Publications by authors named "Felix Sommer"

33 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

Precision Nutrition in Chronic Inflammation.

Front Immunol 2020 23;11:587895. Epub 2020 Nov 23.

Division of Nutriinformatics, Institute of Human Nutrition and Food Science, Kiel University, Kiel, Germany.

The molecular foundation of chronic inflammatory diseases (CIDs) can differ markedly between individuals. As our understanding of the biochemical mechanisms underlying individual disease manifestations and progressions expands, new strategies to adjust treatments to the patient's characteristics will continue to profoundly transform clinical practice. Nutrition has long been recognized as an important determinant of inflammatory disease phenotypes and treatment response. Yet empirical work demonstrating the therapeutic effectiveness of patient-tailored nutrition remains scarce. This is mainly due to the challenges presented by long-term effects of nutrition, variations in inter-individual gastrointestinal microbiota, the multiplicity of human metabolic pathways potentially affected by food ingredients, nutrition behavior, and the complexity of food composition. Historically, these challenges have been addressed in both human studies and experimental model laboratory studies primarily by using individual nutrition data collection in tandem with large-scale biomolecular data acquisition (e.g. genomics, metabolomics, etc.). This review highlights recent findings in the field of precision nutrition and their potential implications for the development of personalized treatment strategies for CIDs. It emphasizes the importance of computational approaches to integrate nutritional information into multi-omics data analysis and to predict which molecular mechanisms may explain how nutrients intersect with disease pathways. We conclude that recent findings point towards the unexhausted potential of nutrition as part of personalized medicine in chronic inflammation.
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http://dx.doi.org/10.3389/fimmu.2020.587895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719806PMC
July 2021

Nutritional Targeting of the Microbiome as Potential Therapy for Malnutrition and Chronic Inflammation.

Nutrients 2020 Oct 3;12(10). Epub 2020 Oct 3.

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

Homeostatic interactions with the microbiome are central for a healthy human physiology and nutrition is the main driving force shaping the microbiome. In the past decade, a wealth of preclinical studies mainly using gnotobiotic animal models demonstrated that malnutrition and chronic inflammation stress these homeostatic interactions and various microbial species and their metabolites or metabolic activities have been associated with disease. For example, the dysregulation of the bacterial metabolism of dietary tryptophan promotes an inflammatory environment and susceptibility to pathogenic infection. Clinical studies have now begun to evaluate the therapeutic potential of nutritional and probiotic interventions in malnutrition and chronic inflammation to ameliorate disease symptoms or even prevent pathogenesis. Here, we therefore summarize the recent progress in this field and propose to move further towards the nutritional targeting of the microbiome for malnutrition and chronic inflammation.
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http://dx.doi.org/10.3390/nu12103032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601849PMC
October 2020

A high-fat diet induces a microbiota-dependent increase in stem cell activity in the Drosophila intestine.

PLoS Genet 2020 05 26;16(5):e1008789. Epub 2020 May 26.

Zoological Institute, Department of Molecular Physiology, Kiel University, Kiel, Germany.

Over-consumption of high-fat diets (HFDs) is associated with several pathologies. Although the intestine is the organ that comes into direct contact with all diet components, the impact of HFD has mostly been studied in organs that are linked to obesity and obesity related disorders. We used Drosophila as a simple model to disentangle the effects of a HFD on the intestinal structure and physiology from the plethora of other effects caused by this nutritional intervention. Here, we show that a HFD, composed of triglycerides with saturated fatty acids, triggers activation of intestinal stem cells in the Drosophila midgut. This stem cell activation was transient and dependent on the presence of an intestinal microbiota, as it was completely absent in germ free animals. Moreover, major components of the signal transduction pathway have been elucidated. Here, JNK (basket) in enterocytes was necessary to trigger synthesis of the cytokine upd3 in these cells. This ligand in turn activated the JAK/STAT pathway in intestinal stem cells. Chronic subjection to a HFD markedly altered both the microbiota composition and the bacterial load. Although HFD-induced stem cell activity was transient, long-lasting changes to the cellular composition, including a substantial increase in the number of enteroendocrine cells, were observed. Taken together, a HFD enhances stem cell activity in the Drosophila gut and this effect is completely reliant on the indigenous microbiota and also dependent on JNK signaling within intestinal enterocytes.
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http://dx.doi.org/10.1371/journal.pgen.1008789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274450PMC
May 2020

NOD2 Influences Trajectories of Intestinal Microbiota Recovery After Antibiotic Perturbation.

