Publications by authors named "Andre Franke"

493 Publications

Short-term physical exercise impacts on the human holobiont obtained by a randomised intervention study.

BMC Microbiol 2021 Jun 2;21(1):162. Epub 2021 Jun 2.

Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Rosalind-Franklin-Str. 12, 24105, Kiel, Germany.

Background: Human well-being has been linked to the composition and functional capacity of the intestinal microbiota. As regular exercise is known to improve human health, it is not surprising that exercise was previously described to positively modulate the gut microbiota, too. However, most previous studies mainly focused on either elite athletes or animal models. Thus, we conducted a randomised intervention study that focused on the effects of different types of training (endurance and strength) in previously physically inactive, healthy adults in comparison to controls that did not perform regular exercise. Overall study duration was ten weeks including six weeks of intervention period. In addition to 16S rRNA gene amplicon sequencing of longitudinally sampled faecal material of participants (six time points), detailed body composition measurements and analysis of blood samples (at baseline and after the intervention) were performed to obtain overall physiological changes within the intervention period. Activity tracker devices (wrist-band wearables) provided activity status and sleeping patterns of participants as well as exercise intensity and heart measurements.

Results: Different biometric responses between endurance and strength activities were identified, such as a significant increase of lymphocytes and decrease of mean corpuscular haemoglobin concentration (MCHC) only within the strength intervention group. In the endurance group, we observed a significant reduction in hip circumference and an increase in physical working capacity (PWC). Though a large variation of microbiota changes were observed between individuals of the same group, we did not find specific collective alterations in the endurance nor the strength groups, arguing for microbiome variations specific to individuals, and therefore, were not captured in our analysis.

Conclusions: We could show that different types of exercise have distinct but moderate effects on the overall physiology of humans and very distinct microbial changes in the gut. The observed overall changes during the intervention highlight the importance of physical activity on well-being. Future studies should investigate the effect of exercise on a longer timescale, investigate different training intensities and consider high-resolution shotgun metagenomics technology.

Trial Registration: DRKS, DRKS00015873 . Registered 12 December 2018; Retrospectively registered.
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http://dx.doi.org/10.1186/s12866-021-02214-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170780PMC
June 2021

Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism.

Nat Commun 2021 05 28;12(1):3216. Epub 2021 May 28.

Institute of Medical Biometry and Statistics, University of Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany.

X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (p < 5 × 10). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington's disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.
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http://dx.doi.org/10.1038/s41467-021-23491-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163740PMC
May 2021

MRI-based Iron Phenotyping and Patient Selection for Next-Generation Sequencing of non-HFE Hemochromatosis Genes.

Hepatology 2021 May 28. Epub 2021 May 28.

Department of Medicine I, Christian Doppler Laboratory on Iron and Phosphate Biology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.

Background & Aims: High serum ferritin is frequent among patients with chronic liver disease and commonly associated with hepatic iron overload. Genetic causes of high liver iron include homozygosity for the p.Cys282Tyr variant in HFE and rare variants in non-HFE genes. The aims of the present study were to describe the landscape and frequency of mutations in hemochromatosis genes and determine if patient selection by non-invasive hepatic iron quantification using magnetic resonance imaging (MRI) improves the diagnostic yield of next-generation sequencing (NGS) in patients with hyperferritinemia.

Approach & Results: A cohort of 410 unselected liver clinic patients with high serum ferritin (defined as ≥200 μg/l for women and ≥300 μg/l for men) was investigated by HFE genotyping and abdominal MRI R2*. Forty-one (10%) patients were homozygous for the p.Cys282Tyr variant in HFE. Of the remaining 369 patients, 256 (69%) had high transferrin saturation (TSAT ≥45%) and 199 (53%) had confirmed hepatic iron overload (liver R2* ≥70 s ). NGS of hemochromatosis genes was carried out in 180 patients with hepatic iron overload and likely pathogenic variants were identified in 68 of 180 (38%) patients, mainly in HFE (79%), CP (25%) and TFR2 (19%). Low spleen iron (R2*< 50 s ), but not TSAT, was significantly associated with the presence of mutations. In 167 patients (93%), no monogenic cause of hepatic iron overload could be identified.

