Publications by authors named "Philipp Rausch"

17 Publications

  • Page 1 of 1

Small Intestinal Tuft Cell Activity Associates With Energy Metabolism in Diet-Induced Obesity.

Front Immunol 2021 28;12:629391. Epub 2021 May 28.

Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark.

Little is known about the involvement of type 2 immune response-promoting intestinal tuft cells in metabolic regulation. We here examined the temporal changes in small intestinal tuft cell number and activity in response to high-fat diet-induced obesity in mice and investigated the relation to whole-body energy metabolism and the immune phenotype of the small intestine and epididymal white adipose tissue. Intake of high fat diet resulted in a reduction in overall numbers of small intestinal epithelial and tuft cells and reduced expression of the intestinal type 2 tuft cell markers and . Amongst >1,700 diet-regulated transcripts in tuft cells, we observed an early association between body mass expansion and increased expression of the gene encoding the serine protease inhibitor neuroserpin. By contrast, tuft cell expression of genes encoding gamma aminobutyric acid (GABA)-receptors was coupled to and and reduced body mass gain. Combined, our results point to a possible role for small intestinal tuft cells in energy metabolism coupled regulation of tuft cell type 2 markers and GABA signaling receptors, while being independent of type 2 immune cell involvement. These results pave the way for further studies into interventions that elicit anti-obesogenic circuits small intestinal tuft cells.
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http://dx.doi.org/10.3389/fimmu.2021.629391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195285PMC
May 2021

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

Comparative analysis of amplicon and metagenomic sequencing methods reveals key features in the evolution of animal metaorganisms.

Microbiome 2019 09 14;7(1):133. Epub 2019 Sep 14.

Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Plön, Germany.

Background: The interplay between hosts and their associated microbiome is now recognized as a fundamental basis of the ecology, evolution, and development of both players. These interdependencies inspired a new view of multicellular organisms as "metaorganisms." The goal of the Collaborative Research Center "Origin and Function of Metaorganisms" is to understand why and how microbial communities form long-term associations with hosts from diverse taxonomic groups, ranging from sponges to humans in addition to plants.

Methods: In order to optimize the choice of analysis procedures, which may differ according to the host organism and question at hand, we systematically compared the two main technical approaches for profiling microbial communities, 16S rRNA gene amplicon and metagenomic shotgun sequencing across our panel of ten host taxa. This includes two commonly used 16S rRNA gene regions and two amplification procedures, thus totaling five different microbial profiles per host sample.

Conclusion: While 16S rRNA gene-based analyses are subject to much skepticism, we demonstrate that many aspects of bacterial community characterization are consistent across methods. The resulting insight facilitates the selection of appropriate methods across a wide range of host taxa. Overall, we recommend single- over multi-step amplification procedures, and although exceptions and trade-offs exist, the V3 V4 over the V1 V2 region of the 16S rRNA gene. Finally, by contrasting taxonomic and functional profiles and performing phylogenetic analysis, we provide important and novel insight into broad evolutionary patterns among metaorganisms, whereby the transition of animals from an aquatic to a terrestrial habitat marks a major event in the evolution of host-associated microbial composition.
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http://dx.doi.org/10.1186/s40168-019-0743-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744666PMC
September 2019

Environmental Microbial Factors Determine the Pattern of Inflammatory Lesions in a Murine Model of Crohn's Disease-Like Inflammation.

Inflamm Bowel Dis 2020 01;26(1):66-79

Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

Crohn's disease (CD) patients can be grouped into patients suffering from ileitis, ileocolitis, jejunoileitis, and colitis. The pathophysiological mechanism underlying this regional inflammation is still unknown. Although most murine models of inflammatory bowel disease (IBD) develop inflammation in the colon, there is an unmet need for novel models that recapitulate the spontaneous and fluctuating nature of inflammation as seen in CD. Recently, mice with an intestinal epithelial cell-specific deletion for Caspase-8 (Casp8ΔIEC mice), which are characterized by cell death-driven ileitis and disrupted Paneth cell homeostasis, have been identified as a novel model of CD-like ileitis. Here we uncovered that genetic susceptibility alone is sufficient to drive ileitis in Casp8ΔIEC mice. In sharp contrast, environmental factors, such as a disease-relevant microbial flora, determine colonic inflammation. Accordingly, depending on the microbial environment, isogenic Casp8ΔIEC mice either exclusively developed ileitis or suffered from pathologies in several parts of the gastrointestinal tract. Colitis in these mice was characterized by massive epithelial cell death, leading to spread of commensal gut microbes to the extra-intestinal space and hence an aberrant activation of the systemic immunity. We further uncovered that Casp8ΔIEC mice show qualitative and quantitative changes in the intestinal microbiome associated with an altered mucosal and systemic immune response. In summary, we identified that inflammation in this murine model of CD-like inflammation is characterized by an immune reaction, presumably directed against a disease-relevant microbiota in a genetically susceptible host, with impaired mucosal barrier function and bacterial clearance at the epithelial interface.
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http://dx.doi.org/10.1093/ibd/izz142DOI Listing
January 2020