Cell Mol Gastroenterol Hepatol 2020 11;10(2):365-389. Epub 2020 Apr 11.

Institute of Clinical Molecular Biology, Kiel, Germany. Electronic address:

Background & Aims: Loss-of-function variants in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) impair the recognition of the bacterial cell wall component muramyl-dipeptide and are associated with an increased risk for developing Crohn's disease. Likewise, exposure to antibiotics increases the individual risk for developing inflammatory bowel disease. Here, we studied the long-term impact of NOD2 on the ability of the gut bacterial and fungal microbiota to recover after antibiotic treatment.

Methods: Two cohorts of 20-week-old and 52-week-old wild-type (WT) C57BL/6J and NOD2 knockout (Nod2-KO) mice were treated with broad-spectrum antibiotics and fecal samples were collected to investigate temporal dynamics of the intestinal microbiota (bacteria and fungi) using 16S ribosomal RNA and internal transcribed spacer 1 sequencing. In addition, 2 sets of germ-free WT mice were colonized with either WT or Nod2-KO after antibiotic donor microbiota and the severity of intestinal inflammation was monitored in the colonized mice.

Results: Antibiotic exposure caused long-term shifts in the bacterial and fungal community composition. Genetic ablation of NOD2 was associated with delayed body weight gain after antibiotic treatment and an impaired recovery of the bacterial gut microbiota. Transfer of the postantibiotic fecal microbiota of Nod2-KO mice induced an intestinal inflammatory response in the colons of germ-free recipient mice compared with respective microbiota from WT controls based on histopathology and gene expression analyses.

Conclusions: Our data show that the bacterial sensor NOD2 contributes to intestinal microbial community composition after antibiotic treatment and may add to the explanation of how defects in the NOD2 signaling pathway are involved in the etiology of Crohn's disease.
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http://dx.doi.org/10.1016/j.jcmgh.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327897PMC
July 2021

Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease.

Nat Commun 2020 04 14;11(1):1775. Epub 2020 Apr 14.

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

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.
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http://dx.doi.org/10.1038/s41467-020-15646-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156516PMC
April 2020

α-Linolenic Acid-Rich Diet Influences Microbiota Composition and Villus Morphology of the Mouse Small Intestine.

Nutrients 2020 Mar 11;12(3). Epub 2020 Mar 11.

Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.

α-Linolenic acid (ALA) is well-known for its anti-inflammatory activity. In contrast, the influence of an ALA-rich diet on intestinal microbiota composition and its impact on small intestine morphology are not fully understood. In the current study, we kept adult C57BL/6J mice for 4 weeks on an ALA-rich or control diet. Characterization of the microbial composition of the small intestine revealed that the ALA diet was associated with an enrichment in and . In contrast, taxa belonging to the Firmicutes phylum, including , cluster XIVa, Lachnospiraceae and , had significantly lower abundance compared to control diet. Metagenome prediction indicated an enrichment in functional pathways such as bacterial secretion system in the ALA group, whereas the two-component system and ALA metabolism pathways were downregulated. We also observed increased levels of ALA and its metabolites eicosapentanoic and docosahexanoic acid, but reduced levels of arachidonic acid in the intestinal tissue of ALA-fed mice. Furthermore, intestinal morphology in the ALA group was characterized by elongated villus structures with increased counts of epithelial cells and reduced epithelial proliferation rate. Interestingly, the ALA diet reduced relative goblet and Paneth cell counts. Of note, high-fat Western-type diet feeding resulted in a comparable adaptation of the small intestine. Collectively, our study demonstrates the impact of ALA on the gut microbiome and reveals the nutritional regulation of gut morphology.
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http://dx.doi.org/10.3390/nu12030732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146139PMC
March 2020

Advancing Our Functional Understanding of Host-Microbiota Interactions: A Need for New Types of Studies.

Bioessays 2020 02 18;42(2):e1900211. Epub 2019 Dec 18.

Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, Rosalind-Franklin-Straße 12, Kiel, 24105, Germany.