Conclusions: In patients without homozygosity for p.Cys282Tyr, coincident pathogenic variants in HFE and non-HFE genes could explain hyperferritinemia with hepatic iron overload in a subset of patients. Unlike HFE hemochromatosis, this type of polygenic hepatic iron overload presents with variable TSAT. High ferritin in blood is an indicator of the iron storage disease hemochromatosis. A simple genetic test establishes this diagnosis in the majority of patients affected. Magnetic resonance imaging of the abdomen can guide further genetic testing.
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http://dx.doi.org/10.1002/hep.31982DOI Listing
May 2021

Identification of two novel bullous pemphigoid- associated alleles, HLA-DQA1*05:05 and -DRB1*07:01, in Germans.

Orphanet J Rare Dis 2021 May 19;16(1):228. Epub 2021 May 19.

CRIS, Center for Research On Inflammation of the Skin, University of Lübeck, Lübeck, Germany.

Bullous pemphigoid (BP) is the most common autoimmune skin blistering disease characterized by autoimmunity against the hemidesmosomal proteins BP180, type XVII collagen, and BP230. To elucidate the genetic basis of susceptibility to BP, we performed the first genome-wide association study (GWAS) in Germans. This GWAS was combined with HLA locus targeted sequencing in an additional independent BP cohort. The strongest association with BP in Germans tested in this study was observed in the two HLA loci, HLA-DQA1*05:05 and HLA-DRB1*07:01. Further studies with increased sample sizes and complex studies integrating multiple pathogenic drivers will be conducted.
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http://dx.doi.org/10.1186/s13023-021-01863-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136166PMC
May 2021

Mass burial genomics reveals outbreak of enteric paratyphoid fever in the Late Medieval trade city Lübeck.

iScience 2021 May 20;24(5):102419. Epub 2021 Apr 20.

Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany.

Medieval Europe was repeatedly affected by outbreaks of infectious diseases, some of which reached epidemic proportions. A Late Medieval mass burial next to the Heiligen-Geist-Hospital in Lübeck (present-day Germany) contained the skeletal remains of more than 800 individuals who had presumably died from infectious disease. From 92 individuals, we screened the ancient DNA extracts for the presence of pathogens to determine the cause of death. Metagenomic analysis revealed evidence of subsp. serovar Paratyphi C, suggesting an outbreak of enteric paratyphoid fever. Three reconstructed . Paratyphi C genomes showed close similarity to a strain from Norway (1200 CE). Radiocarbon dates placed the disease outbreak in Lübeck between 1270 and 1400 cal CE, with historical records indicating 1367 CE as the most probable year. The deceased were of northern and eastern European descent, confirming Lübeck as an important trading center of the Hanseatic League in the Baltic region.
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http://dx.doi.org/10.1016/j.isci.2021.102419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100618PMC
May 2021

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels.

Alzheimers Dement 2021 May 14. Epub 2021 May 14.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.

Introduction: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively.

Methods: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates.

Results: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1.

Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
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http://dx.doi.org/10.1002/alz.12330DOI Listing
May 2021

Effect of various weight loss interventions on serum NT-proBNP concentration in severe obese subjects without clinical manifest heart failure.

Sci Rep 2021 May 12;11(1):10096. Epub 2021 May 12.

Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Internal Medicine 1, University of Kiel, Arnold Heller Straße 3, 24105, Kiel, Germany.

