.3 (p < 0.001) and median waist circumference by 11.0 cm (p < 0.001). Two participants discontinued insulin therapy, 4 could reduce their dosage of oral antidiabetic agents, and 6 completely discontinued their antidiabetic medication. Insulin dose decreased from 0.63 (0.38-0.89) to 0.39 (0.15-0.70) units/kg body weight (p < 0.001). No patient experienced hypoglycemic episodes or hospital emergency visits. Triglycerides and total cholesterol decreased as well as surrogate markers of liver function. However, the levels of high-density and low-density lipoprotein cholesterol (HDL-C and LDL-C) as well as uric acid remain unchanged. Regarding quality of life, the median physical health score increased from 44.5 (39.7-51.4) at baseline to 48.0 (43.1-55.3; p = 0.007), and the median mental health score decreased from 42.1 (36.1-46.7) to 37.4 (30.3-43.7; p = 0.004).

Conclusions: A structured weight-loss program is effective in the short term in reducing HbA1c, weight, and antidiabetic medication in patients with T2DM who are overweight or obese. Levels of HDL-C and LDL-C were not affected by short-term weight loss. The decline in mental health and the long-term effects of improved glycemic control require further trials.
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http://dx.doi.org/10.1159/000511453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983589PMC
February 2021

From heterogeneous healthcare data to disease-specific biomarker networks: A hierarchical Bayesian network approach.

PLoS Comput Biol 2021 02 12;17(2):e1008735. Epub 2021 Feb 12.

Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany.

In this work, we introduce an entirely data-driven and automated approach to reveal disease-associated biomarker and risk factor networks from heterogeneous and high-dimensional healthcare data. Our workflow is based on Bayesian networks, which are a popular tool for analyzing the interplay of biomarkers. Usually, data require extensive manual preprocessing and dimension reduction to allow for effective learning of Bayesian networks. For heterogeneous data, this preprocessing is hard to automatize and typically requires domain-specific prior knowledge. We here combine Bayesian network learning with hierarchical variable clustering in order to detect groups of similar features and learn interactions between them entirely automated. We present an optimization algorithm for the adaptive refinement of such group Bayesian networks to account for a specific target variable, like a disease. The combination of Bayesian networks, clustering, and refinement yields low-dimensional but disease-specific interaction networks. These networks provide easily interpretable, yet accurate models of biomarker interdependencies. We test our method extensively on simulated data, as well as on data from the Study of Health in Pomerania (SHIP-TREND), and demonstrate its effectiveness using non-alcoholic fatty liver disease and hypertension as examples. We show that the group network models outperform available biomarker scores, while at the same time, they provide an easily interpretable interaction network.
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http://dx.doi.org/10.1371/journal.pcbi.1008735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906470PMC
February 2021

Identification and validation of a multivariable prediction model based on blood plasma and serum metabolomics for the distinction of chronic pancreatitis subjects from non-pancreas disease control subjects.

Gut 2021 Nov 4;70(11):2150-2158. Epub 2021 Feb 4.

Department of Medicine A, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany

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.
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http://dx.doi.org/10.1136/gutjnl-2020-320723DOI Listing
November 2021

Association of proton pump inhibitor use with endothelial function and metabolites of the nitric oxide pathway: A cross-sectional study.

Pharmacotherapy 2021 02 4;41(2):198-204. Epub 2021 Feb 4.

Chair of Epidemiology, Ludwig-Maximilians-Universität München, UNIKA-T Augsburg, Augsburg, Germany.

Study Objective: Long-term intake of proton pump inhibitors (PPIs) might increase the risk of cardiovascular events. One suggested mechanism is that PPIs inhibit the enzyme dimethylarginine dimethylaminohydrolase (DDAH) and thereby block the degradation of endothelial asymmetrical dimethylarginine (ADMA). Excess ADMA in turn leads to impaired endothelial nitric oxide (NO) generation. So far, this mechanism has only been established in human cell cultures. Previous studies that examined this pathway in human populations measured circulating ADMA and found no association with PPI use and excess plasma ADMA. But in a recent study, plasma ADMA was not correlated with intracellular ADMA. We therefore focused on changes in plasma citrulline as an indicator for potential DDAH inhibition.