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http://dx.doi.org/10.1002/bies.201900211DOI Listing
February 2020

The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice.

mBio 2019 10 22;10(5). Epub 2019 Oct 22.

Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany

Atherosclerotic plaque development depends on chronic inflammation of the arterial wall. A dysbiotic gut microbiota can cause low-grade inflammation, and microbiota composition was linked to cardiovascular disease risk. However, the role of this environmental factor in atherothrombosis remains undefined. To analyze the impact of gut microbiota on atherothrombosis, we rederived low-density lipoprotein receptor-deficient ( ) mice as germfree (GF) and kept these mice for 16 weeks on an atherogenic high-fat Western diet (HFD) under GF isolator conditions and under conventionally raised specific-pathogen-free conditions (CONV-R). In spite of reduced diversity of the cecal gut microbiome, caused by atherogenic HFD, GF mice and CONV-R mice exhibited atherosclerotic lesions of comparable sizes in the common carotid artery. In contrast to HFD-fed mice, showing no difference in total cholesterol levels, CONV-R mice fed control diet (CD) had significantly reduced total plasma cholesterol, very-low-density lipoprotein (VLDL), and LDL levels compared with GF mice. Myeloid cell counts in blood as well as leukocyte adhesion to the vessel wall at the common carotid artery of GF mice on HFD were diminished compared to CONV-R controls. Plasma cytokine profiling revealed reduced levels of the proinflammatory chemokines CCL7 and CXCL1 in GF mice, whereas the T-cell-related interleukin 9 (IL-9) and IL-27 were elevated. In the atherothrombosis model of ultrasound-induced rupture of the common carotid artery plaque, thrombus area was significantly reduced in GF mice relative to CONV-R mice. , this atherothrombotic phenotype was explained by decreased adhesion-dependent platelet activation and thrombus growth of HFD-fed GF mice on type III collagen. Our results demonstrate a functional role for the commensal microbiota in atherothrombosis. In a ferric chloride injury model of the carotid artery, GF C57BL/6J mice had increased occlusion times compared to colonized controls. Interestingly, in late atherosclerosis, HFD-fed GF mice had reduced plaque rupture-induced thrombus growth in the carotid artery and diminished thrombus formation under arterial flow conditions.
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http://dx.doi.org/10.1128/mBio.02298-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805995PMC
October 2019

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

Nuclear Charge Radii of ^{10,11}B.

Phys Rev Lett 2019 May;122(18):182501

Institut für Kernphysik, TU Darmstadt, 64289 Darmstadt, Germany.

The first laser spectroscopic determination of the change in the nuclear charge radius for a five-electron system is reported. This is achieved by combining high-accuracy ab initio mass-shift calculations and a high-accuracy measurement of the isotope shift in the 2s^{2}2p  ^{2}P_{1/2}→2s^{2}3s  ^{2}S_{1/2} ground state transition in boron atoms. Accuracy is increased by orders of magnitude for the stable isotopes ^{10,11}B and the results are used to extract their difference in the mean-square charge radius ⟨r_{c}^{2}⟩^{11}-⟨r_{c}^{2}⟩^{10}=-0.49(12)  fm^{2}. The result is qualitatively explained by a possible cluster structure of the boron nuclei and quantitatively used to benchmark new ab initio nuclear structure calculations using the no-core shell model and Green's function Monte Carlo approaches. These results are the foundation for a laser spectroscopic determination of the charge radius of the proton-halo candidate ^{8}B.
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http://dx.doi.org/10.1103/PhysRevLett.122.182501DOI Listing
May 2019

Functions of the Microbiota for the Physiology of Animal Metaorganisms.

J Innate Immun 2019 19;11(5):393-404. Epub 2018 Dec 19.

Institute of Clinical Molecular Biology, Christian Albrecht University Kiel, Kiel, Germany,

Animals are usually regarded as independent entities within their respective environments. However, within an organism, eukaryotes and prokaryotes interact dynamically to form the so-called metaorganism or holobiont, where each partner fulfils its versatile and crucial role. This review focuses on the interplay between microorganisms and multicellular eukaryotes in the context of host physiology, in particular aging and mucus-associated crosstalk. In addition to the interactions between bacteria and the host, we highlight the importance of viruses and nonmodel organisms. Moreover, we discuss current culturing and computational methodologies that allow a deeper understanding of underlying mechanisms controlling the physiology of metaorganisms.
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http://dx.doi.org/10.1159/000495115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738199PMC
June 2020

Grow With the Challenge - Microbial Effects on Epithelial Proliferation, Carcinogenesis, and Cancer Therapy.