Obesity is associated with a "natriuretic handicap" indicated by reduced N-terminal fragment of proBNP (NT-proBNP) concentration. While gastric bypass surgery improves the natriuretic handicap, it is presently unclear if sleeve gastrectomy exhibits similar effects. We examined NT-proBNP serum concentration in n = 72 obese participants without heart failure before and 6 months after sleeve gastrectomy (n = 28), gastric bypass surgery (n = 19), and 3-month 800 kcal/day very-low calorie diet (n = 25). A significant weight loss was observed in all intervention groups. Within 6 months, NT-proBNP concentration tended to increase by a median of 44.3 pg/mL in the sleeve gastrectomy group (p = 0.07), while it remained unchanged in the other groups (all p ≥ 0.50). To gain insights into potential effectors, we additionally analyzed NT-proBNP serum concentration in n = 387 individuals with different metabolic phenotypes. Here, higher NT-proBNP levels were associated with lower nutritional fat and protein but not with carbohydrate intake. Of interest, NT-proBNP serum concentrations were inversely correlated with fasting glucose concentration in euglycemic individuals but not in individuals with prediabetes or type 2 diabetes. In conclusion, sleeve gastrectomy tended to increase NT-proBNP levels in obese individuals and might improve the obesity-associated "natriuretic handicap". Thereby, nutritional fat and protein intake and the individual glucose homeostasis might be metabolic determinants of NT-proBNP serum concentration.
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http://dx.doi.org/10.1038/s41598-021-89426-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115663PMC
May 2021

Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.

Gut 2021 Apr 22. Epub 2021 Apr 22.

Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna, Austria.

Objective: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.

Design: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.

Results: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.

Conclusion: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
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http://dx.doi.org/10.1136/gutjnl-2020-323868DOI Listing
April 2021

Primate phageomes are structured by superhost phylogeny and environment.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

Epidemiology of Highly Pathogenic Organisms, Robert Koch Institute, 13353 Berlin, Germany;

Humans harbor diverse communities of microorganisms, the majority of which are bacteria in the gastrointestinal tract. These gut bacterial communities in turn host diverse bacteriophage (hereafter phage) communities that have a major impact on their structure, function, and, ultimately, human health. However, the evolutionary and ecological origins of these human-associated phage communities are poorly understood. To address this question, we examined fecal phageomes of 23 wild nonhuman primate taxa, including multiple representatives of all the major primate radiations. We find relatives of the majority of human-associated phages in wild primates. Primate taxa have distinct phageome compositions that exhibit a clear phylosymbiotic signal, and phage-superhost codivergence is often detected for individual phages. Within species, neighboring social groups harbor compositionally and evolutionarily distinct phageomes, which are structured by superhost social behavior. Captive nonhuman primate phageome composition is intermediate between that of their wild counterparts and humans. Phage phylogenies reveal replacement of wild great ape-associated phages with human-associated ones in captivity and, surprisingly, show no signal for the persistence of wild-associated phages in captivity. Together, our results suggest that potentially labile primate-phage associations have persisted across millions of years of evolution. Across primates, these phylosymbiotic and sometimes codiverging phage communities are shaped by transmission between groupmates through grooming and are dramatically modified when primates are moved into captivity.
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http://dx.doi.org/10.1073/pnas.2013535118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053973PMC
April 2021

Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4 T cells in primary sclerosing cholangitis.

J Hepatol 2021 Mar 24. Epub 2021 Mar 24.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany. Electronic address:

Background & Aims: Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver.

Methods: Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on samples from patients with PSC (n = 24), controls with other liver diseases and HDs.

Results: We identified a population of intrahepatic naive-like CD4 T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested that these cells had the developmental propensity to acquire a T helper 17 (T17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards T17 cells.

Conclusion: We report the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4 T cells in PSC harbour the propensity to develop into T17 cells.

Lay Summary: The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-resident CD4 T cells which are expanded in the livers of patients with PSC compared to healthy liver tissue and other liver diseases. These cells are likely to contribute to the pathogenesis of PSC and could be targeted in novel therapeutic approaches.
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http://dx.doi.org/10.1016/j.jhep.2021.03.016DOI Listing
March 2021

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality.

medRxiv 2021 Mar 12. Epub 2021 Mar 12.

Background: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium.

Method: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors.

Findings: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2-1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3-1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors.

Interpretation: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality-and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management.

Funding: Funding was obtained by each of the participating cohorts individually.
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http://dx.doi.org/10.1101/2021.03.07.21252875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987046PMC
March 2021

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

Sci Rep 2021 Mar 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

Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model.

Front Immunol 2021 25;12:636061. Epub 2021 Feb 25.

Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO) at Hospital St. Hedwig of the Order of St. John, Regensburg, Germany.