Mucispirillum schaedleri Antagonizes Salmonella Virulence to Protect Mice against Colitis.

Cell Host Microbe 2019 05 18;25(5):681-694.e8. Epub 2019 Apr 18.

Max-von-Pettenkofer Institute, LMU Munich, Pettenkoferstr. 9a, 80336 Munich, Germany; German Center for Infection Research (DZIF), partner site LMU Munich, 80336 Munich, Germany. Electronic address:

The microbiota and the gastrointestinal mucus layer play a pivotal role in protection against non-typhoidal Salmonella enterica serovar Typhimurium (S. Tm) colitis. Here, we analyzed the course of Salmonella colitis in mice lacking a functional mucus layer in the gut. Unexpectedly, in contrast to mucus-proficient littermates, genetically deficient mice were protected against Salmonella-induced gut inflammation in the streptomycin colitis model. This correlated with microbiota alterations and enrichment of the bacterial phylum Deferribacteres. Using gnotobiotic mice associated with defined bacterial consortia, we causally linked Mucispirillum schaedleri, currently the sole known representative of Deferribacteres present in the mammalian microbiota, to host protection against S. Tm colitis. Inhibition by M. schaedleri involves interference with S. Tm invasion gene expression, partly by competing for anaerobic electron acceptors. In conclusion, this study establishes M. schaedleri, a core member of the murine gut microbiota, as a key antagonist of S. Tm virulence in the gut.
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http://dx.doi.org/10.1016/j.chom.2019.03.004DOI Listing
May 2019

The Iceman's Last Meal Consisted of Fat, Wild Meat, and Cereals.

Curr Biol 2018 07 12;28(14):2348-2355.e9. Epub 2018 Jul 12.

SLING, Life Sciences Institute, National University of Singapore, Singapore; Department of Biochemistry, National University of Singapore, Singapore.

The history of humankind is marked by the constant adoption of new dietary habits affecting human physiology, metabolism, and even the development of nutrition-related disorders. Despite clear archaeological evidence for the shift from hunter-gatherer lifestyle to agriculture in Neolithic Europe [1], very little information exists on the daily dietary habits of our ancestors. By undertaking a complementary -omics approach combined with microscopy, we analyzed the stomach content of the Iceman, a 5,300-year-old European glacier mummy [2, 3]. He seems to have had a remarkably high proportion of fat in his diet, supplemented with fresh or dried wild meat, cereals, and traces of toxic bracken. Our multipronged approach provides unprecedented analytical depth, deciphering the nutritional habit, meal composition, and food-processing methods of this Copper Age individual.
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http://dx.doi.org/10.1016/j.cub.2018.05.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065529PMC
July 2018

Application of the distance-based F test in an mGWAS investigating β diversity of intestinal microbiota identifies variants in SLC9A8 (NHE8) and 3 other loci.

Gut Microbes 2018 01 28;9(1):68-75. Epub 2017 Aug 28.

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

Factors shaping the human intestinal microbiota range from environmental influences, like smoking and exercise, over dietary patterns and disease to the host's genetic variation. Recently, we could show in a microbiome genome-wide association study (mGWAS) targeting genetic variation influencing the β diversity of gut microbial communities, that approximately 10% of the overall gut microbiome variation can be explained by host genetics. Here, we report on the application of a new method for genotype-β-diversity association testing, the distance-based F (DBF) test. With this we identified 4 loci with genome-wide significant associations, harboring the genes CBEP4, SLC9A8, TNFSF4, and SP140, respectively. Our findings highlight the utility of the high-performance DBF test in β diversity GWAS and emphasize the important role of host genetics and immunity in shaping the human intestinal microbiota.
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http://dx.doi.org/10.1080/19490976.2017.1356979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939986PMC
January 2018

Multigenerational Influences of the Gene on the Dynamics of the Gut Microbiota in Mice.