Front Microbiol 2018 20;9:2020. Epub 2018 Sep 20.

Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.

The eukaryotic host is in close contact to myriads of resident and transient microbes, which influence the crucial physiological pathways. Emerging evidence points to their role of host-microbe interactions for controlling tissue homeostasis, cell fate decisions, and regenerative capacity in epithelial barrier organs including the skin, lung, and gut. In humans and mice, it has been shown that the malignant tumors of these organs harbor an altered microbiota. Mechanistic studies have shown that the altered metabolic properties and secreted factors contribute to epithelial carcinogenesis and tumor progression. Exciting recent work points toward a crucial influence of the associated microbial communities on the response to chemotherapy and immune-check point inhibitors during cancer treatment, which suggests that the modulation of the microbiota might be a powerful tool for personalized oncology. In this article, we provide an overview of how the bacterial signals and signatures may influence epithelial homeostasis across taxa from cnidarians to vertebrates and delineate mechanisms, which might be potential targets for therapy of human diseases by either harnessing barrier integrity (infection and inflammation) or restoring uncontrolled proliferation (cancer).
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http://dx.doi.org/10.3389/fmicb.2018.02020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159313PMC
September 2018

Publisher Correction: Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition.

Nature 2018 11;563(7731):E25

Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.

In Fig. 1d of this Letter, the third group along should have been labelled 'WT' rather than 'Tlr5'. This has been corrected online.
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http://dx.doi.org/10.1038/s41586-018-0507-2DOI Listing
November 2018

Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition.

Nature 2018 08 8;560(7719):489-493. Epub 2018 Aug 8.

Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.

Alterations in enteric microbiota are associated with several highly prevalent immune-mediated and metabolic diseases, and experiments involving faecal transplants have indicated that such alterations have a causal role in at least some such conditions. The postnatal period is particularly critical for the development of microbiota composition, host-microbe interactions and immune homeostasis. However, the underlying molecular mechanisms of this neonatal priming period have not been defined. Here we report the identification of a host-mediated regulatory circuit of bacterial colonization that acts solely during the early neonatal period but influences life-long microbiota composition. We demonstrate age-dependent expression of the flagellin receptor Toll-like receptor 5 (TLR5) in the gut epithelium of neonate mice. Using competitive colonization experiments, we demonstrate that epithelial TLR5-mediated REG3γ production is critical for the counter-selection of colonizing flagellated bacteria. Comparative microbiota transfer experiments in neonate and adult wild-type and Tlr5-deficient germ-free mice reveal that neonatal TLR5 expression strongly influences the composition of the microbiota throughout life. Thus, the beneficial microbiota in the adult host is shaped during early infancy. This might explain why environmental factors that disturb the establishment of the microbiota during early life can affect immune homeostasis and health in adulthood.
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http://dx.doi.org/10.1038/s41586-018-0395-5DOI Listing
August 2018

Exposure to the gut microbiota drives distinct methylome and transcriptome changes in intestinal epithelial cells during postnatal development.

Genome Med 2018 04 13;10(1):27. Epub 2018 Apr 13.

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

Background: The interplay of epigenetic processes and the intestinal microbiota may play an important role in intestinal development and homeostasis. Previous studies have established that the microbiota regulates a large proportion of the intestinal epithelial transcriptome in the adult host, but microbial effects on DNA methylation and gene expression during early postnatal development are still poorly understood. Here, we sought to investigate the microbial effects on DNA methylation and the transcriptome of intestinal epithelial cells (IECs) during postnatal development.

Methods: We collected IECs from the small intestine of each of five 1-, 4- and 12 to 16-week-old mice representing the infant, juvenile, and adult states, raised either in the presence or absence of a microbiota. The DNA methylation profile was determined using reduced representation bisulfite sequencing (RRBS) and the epithelial transcriptome by RNA sequencing using paired samples from each individual mouse to analyze the link between microbiota, gene expression, and DNA methylation.