Asthma and allergies are complex, chronic inflammatory diseases in which genetic and environmental factors are crucial. Protection against asthma and allergy development in the context of farming environment is established by early animal contact, unpasteurized milk consumption and gut microbiota maturation. The human β-defensin 2 (hBD-2) is a host defense peptide present almost exclusively in epithelial tissues, with pronounced immunomodulatory properties, which has recently been shown to ameliorate asthma and IBD in animal models. We hypothesized that adequate hBD-2 secretion plays a role in the protection against asthma and allergy development and that genetic variations in the complex gene locus coding for hBD-2 may be a risk factor for developing these diseases, if as a consequence, hBD-2 is insufficiently produced. We used MALDI-TOF MS genotyping, sequencing and a RFLP assay to study the genetic variation including mutations, polymorphisms and copy number variations in the locus harboring both genes coding for hBD-2 ( and . We administered hBD-2 orally in a mouse model of house dust mite (HDM)-asthma before allergy challenge to explore its prophylactic potential, thereby mimicking a protective farm effect. Despite the high complexity of the region harboring and we identified numerous genetic variants to be associated with asthma and allergy in the GABRIELA Ulm population of 1,238 children living in rural areas, including rare mutations, polymorphisms and a lack of the . Furthermore, we found that prophylactic oral administration of hBD-2 significantly curbed lung resistance and pulmonary inflammation in our HDM mouse model. These data indicate that inadequate genetic capacity for hBD-2 is associated with increased asthma and allergy risk while adequate and early hBD-2 administration (in a mouse model) prevents atopic asthma. This suggests that hBD-2 could be involved in the protective farm effect and may be an excellent candidate to confer protection against asthma development.
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http://dx.doi.org/10.3389/fimmu.2021.636061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946850PMC
February 2021

Intestinal protozoan infections shape fecal bacterial microbiota in children from Guinea-Bissau.

PLoS Negl Trop Dis 2021 03 3;15(3):e0009232. Epub 2021 Mar 3.

Cancer and Inflammation Research, Department of Molecular Medicine, University of Southern Denmark, Denmark.

Intestinal parasitic infections, caused by helminths and protozoa, are globally distributed and major causes of worldwide morbidity. The gut microbiota may modulate parasite virulence and host response upon infection. The complex interplay between parasites and the gut microbiota is poorly understood, partly due to sampling difficulties in remote areas with high parasite burden. In a large study of children in Guinea-Bissau, we found high prevalence of intestinal parasites. By sequencing of the 16S rRNA genes of fecal samples stored on filter paper from a total of 1,204 children, we demonstrate that the bacterial microbiota is not significantly altered by helminth infections, whereas it is shaped by the presence of both pathogenic and nonpathogenic protozoa, including Entamoeba (E.) spp. and Giardia (G.) lamblia. Within-sample diversity remains largely unaffected, whereas overall community composition is significantly affected by infection with both nonpathogenic E. coli (R2 = 0.0131, P = 0.0001) and Endolimax nana (R2 = 0.00902, P = 0.0001), and by pathogenic E. histolytica (R2 = 0.0164, P = 0.0001) and G. lamblia (R2 = 0.00676, P = 0.0001). Infections with multiple parasite species induces more pronounced shifts in microbiota community than mild ones. A total of 31 bacterial genera across all four major bacterial phyla were differentially abundant in protozoan infection as compared to noninfected individuals, including increased abundance of Prevotella, Campylobacter and two Clostridium clades, and decreased abundance of Collinsella, Lactobacillus, Ruminococcus, Veillonella and one Clostridium clade. In the present study, we demonstrate that the fecal bacterial microbiota is shaped by intestinal parasitic infection, with most pronounced associations for protozoan species. Our results provide insights into the interplay between the microbiota and intestinal parasites, which are valuable to understand infection biology and design further studies aimed at optimizing treatment strategies.
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http://dx.doi.org/10.1371/journal.pntd.0009232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959362PMC
March 2021

Current Developments of Clinical Sequencing and the Clinical Utility of Polygenic Risk Scores in Inflammatory Diseases.

Front Immunol 2020 29;11:577677. Epub 2021 Jan 29.

Department of Dermatology, Quincke Research Center, University Hospital Schleswig-Holstein, Kiel, Germany.