Design: We analyzed the association between regular daily PPI intake and flow-mediated dilation (FMD) of the brachial artery as well as plasma concentrations of citrulline, arginine, ADMA, and symmetric dimethylarginine using inverse probability weighting to adjust for confounding and censoring.

Data Source: Data of 1298 participants from two independent cohorts of the population-based Study of Health in Pomerania were used.

Patients: Participants of the population-based Study of Health in Pomerania are a stratified random sample of the study region.

Intervention: Regular daily intake of PPIs.

Measurements: FMD of the brachial artery and plasma concentrations of citrulline, arginine, ADMA, and symmetric dimethylarginine.

Main Results: Eighty-seven participants (57.5% female) were regular daily users of PPIs. In the fully adjusted models, associations were identified for FMD and plasma citrulline concentrations. PPI users revealed a 0.99% (95% CI: -1.96 to -0.02) lower FMD and 3.03 µmol/L (95% CI: -4.96 to -1.10) lower plasma citrulline levels as compared to non-users.

Conclusion: Our data provide evidence that long-term intake of PPIs might inhibit human DDAH activity, resulting in impaired endothelial NO production and reduced vascular function. In the long run, this might explain an increased risk for cardiovascular diseases associated with long-term PPI use.
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http://dx.doi.org/10.1002/phar.2504DOI Listing
February 2021

Exocrine Pancreatic Function Modulates Plasma Metabolites Through Changes in Gut Microbiota Composition.

J Clin Endocrinol Metab 2021 04;106(5):e2290-e2298

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

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.
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http://dx.doi.org/10.1210/clinem/dgaa961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186556PMC
April 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515199PMC
February 2021

Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome.

Nat Genet 2021 02 18;53(2):147-155. Epub 2021 Jan 18.

Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.

The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory, neurologic and neoplastic diseases. Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain. Nevertheless, twin studies clearly suggest host genetics as a driver of microbiome composition. In a genome-wide association analysis of 8,956 German individuals, we identified 38 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with Bacteroides and Faecalibacterium spp. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics and its associated microbial communities as a 'metaorganism' broaden our understanding of disease etiology, and emphasize the potential for implementing microbiota in disease treatment and management.
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http://dx.doi.org/10.1038/s41588-020-00747-1DOI Listing
February 2021

Lack of association between proton pump inhibitor use and brain aging: a cross-sectional study.

Eur J Clin Pharmacol 2021 Jul 13;77(7):1039-1048. Epub 2021 Jan 13.

Chair of Epidemiology, Ludwig-Maximilians-Universität München, UNIKA-T Augsburg, Neusässer Str. 47, 86156, Augsburg, Germany.

Purpose: Due to conflicting scientific evidence for an increased risk of dementia by intake of proton pump inhibitors (PPIs), this study investigates associations between PPI use and brain volumes, estimated brain age, and cognitive function in the general population.

Methods: Two surveys of the population-based Study of Health in Pomerania (SHIP) conducted in Northeast Germany were used. In total, 2653 participants underwent brain magnetic resonance imaging (MRI) and were included in the primary analysis. They were divided into two groups according to their PPI intake and compared with regard to their brain volumes (gray matter, white matter, total brain, and hippocampus) and estimated brain age. Multiple regression was used to adjust for confounding factors. Cognitive function was evaluated by the Verbal Learning and Memory Test (VLMT) and the Nuremberg Age Inventory (NAI) and put in relation to PPI use.

Results: No association was found between PPI use and brain volumes or the estimated brain age. The VLMT score was 1.11 lower (95% confidence interval: - 2.06 to - 0.16) in immediate recall, and 0.72 lower (95% CI: - 1.22 to - 0.22) in delayed recall in PPI users than in non-users. PPI use was unrelated to the NAI score.

Conclusions: The present study does not support a relationship between PPI use and brain aging.
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http://dx.doi.org/10.1007/s00228-020-03068-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184524PMC
July 2021

Acute Pancreatitis: Genetic Risk and Clinical Implications.

J Clin Med 2021 Jan 7;10(2). Epub 2021 Jan 7.

Department of Medicine A, University Medicine Greifswald, 17475 Greifswald, Germany.

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.
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http://dx.doi.org/10.3390/jcm10020190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825757PMC
January 2021

Whole-Exome Sequencing Identifies SLC52A1 and ZNF106 Variants as Novel Genetic Risk Factors for (Early) Multiple-Organ Failure in Acute Pancreatitis.