Front Microbiol 2017 8;8:991. Epub 2017 Jun 8.

Group Evolutionary Genomics, Max Planck Institute for Evolutionary BiologyPlön, Germany.

The gene encodes an α-1,2-fucosyltransferase responsible for the expression of ABO histo-blood-group antigens on mucosal surfaces and bodily secretions. Individuals who carry at least one functional allele are known as "" whereas those homozygous for loss-of-function mutations are known as "" individuals are more susceptible to chronic inflammatory disorders such as Crohn's Disease, which may be mediated by alterations in the microbiota. Here, we investigated the dynamics of microbial community assembly with respect to genotype using a -deficient mouse model, taking the genotype of the maternal lineage over two generations into account. We found strong differences in community assembly of microbial communities over time, depending on the genotype of the host and that of their progenitors. By applying network analyses, we further identified patterns of specialization and stabilization over time, which are influenced by the host and parental genotype during the process of community development. We also show genotype- and breeding-dependent patterns of community susceptibility to disturbance in a novel approach integrating ecological- and network analysis. Our results indicate that it may be important to investigate the influence of genotype in a familial context in order to fully understand its role in the etiology of chronic inflammatory disorders.
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http://dx.doi.org/10.3389/fmicb.2017.00991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463037PMC
June 2017

Boolean analysis reveals systematic interactions among low-abundance species in the human gut microbiome.

PLoS Comput Biol 2017 Jun 22;13(6):e1005361. Epub 2017 Jun 22.

Computational Systems Biology, Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany.

The analysis of microbiome compositions in the human gut has gained increasing interest due to the broader availability of data and functional databases and substantial progress in data analysis methods, but also due to the high relevance of the microbiome in human health and disease. While most analyses infer interactions among highly abundant species, the large number of low-abundance species has received less attention. Here we present a novel analysis method based on Boolean operations applied to microbial co-occurrence patterns. We calibrate our approach with simulated data based on a dynamical Boolean network model from which we interpret the statistics of attractor states as a theoretical proxy for microbiome composition. We show that for given fractions of synergistic and competitive interactions in the model our Boolean abundance analysis can reliably detect these interactions. Analyzing a novel data set of 822 microbiome compositions of the human gut, we find a large number of highly significant synergistic interactions among these low-abundance species, forming a connected network, and a few isolated competitive interactions.
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http://dx.doi.org/10.1371/journal.pcbi.1005361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480827PMC
June 2017

Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2.

Blood 2017 07 1;130(4):542-553. Epub 2017 Jun 1.

Center for Thrombosis and Hemostasis, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany.

The symbiotic gut microbiota play pivotal roles in host physiology and the development of cardiovascular diseases, but the microbiota-triggered pattern recognition signaling mechanisms that impact thrombosis are poorly defined. In this article, we show that germ-free (GF) and Toll-like receptor-2 ()-deficient mice have reduced thrombus growth after carotid artery injury relative to conventionally raised controls. GF and wild-type (WT) mice were indistinguishable, but colonization with microbiota restored a significant difference in thrombus growth between the genotypes. We identify reduced plasma levels of von Willebrand factor (VWF) and reduced VWF synthesis, specifically in hepatic endothelial cells, as a critical factor that is regulated by gut microbiota and determines thrombus growth in mice. Static platelet aggregate formation on extracellular matrix was similarly reduced in GF WT, , and heterozygous mice that are all characterized by a modest reduction in plasma VWF levels. Defective platelet matrix interaction can be restored by exposure to WT plasma or to purified VWF depending on the VWF integrin binding site. Moreover, administration of VWF rescues defective thrombus growth in mice in vivo. These experiments delineate an unexpected pathway in which microbiota-triggered TLR2 signaling alters the synthesis of proadhesive VWF by the liver endothelium and favors platelet integrin-dependent thrombus growth.
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http://dx.doi.org/10.1182/blood-2016-11-754416DOI Listing
July 2017

Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota.

Nat Genet 2016 11 10;48(11):1396-1406. Epub 2016 Oct 10.

BioDonostia Health Research Institute, San Sebastian and Ikerbasque, Basque Foundation for Science, Bilbao, Spain.

Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observe significant shifts in the microbiota of Vdr mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 × 10) associations at multiple additional loci identify other important points of host-microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota, whereby individual effects are relatively small.
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http://dx.doi.org/10.1038/ng.3695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626933PMC
November 2016

Analysis of factors contributing to variation in the C57BL/6J fecal microbiota across German animal facilities.