Results: We found that microbiota-dependent and -independent processes act together to shape the postnatal development of the transcriptome and DNA methylation signatures of IECs. The bacterial effect on the transcriptome increased over time, whereas most microbiota-dependent DNA methylation differences were detected already early after birth. Microbiota-responsive transcripts could be attributed to stage-specific cellular programs during postnatal development and regulated gene sets involved primarily immune pathways and metabolic processes. Integrated analysis of the methylome and transcriptome data identified 126 genomic loci at which coupled differential DNA methylation and RNA transcription were associated with the presence of intestinal microbiota. We validated a subset of differentially expressed and methylated genes in an independent mouse cohort, indicating the existence of microbiota-dependent "functional" methylation sites which may impact on long-term gene expression signatures in IECs.

Conclusions: Our study represents the first genome-wide analysis of microbiota-mediated effects on maturation of DNA methylation signatures and the transcriptional program of IECs after birth. It indicates that the gut microbiota dynamically modulates large portions of the epithelial transcriptome during postnatal development, but targets only a subset of microbially responsive genes through their DNA methylation status.
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http://dx.doi.org/10.1186/s13073-018-0534-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899322PMC
April 2018

The resilience of the intestinal microbiota influences health and disease.

Nat Rev Microbiol 2017 Oct 19;15(10):630-638. Epub 2017 Jun 19.

Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, Rosalind-Franklin-Straße 12, 24105 Kiel, Germany.

The composition of the intestinal microbiota varies among individuals and throughout development, and is dependent on host and environmental factors. However, although the microbiota is constantly exposed to environmental challenges, its composition and function in an individual are stable against perturbations, as microbial communities are resilient and resistant to change. The maintenance of a beneficial microbiota requires a homeostatic equilibrium within microbial communities, and also between the microorganisms and the intestinal interface of the host. The resilience of the healthy microbiota protects us from dysbiosis-related diseases, such as inflammatory bowel disease (IBD) or metabolic disorder. By contrast, a resilient dysbiotic microbiota may cause disease. In this Opinion article, we propose that microbial resilience has a key role in health and disease. We will discuss the concepts and mechanisms of microbial resilience against dietary, antibiotic or bacteriotherapy-induced perturbations and the implications for human health.
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http://dx.doi.org/10.1038/nrmicro.2017.58DOI Listing
October 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

Age-Dependent Susceptibility to Enteropathogenic Escherichia coli (EPEC) Infection in Mice.

PLoS Pathog 2016 05 9;12(5):e1005616. Epub 2016 May 9.

Institute for Medical Microbiology, RWTH Aachen University Hospital, Aachen, Germany.

Enteropathogenic Escherichia coli (EPEC) represents a major causative agent of infant diarrhea associated with significant morbidity and mortality in developing countries. Although studied extensively in vitro, the investigation of the host-pathogen interaction in vivo has been hampered by the lack of a suitable small animal model. Using RT-PCR and global transcriptome analysis, high throughput 16S rDNA sequencing as well as immunofluorescence and electron microscopy, we characterize the EPEC-host interaction following oral challenge of newborn mice. Spontaneous colonization of the small intestine and colon of neonate mice that lasted until weaning was observed. Intimate attachment to the epithelial plasma membrane and microcolony formation were visualized only in the presence of a functional bundle forming pili (BFP) and type III secretion system (T3SS). Similarly, a T3SS-dependent EPEC-induced innate immune response, mediated via MyD88, TLR5 and TLR9 led to the induction of a distinct set of genes in infected intestinal epithelial cells. Infection-induced alterations of the microbiota composition remained restricted to the postnatal period. Although EPEC colonized the adult intestine in the absence of a competing microbiota, no microcolonies were observed at the small intestinal epithelium. Here, we introduce the first suitable mouse infection model and describe an age-dependent, virulence factor-dependent attachment of EPEC to enterocytes in vivo.
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http://dx.doi.org/10.1371/journal.ppat.1005616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861285PMC
May 2016

Know your neighbor: Microbiota and host epithelial cells interact locally to control intestinal function and physiology.

Bioessays 2016 May 18;38(5):455-64. Epub 2016 Mar 18.

Department of Molecular and Clinical Medicine, The Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.