Ann Surg 2021 Jan 8;Publish Ahead of Print. Epub 2021 Jan 8.

Department of Surgery, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands Department of Medicine A, University Medicine Greifswald, Greifswald, Germany Departments of Clinical Chemistry, Genetics and Pediatrics, Amsterdam Gastroenterology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands Department of Surgery, University Medical Center, Utrecht, The Netherlands; Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.

Objective: The aim of this study was to identify genetic variants associated with early multiple organ failure (MOF) in acute pancreatitis.

Summary Background Data: MOF is a life-threatening complication of acute pancreatitis, and risk factors are largely unknown, especially in early persistent MOF. Genetic risk factors are thought to enhance severity in complex diseases such as acute pancreatitis.

Methods: A 2-phase study design was conducted. First, we exome sequenced 9 acute pancreatitis patients with early persistent MOF and 9 case-matched patients with mild edematous pancreatitis (phenotypic extremes) from our initial Dutch cohort of 387 patients. Secondly, 48 candidate variants that were overrepresented in MOF patients and 10 additional variants known from literature were genotyped in a replication cohort of 286 Dutch and German patients.

Results: Exome sequencing resulted in 161,696 genetic variants, of which the 38,333 nonsynonymous variants were selected for downstream analyses. Of these, 153 variants were overrepresented in patients with multiple-organ failure, as compared with patients with mild acute pancreatitis. In total, 58 candidate variants were genotyped in the joined Dutch and German replication cohort. We found the rs12440118 variant of ZNF106 to be overrepresented in patients with MOF (minor allele frequency 20.4% vs 11.6%, Padj = 0.026). Additionally, SLC52A1 rs346821 was found to be overrepresented (minor allele frequency 48.0% vs 42.4%, Padj = 0.003) in early MOF. None of the variants known from literature were associated.

Conclusions: This study indicates that SLC52A1, a riboflavin plasma membrane transporter, and ZNF106, a zinc finger protein, may be involved in disease progression toward (early) MOF in acute pancreatitis.
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http://dx.doi.org/10.1097/SLA.0000000000004312DOI Listing
January 2021

Role of Bile Acids and Bile Salts in Acute Pancreatitis: From the Experimental to Clinical Studies.

Pancreas 2021 01;50(1):3-11

From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

Abstract: Acute pancreatitis (AP) is one of the most common gastroenterological disorders leading to hospitalization. It has long been debated whether biliary AP, about 30% to 50% of all cases, is induced by bile acids (BAs) when they reach the pancreas via reflux or via the systemic blood circulation.Besides their classical function in digestion, BAs have become an attractive research target because of their recently discovered property as signaling molecules. The underlying mechanisms of BAs have been investigated in various studies. Bile acids are internalized into acinar cells through specific G-protein-coupled BA receptor 1 and various transporters. They can further act via different receptors: the farnesoid X, ryanodine, and inositol triphosphate receptor. Bile acids induce a sustained Ca2+ influx from the endoplasmic reticulum and release of Ca2+ from acidic stores into the cytosol of acinar cells. The overload of intracellular Ca2+ results in mitochondrial depolarization and subsequent acinar cell necrosis. In addition, BAs have a biphasic effect on pancreatic ductal cells. A more detailed characterization of the mechanisms through which BAs contribute to the disease pathogenesis and severity will greatly improve our understanding of the underlying pathophysiology and may allow for the development of therapeutic and preventive strategies for gallstone-inducedAP.
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http://dx.doi.org/10.1097/MPA.0000000000001706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748038PMC
January 2021

The is steaming ahead.

United European Gastroenterol J 2020 12;8(10):1139-1140

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

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http://dx.doi.org/10.1177/2050640620973079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724524PMC
December 2020

Long-term instability of the intestinal microbiome is associated with metabolic liver disease, low microbiota diversity, diabetes mellitus and impaired exocrine pancreatic function.

Gut 2021 03 9;70(3):522-530. Epub 2020 Nov 9.

Department of Medicine A, University Medicine Greifswald, Greifswald, Germany

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 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 or . 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.
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http://dx.doi.org/10.1136/gutjnl-2020-322753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873430PMC
March 2021
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