Int J Med Microbiol 2016 Aug 15;306(5):343-355. Epub 2016 Mar 15.

Max Planck Institute for Evolutionary Biology, Evolutionary Genomics, August-Thienemann-Str. 2, 24306, Plön, Germany; Institute for Experimental Medicine, Evolutionary Genomics, Christian-Albrechts-University of Kiel, Arnold-Heller-Str. 3, Haus 17, 24105 Kiel, Germany. Electronic address:

The intestinal microbiota is involved in many physiological processes and it is increasingly recognized that differences in community composition can influence the outcome of a variety of murine models used in biomedical research. In an effort to describe and account for the variation in intestinal microbiota composition across the animal facilities of participating members of the DFG Priority Program 1656 "Intestinal Microbiota", we performed a survey of C57BL/6J mice from 21 different mouse rooms/facilities located at 13 different institutions across Germany. Fresh feces was sampled from five mice per room/facility using standardized procedures, followed by extraction and 16S rRNA gene profiling (V1-V2 region, Illumina MiSeq) at both the DNA and RNA (reverse transcribed to cDNA) level. In order to determine the variables contributing to bacterial community differences, we collected detailed questionnaires of animal husbandry practices and incorporated this information into our analyses. We identified considerable variation in a number of descriptive aspects including the proportions of major phyla, alpha- and beta diversity, all of which displayed significant associations to specific aspects of husbandry. Salient findings include a reduction in alpha diversity with the use of irradiated chow, an increase in inter-individual variability (beta diversity) with respect to barrier access and open cages and an increase in bacterial community divergence with time since importing from a vendor. We further observe a high degree of facility-level individuality, which is likely due to each facility harboring its own unique combination of multiple varying attributes of animal husbandry. While it is important to account and control for such differences between facilities, the documentation of such diversity may also serve as a valuable future resource for investigating the origins of microbial-driven host phenotypes.
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http://dx.doi.org/10.1016/j.ijmm.2016.03.004DOI Listing
August 2016

Expression of the Blood-Group-Related Gene B4galnt2 Alters Susceptibility to Salmonella Infection.

PLoS Pathog 2015 Jul 2;11(7):e1005008. Epub 2015 Jul 2.

Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany; Models of Inflammation, Research Center Borstel, Borstel, Germany.

Glycans play important roles in host-microbe interactions. Tissue-specific expression patterns of the blood group glycosyltransferase β-1,4-N-acetylgalactosaminyltransferase 2 (B4galnt2) are variable in wild mouse populations, and loss of B4galnt2 expression is associated with altered intestinal microbiota. We hypothesized that variation in B4galnt2 expression alters susceptibility to intestinal pathogens. To test this, we challenged mice genetically engineered to express different B4galnt2 tissue-specific patterns with a Salmonella Typhimurium infection model. We found B4galnt2 intestinal expression was strongly associated with bacterial community composition and increased Salmonella susceptibility as evidenced by increased intestinal inflammatory cytokines and infiltrating immune cells. Fecal transfer experiments demonstrated a crucial role of the B4galnt2-dependent microbiota in conferring susceptibility to intestinal inflammation, while epithelial B4galnt2 expression facilitated epithelial invasion of S. Typhimurium. These data support a critical role for B4galnt2 in gastrointestinal infections. We speculate that B4galnt2-specific differences in host susceptibility to intestinal pathogens underlie the strong signatures of balancing selection observed at the B4galnt2 locus in wild mouse populations.
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http://dx.doi.org/10.1371/journal.ppat.1005008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489644PMC
July 2015

Geographical patterns of the standing and active human gut microbiome in health and IBD.

Gut 2016 Feb 7;65(2):238-48. Epub 2015 Jan 7.

Department of General Internal Medicine, Christian-Albrechts-University of Kiel, University Hospital Schleswig-Holstein, Kiel, Germany.

Objective: A global increase of IBD has been reported, especially in countries that previously had low incidence rates. Also, the knowledge of the human gut microbiome is steadily increasing, however, limited information regarding its variation on a global scale is available. In the light of the microbial involvement in IBDs, we aimed to (1) identify shared and distinct IBD-associated mucosal microbiota patterns from different geographical regions including Europe (Germany, Lithuania) and South Asia (India) and (2) determine whether profiling based on 16S rRNA transcripts provides additional resolution, both of which may hold important clinical relevance.