Interactions between the host and its associated microbiota differ spatially and the local cross talk determines organ function and physiology. Animals and their organs are not uniform but contain several functional and cellular compartments and gradients. In the intestinal tract, different parts of the gut carry out different functions, tissue structure varies accordingly, epithelial cells are differentially distributed and gradients exist for several physicochemical parameters such as nutrients, pH, or oxygen. Consequently, the microbiota composition also differs along the length of the gut, but also between lumen and mucosa of the same intestinal segment, and even along the crypt-villus axis in the epithelium. Thus, host-microbiota interactions are highly site-specific and the local cross talk determines intestinal function and physiology. Here we review recent advances in our understanding of site-specific host-microbiota interactions and discuss their functional relevance for host physiology.
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http://dx.doi.org/10.1002/bies.201500151DOI Listing
May 2016

The Gut Microbiota Modulates Energy Metabolism in the Hibernating Brown Bear Ursus arctos.

Cell Rep 2016 Feb 4;14(7):1655-1661. Epub 2016 Feb 4.

The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, 41345 Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address:

Hibernation is an adaptation that helps many animals to conserve energy during food shortage in winter. Brown bears double their fat depots during summer and use these stored lipids during hibernation. Although bears seasonally become obese, they remain metabolically healthy. We analyzed the microbiota of free-ranging brown bears during their active phase and hibernation. Compared to the active phase, hibernation microbiota had reduced diversity, reduced levels of Firmicutes and Actinobacteria, and increased levels of Bacteroidetes. Several metabolites involved in lipid metabolism, including triglycerides, cholesterol, and bile acids, were also affected by hibernation. Transplantation of the bear microbiota from summer and winter to germ-free mice transferred some of the seasonal metabolic features and demonstrated that the summer microbiota promoted adiposity without impairing glucose tolerance, suggesting that seasonal variation in the microbiota may contribute to host energy metabolism in the hibernating brown bear.
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http://dx.doi.org/10.1016/j.celrep.2016.01.026DOI Listing
February 2016

Microbiota-induced obesity requires farnesoid X receptor.

Gut 2017 03 6;66(3):429-437. Epub 2016 Jan 6.

Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.

Objective: The gut microbiota has been implicated as an environmental factor that modulates obesity, and recent evidence suggests that microbiota-mediated changes in bile acid profiles and signalling through the bile acid nuclear receptor farnesoid X receptor (FXR) contribute to impaired host metabolism. Here we investigated if the gut microbiota modulates obesity and associated phenotypes through FXR.

Design: We fed germ-free (GF) and conventionally raised (CONV-R) wild-type and mice a high-fat diet (HFD) for 10 weeks. We monitored weight gain and glucose metabolism and analysed the gut microbiota and bile acid composition, beta-cell mass, accumulation of macrophages in adipose tissue, liver steatosis, and expression of target genes in adipose tissue and liver. We also transferred the microbiota of wild-type and -deficient mice to GF wild-type mice.

Results: The gut microbiota promoted weight gain and hepatic steatosis in an FXR-dependent manner, and the bile acid profiles and composition of faecal microbiota differed between and wild-type mice. The obese phenotype in colonised wild-type mice was associated with increased beta-cell mass, increased adipose inflammation, increased steatosis and expression of genes involved in lipid uptake. By transferring the caecal microbiota from HFD-fed and wild-type mice into GF mice, we showed that the obesity phenotype was transferable.

Conclusions: Our results indicate that the gut microbiota promotes diet-induced obesity and associated phenotypes through FXR, and that FXR may contribute to increased adiposity by altering the microbiota composition.
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http://dx.doi.org/10.1136/gutjnl-2015-310283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534765PMC
March 2017

Neurotensin Is Coexpressed, Coreleased, and Acts Together With GLP-1 and PYY in Enteroendocrine Control of Metabolism.

Endocrinology 2016 Jan 15;157(1):176-94. Epub 2015 Oct 15.

Novo Nordisk Foundation Center for Basic Metabolic Research (K.V.G., C.F.R., B.S., M.S.E., A.N.M., J.P., M.K.N., K.L.E., F.B., J.J.H., B.H., T.W.S.), Section for Metabolic Receptology and Enteroendocrinology; Laboratory for Molecular Pharmacology (K.V.G., C.F.R., M.S.E., A.N.M., M.K.N., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Department of Biomedical Sciences (B.S., J.P., S.S.P., J.J.H.), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark; Department of Molecular and Clinical Medicine (F.S., F.B.), Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, University of Gothenburg, 413 45 Gothenburg, Sweden; Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Merck Research Laboratories (A.R.N., T.K., A.D.H.), Kenilworth, NJ 07033; and Department of Pharmacology (S.O.), Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.