In this mini-review, we highlight selected research by the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence "Precision Medicine in Chronic Inflammation" focusing on clinical sequencing and the clinical utility of polygenic risk scores as well as its implication on precision medicine in the field of the inflammatory diseases inflammatory bowel disease, atopic dermatitis and coronary artery disease. Additionally, we highlight current developments and discuss challenges to be faced in the future. Exemplary, we point to residual challenges in detecting disease-relevant variants resulting from difficulties in the interpretation of candidate variants and their potential interactions. While polygenic risk scores represent promising tools for the stratification of patient groups, currently, polygenic risk scores are not accurate enough for clinical setting. Precision medicine, incorporating additional data from genomics, transcriptomics and proteomics experiments, may enable the identification of distinct disease pathogeneses. In the future, data-intensive biomedical innovation will hopefully lead to improved patient stratification for personalized medicine.
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http://dx.doi.org/10.3389/fimmu.2020.577677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901950PMC
June 2021

A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis.

Sci Transl Med 2021 Feb;13(582)

Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease without clear etiology or effective treatment. Genetic factors contribute to PSC pathogenesis, but so far, no causative mutation has been found. We performed whole-exome sequencing in a family with autosomal dominant inheritance of PSC and identified a heterozygous germline missense mutation in , encoding a K849T variant of CD100. The mutation was located in an evolutionarily conserved, unstructured cytosolic region of CD100 affecting downstream signaling. It was found to alter the function of CD100-expressing cells with a bias toward the T cell compartment that caused increased proliferation and impaired interferon-γ (IFN-γ) production after stimulation. Homologous mutation knock-in mice developed similar IFN-γ impairment in T cells and were more prone to develop severe cholangitis when exposed to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Transfer of wild-type T cells to knock-in mice before and during DDC exposure attenuated cholangitis. Taken together, we identified an inherited mutation in the disordered cytosolic region of CD100 resulting in T cell functional defects. Our findings suggest a protective role for T cells in PSC that might be used therapeutically.
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http://dx.doi.org/10.1126/scitranslmed.abb0036DOI Listing
February 2021

Clinical correlates of anti-SARS-CoV-2 antibody profiles in Spanish COVID-19 patients from a high incidence region.

Sci Rep 2021 02 23;11(1):4363. Epub 2021 Feb 23.

Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany.

Laboratory testing for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consists of two pillars: the detection of viral RNA via rt-PCR as the diagnostic gold standard in acute cases, and the detection of antibodies against SARS-CoV-2. However, concerning the latter, questions remain about their diagnostic and prognostic value and it is not clear whether all patients develop detectable antibodies. We examined sera from 347 Spanish COVID-19 patients, collected during the peak of the epidemic outbreak in Spain, for the presence of IgA and IgG antibodies against SARS-CoV-2 and evaluated possible associations with age, sex and disease severity (as measured by duration of hospitalization, kind of respiratory support, treatment in ICU and death). The presence and to some degree the levels of anti-SARS-CoV-2 antibodies depended mainly on the amount of time between onset of symptoms and the collection of serum. A subgroup of patients did not develop antibodies at the time of sample collection. Compared to the patients that did, no differences were found. The presence and level of antibodies was not associated with age, sex, duration of hospitalization, treatment in the ICU or death. The case-fatality rate increased exponentially with older age. Neither the presence, nor the levels of anti-SARS-CoV-2 antibodies served as prognostic markers in our cohort. This is discussed as a possible consequence of the timing of the sample collection. Age is the most important risk factor for an adverse outcome in our cohort. Some patients appear not to develop antibodies within a reasonable time frame. It is unclear, however, why that is, as these patients differ in no respect examined by us from those who developed antibodies.
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http://dx.doi.org/10.1038/s41598-021-83969-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902674PMC
February 2021

Association Between Collagenous and Lymphocytic Colitis and Risk of Severe Coronavirus Disease 2019.

Gastroenterology 2021 06 19;160(7):2585-2587.e3. Epub 2021 Feb 19.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom; Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2021.02.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892313PMC
June 2021

Single- and Multimarker Genome-Wide Scans Evidence Novel Genetic Risk Modifiers for Venous Thromboembolism.