Design: In this study, we analyse a set of 89 mucosal biopsies sampled from individuals of German, Lithuanian and Indian origins, using bacterial community profiling of a roughly equal number of healthy controls, patients with Crohn's disease and UC from each location, and analyse 16S rDNA and rRNA as proxies for standing and active microbial community structure, respectively.

Results: We find pronounced population-specific as well as general disease patterns in the major phyla and patterns of diversity, which differ between the standing and active communities. The geographical origin of samples dominates the patterns of β diversity with locally restricted disease clusters and more pronounced effects in the active microbial communities. However, two genera belonging to the Clostridium leptum subgroup, Faecalibacteria and Papillibacter, display consistent patterns with respect to disease status and may thus serve as reliable 'microbiomarkers'.

Conclusions: These analyses reveal important interactions of patients' geographical origin and disease in the interpretation of disease-associated changes in microbial communities and highlight the added value of analysing communities on both the 16S rRNA gene (DNA) and transcript (RNA) level.
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http://dx.doi.org/10.1136/gutjnl-2014-308341DOI Listing
February 2016

Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.

J Hepatol 2012 Aug 18;57(2):366-75. Epub 2012 Apr 18.

Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Background & Aims: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS).

Methods: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing.

Results: Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined)=2.1 × 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb)=1.9 × 10(-6), rs281377; p(comb)=2.1 × 10(-6) and rs601338; p(comb)=2.7 × 10(-6)) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients.

Conclusions: We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC.
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http://dx.doi.org/10.1016/j.jhep.2012.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399030PMC
August 2012

Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype.

Proc Natl Acad Sci U S A 2011 Nov 8;108(47):19030-5. Epub 2011 Nov 8.

Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, D-24105 Kiel, Germany.

The FUT2 (Secretor) gene is responsible for the presence of ABO histo-blood group antigens on the gastrointestinal mucosa and in bodily secretions. Individuals lacking a functional copy of FUT2 are known as "nonsecretors" and display an array of differences in susceptibility to infection and disease, including Crohn disease. To determine whether variation in resident microbial communities with respect to FUT2 genotype is a potential factor contributing to susceptibility, we performed 454-based community profiling of the intestinal microbiota in a panel of healthy subjects and Crohn disease patients and determined their genotype for the primary nonsecretor allele in Caucasian populations, W143X (G428A). Consistent with previous studies, we observe significant deviations in the microbial communities of individuals with Crohn disease. Furthermore, the FUT2 genotype explains substantial differences in community composition, diversity, and structure, and we identified several bacterial species displaying disease-by-genotype associations. These findings indicate that alterations in resident microbial communities may in part explain the variety of host susceptibilities surrounding nonsecretor status and that FUT2 is an important genetic factor influencing host-microbial diversity.
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http://dx.doi.org/10.1073/pnas.1106408108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223430PMC
November 2011

Major histocompatibility complex variation and age-specific endoparasite load in subadult European rabbits.

Mol Ecol 2010 Oct 13;19(19):4155-67. Epub 2010 Aug 13.

Department of Animal Physiology, University of Bayreuth, D-95440 Bayreuth, GermanyLimnological Institute, University of Konstanz, D-78464 Konstanz, Germany.

Genes of the major histocompatibility complex (MHC) play a fundamental role in the vertebrate immune response and are amongst the most polymorphic genes in vertebrate genomes. It is generally agreed that the highly polymorphic nature of the MHC is maintained through host-parasite co-evolution. Two nonexclusive mechanisms of selection are supposed to act on MHC genes: superiority of MHC heterozygous individuals (overdominance) and an advantage for rare MHC alleles. However, the precise mechanisms and their relative importance are still unknown. Here, we examined MHC dependent parasite load in European rabbits (Oryctolagus cuniculus) from a distinct population with low MHC diversity (three alleles, six genotypes). Using a multivariate approach, we tested for associations of individual MHC class II DRB constitution and the rabbits' intestinal burden with nematodes and coccidia. Rabbits having a particular allele showed lower infestations with hepatic coccidia (E. stiedai). However, a comparison of all six genotypes in the population revealed that carriers of this allele only benefit when they are heterozygous, and furthermore, MHC heterozygosity in general did not affect individual parasite load. In conclusion, this study suggests an immunogenetic basis of European rabbit resistance to hepatic coccidiosis, which can strongly limit survival to maturity in this species. Our study gives a complex picture of MHC-parasite correlations, unveiling the limits of the classical hypotheses of how MHC polymorphism is maintained in natural systems.
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http://dx.doi.org/10.1111/j.1365-294X.2010.04766.xDOI Listing
October 2010