The 2 gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are well known to be coexpressed, costored, and released together to coact in the control of key metabolic target organs. However, recently, it became clear that several other gut hormones can be coexpressed in the intestinal-specific lineage of enteroendocrine cells. Here, we focus on the anatomical and functional consequences of the coexpression of neurotensin with GLP-1 and PYY in the distal small intestine. Fluorescence-activated cell sorting analysis, laser capture, and triple staining demonstrated that GLP-1 cells in the crypts become increasingly multihormonal, ie, coexpressing PYY and neurotensin as they move up the villus. Proglucagon promoter and pertussis toxin receptor-driven cell ablation and reappearance studies indicated that although all the cells die, the GLP-1 cells reappear more quickly than PYY- and neurotensin-positive cells. High-resolution confocal fluorescence microscopy demonstrated that neurotensin is stored in secretory granules distinct from GLP-1 and PYY storing granules. Nevertheless, the 3 peptides were cosecreted from both perfused small intestines and colonic crypt cultures in response to a series of metabolite, neuropeptide, and hormonal stimuli. Importantly, neurotensin acts synergistically, ie, more than additively together with GLP-1 and PYY to decrease palatable food intake and inhibit gastric emptying, but affects glucose homeostasis in a more complex manner. Thus, neurotensin is a major gut hormone deeply integrated with GLP-1 and PYY, which should be taken into account when exploiting the enteroendocrine regulation of metabolism pharmacologically.
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http://dx.doi.org/10.1210/en.2015-1600DOI Listing
January 2016

Site-specific programming of the host epithelial transcriptome by the gut microbiota.

Genome Biol 2015 Mar 28;16:62. Epub 2015 Mar 28.

The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, 41345, Sweden.

Background: The intestinal epithelium separates us from the microbiota but also interacts with it and thus affects host immune status and physiology. Previous studies investigated microbiota-induced responses in the gut using intact tissues or unfractionated epithelial cells, thereby limiting conclusions about regional differences in the epithelium. Here, we sought to investigate microbiota-induced transcriptional responses in specific fractions of intestinal epithelial cells. To this end, we used microarray analysis of laser capture microdissection (LCM)-harvested ileal and colonic tip and crypt epithelial fractions from germ-free and conventionally raised mice and from mice during the time course of colonization.

Results: We found that about 10% of the host's transcriptome was microbially regulated, mainly including genes annotated with functions in immunity, cell proliferation, and metabolism. The microbial impact on host gene expression was highly site specific, as epithelial responses to the microbiota differed between cell fractions. Specific transcriptional regulators were enriched in each fraction. In general, the gut microbiota induced a more rapid response in the colon than in the ileum.

Conclusions: Our study indicates that the microbiota engage different regulatory networks to alter host gene expression in a particular niche. Understanding host-microbiota interactions on a cellular level may facilitate signaling pathways that contribute to health and disease and thus provide new therapeutic strategies.
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http://dx.doi.org/10.1186/s13059-015-0614-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404278PMC
March 2015

The composition of the gut microbiota shapes the colon mucus barrier.

EMBO Rep 2015 Feb 18;16(2):164-77. Epub 2014 Dec 18.

Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden

Two C57BL/6 mice colonies maintained in two rooms of the same specific pathogen-free (SPF) facility were found to have different gut microbiota and a mucus phenotype that was specific for each colony. The thickness and growth of the colon mucus were similar in the two colonies. However, one colony had mucus that was impenetrable to bacteria or beads the size of bacteria-which is comparable to what we observed in free-living wild mice-whereas the other colony had an inner mucus layer penetrable to bacteria and beads. The different properties of the mucus depended on the microbiota, as they were transmissible by transfer of caecal microbiota to germ-free mice. Mice with an impenetrable mucus layer had increased amounts of Erysipelotrichi, whereas mice with a penetrable mucus layer had higher levels of Proteobacteria and TM7 bacteria in the distal colon mucus. Thus, our study shows that bacteria and their community structure affect mucus barrier properties in ways that can have implications for health and disease. It also highlights that genetically identical animals housed in the same facility can have rather distinct microbiotas and barrier structures.
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http://dx.doi.org/10.15252/embr.201439263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4328744PMC
February 2015

The Bavarian royal drama of 1886 and the misuse of psychiatry: new results.