Thromb Haemost 2021 Feb 16. Epub 2021 Feb 16.

Institute for Clinical Chemistry and Coagulation Center, University Hospital Schleswig Holstein, Kiel/Lübeck, Germany.

Previous genome-wide association studies (GWASs) have established several susceptibility genes for venous thromboembolism (VTE) and suggested many others. However, a large proportion of the genetic variance in VTE remains unexplained. Here, we report genome-wide single- and multimarker as well as gene-level associations with VTE in 964 cases and 899 healthy controls of European ancestry. We report 19 loci at the genome-wide level of association ( ≤ 5 × 10). Our results add to the strong support for the association of genetic variants in , , and with VTE, and identify several loci that have not been previously associated with VTE. Altogether, our novel findings suggest that 20 susceptibility genes for VTE were newly discovered by our study. These genes may impact the production and prothrombotic functions of platelets, endothelial cells, and white and red blood cells. Moreover, the majority of these genes have been previously associated with cardiovascular diseases and/or risk factors for VTE. Future studies are warranted to validate our findings and to investigate the shared genetic architecture with susceptibility factors for other cardiovascular diseases impacting VTE risk.
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http://dx.doi.org/10.1055/s-0041-1723988DOI Listing
February 2021

Depletion of erythropoietic miR-486-5p and miR-451a improves detectability of rare microRNAs in peripheral blood-derived small RNA sequencing libraries.

NAR Genom Bioinform 2020 Mar 12;2(1):lqaa008. Epub 2020 Feb 12.

Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, DE 24105 Kiel, Germany.

Erythroid-specific miR-451a and miR-486-5p are two of the most dominant microRNAs (miRNAs) in human peripheral blood. In small RNA sequencing libraries, their overabundance reduces diversity as well as complexity and consequently causes negative effects such as missing detectability and inaccurate quantification of low abundant miRNAs. Here we present a simple, cost-effective and easy to implement hybridization-based method to deplete these two erythropoietic miRNAs from blood-derived RNA samples. By utilization of blocking oligonucleotides, this method provides a highly efficient and specific depletion of miR-486-5p and miR-451a, which leads to a considerable increase of measured expression as well as detectability of low abundant miRNA species. The blocking oligos are compatible with common 5' ligation-dependent small RNA library preparation protocols, including commercially available kits, such as Illumina TruSeq and Perkin Elmer NEXTflex. Furthermore, the here described method and oligo design principle can be easily adapted to target many other miRNA molecules, depending on context and research question.
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http://dx.doi.org/10.1093/nargab/lqaa008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671325PMC
March 2020

Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations.

Hum Mol Genet 2021 Apr;30(5):356-369

Schools of Mathematics and Statistics and BioSciences and Melbourne Integrative Genomics, University of Melbourne, Victoria 3010, Australia.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.
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http://dx.doi.org/10.1093/hmg/ddab017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098114PMC
April 2021

Genome-wide study of a Neolithic Wartberg grave community reveals distinct HLA variation and hunter-gatherer ancestry.

Commun Biol 2021 Jan 25;4(1):113. Epub 2021 Jan 25.

Institute of Clinical Molecular Biology, Kiel University, Rosalind-Franklin-Strasse 12, 24105, Kiel, Germany.

The Wartberg culture (WBC, 3500-2800 BCE) dates to the Late Neolithic period, a time of important demographic and cultural transformations in western Europe. We performed genome-wide analyses of 42 individuals who were interred in a WBC collective burial in Niedertiefenbach, Germany (3300-3200 cal. BCE). The results showed that the farming population of Niedertiefenbach carried a surprisingly large hunter-gatherer ancestry component (34-58%). This component was most likely introduced during the cultural transformation that led to the WBC. In addition, the Niedertiefenbach individuals exhibited a distinct human leukocyte antigen gene pool, possibly reflecting an immune response that was geared towards detecting viral infections.
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http://dx.doi.org/10.1038/s42003-020-01627-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835224PMC
January 2021

Exome-Wide Association Study Identifies FN3KRP and PGP as New Candidate Longevity Genes.

J Gerontol A Biol Sci Med Sci 2021 Apr;76(5):786-795

Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Germany.

Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery p-value (1 × 10E-04). Furthermore, we validated the previously reported longevity locus cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified 2 new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, that is, the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).
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http://dx.doi.org/10.1093/gerona/glab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087267PMC
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
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

Longitudinal high-throughput TCR repertoire profiling reveals the dynamics of T-cell memory formation after mild COVID-19 infection.

Elife 2021 01 5;10. Epub 2021 Jan 5.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation.

COVID-19 is a global pandemic caused by the SARS-CoV-2 coronavirus. T cells play a key role in the adaptive antiviral immune response by killing infected cells and facilitating the selection of virus-specific antibodies. However, neither the dynamics and cross-reactivity of the SARS-CoV-2-specific T-cell response nor the diversity of resulting immune memory is well understood. In this study, we use longitudinal high-throughput T-cell receptor (TCR) sequencing to track changes in the T-cell repertoire following two mild cases of COVID-19. In both donors, we identified CD4 and CD8 T-cell clones with transient clonal expansion after infection. We describe characteristic motifs in TCR sequences of COVID-19-reactive clones and show preferential occurrence of these motifs in publicly available large dataset of repertoires from COVID-19 patients. We show that in both donors, the majority of infection-reactive clonotypes acquire memory phenotypes. Certain T-cell clones were detected in the memory fraction at the pre-infection time point, suggesting participation of pre-existing cross-reactive memory T cells in the immune response to SARS-CoV-2.
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http://dx.doi.org/10.7554/eLife.63502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806265PMC
January 2021

Genetic variability of immune-related lncRNAs: polymorphisms in LINC-PINT and LY86-AS1 are associated with pemphigus foliaceus susceptibility.

Exp Dermatol 2021 Jun 15;30(6):831-840. Epub 2021 Jan 15.

Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil.

Pemphigus foliaceus (PF) is an autoimmune blistering disease of the skin, clinically characterized by erosions and, histopathologically, by acantholysis. PF is endemic in the Brazilian Central-Western region. Numerous single nucleotide polymorphisms (SNPs) have been shown to affect the susceptibility for PF, including SNPs at long non-coding RNA (lncRNA) genes, which are known to participate in many physiological and pathogenic processes, such as autoimmunity. Here, we investigated whether the genetic variation of immune-related lncRNA genes affects the risk for endemic and sporadic forms of PF. We analysed 692 novel SNPs for PF from 135 immune-related lncRNA genes in 227 endemic PF patients and 194 controls. The SNPs were genotyped by Illumina microarray and analysed by applying logistic regression at additive model, with correction for sex and population structure. Six associated SNPs were also evaluated in an independent German cohort of 76 sporadic PF patients and 150 controls. Further, we measured the expression levels of two associated lncRNA genes (LINC-PINT and LY86-AS1) by quantitative PCR, stratified by genotypes, in peripheral blood mononuclear cells of healthy subjects. We found 27 SNPs in 11 lncRNA genes associated with endemic PF (p < .05 without overlapping with protein-coding genes). Among them, the LINC-PINT SNP rs10228040*A (OR = 1.47, p = .012) was also associated with increased susceptibility for sporadic PF (OR = 2.28, p = .002). Moreover, the A+ carriers of LY86-AS1*rs12192707 mark lowest LY86-AS1 RNA levels, which might be associated with a decreasing autoimmune response. Our results suggest a critical role of lncRNA variants in immunopathogenesis of both PF endemic and sporadic forms.
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http://dx.doi.org/10.1111/exd.14275DOI Listing
June 2021

Altered Gut Microbial Metabolism of Essential Nutrients in Primary Sclerosing Cholangitis.

Gastroenterology 2021 Apr 31;160(5):1784-1798.e0. Epub 2020 Dec 31.

Norwegian Primary Sclerosing Cholangitis Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. Electronic address:

Background & Aims: To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD).

Methods: Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses.

Results: Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Q < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation-free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD.

Conclusions: The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
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http://dx.doi.org/10.1053/j.gastro.2020.12.058DOI Listing
April 2021