Hist Psychiatry 2013 Sep;24(3):274-91

Heidelberg Academy of Sciences and Humanities, and Central Institute of Mental Health, Mannheim, Germany.

The deaths of King Ludwig II of Bavaria and Bernhard von Gudden, Professor of Psychiatry in Munich, in Lake Starnberg near Munich on 13 June 1886 have often been mentioned in the psychiatric-historical literature and in fiction. Von Gudden had written a psychiatric assessment of the King, rating him permanently mentally ill and incapable of reigning. Ludwig II was declared legally incapacitated, dethroned and psychiatrically interned. We will report on an interdisciplinary research project conducted at the Heidelberg Academy of Sciences and Humanities. Information was collected from state, local and private archives in Germany and abroad on: (1) the correctness of the psychiatric assessment in form and content; (2) the constitutional basis of the deposition; and (3) its background, motives and execution. The results show that the psychiatric assessment was incorrect in substance and form. They highlight how those in power used psychiatry for their own purposes.
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http://dx.doi.org/10.1177/0957154X13483047DOI Listing
September 2013

Regulation of polyp-to-jellyfish transition in Aurelia aurita.

Curr Biol 2014 Feb 16;24(3):263-73. Epub 2014 Jan 16.

Zoologisches Institut, Christian-Albrechts-Universität zu Kiel, Am Botanischen Garten 1-9, 24118 Kiel, Germany; Department of Invertebrate Zoology, Saint Petersburg State University, Universitetskaya naberezhnaya 7/9, 199034 Saint Petersburg, Russia. Electronic address:

Background: The life cycle of scyphozoan cnidarians alternates between sessile asexual polyps and pelagic medusa. Transition from one life form to another is triggered by environmental signals, but the molecular cascades involved in the drastic morphological and physiological changes remain unknown.

Results: We show in the moon jelly Aurelia aurita that the molecular machinery controlling transition of the sessile polyp into a free-swimming jellyfish consists of two parts. One is conserved and relies on retinoic acid signaling. The second, novel part is based on secreted proteins that are strongly upregulated prior to metamorphosis in response to the seasonal temperature changes. One of these proteins functions as a temperature-sensitive "timer" and encodes the precursor of the strobilation hormone of Aurelia.

Conclusions: Our findings uncover the molecule framework controlling the polyp-to-jellyfish transition in a basal metazoan and provide insights into the evolution of complex life cycles in the animal kingdom.
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http://dx.doi.org/10.1016/j.cub.2013.12.003DOI Listing
February 2014

Altered mucus glycosylation in core 1 O-glycan-deficient mice affects microbiota composition and intestinal architecture.

PLoS One 2014 9;9(1):e85254. Epub 2014 Jan 9.

The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden ; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

A functional mucus layer is a key requirement for gastrointestinal health as it serves as a barrier against bacterial invasion and subsequent inflammation. Recent findings suggest that mucus composition may pose an important selection pressure on the gut microbiota and that altered mucus thickness or properties such as glycosylation lead to intestinal inflammation dependent on bacteria. Here we used TM-IEC C1galt (-/-) mice, which carry an inducible deficiency of core 1-derived O-glycans in intestinal epithelial cells, to investigate the effects of mucus glycosylation on susceptibility to intestinal inflammation, gut microbial ecology and host physiology. We found that TM-IEC C1galt (-/-) mice did not develop spontaneous colitis, but they were more susceptible to dextran sodium sulphate-induced colitis. Furthermore, loss of core 1-derived O-glycans induced inverse shifts in the abundance of the phyla Bacteroidetes and Firmicutes. We also found that mucus glycosylation impacts intestinal architecture as TM-IEC C1galt(-/-) mice had an elongated gastrointestinal tract with deeper ileal crypts, a small increase in the number of proliferative epithelial cells and thicker circular muscle layers in both the ileum and colon. Alterations in the length of the gastrointestinal tract were partly dependent on the microbiota. Thus, the mucus layer plays a role in the regulation of gut microbiota composition, balancing intestinal inflammation, and affects gut architecture.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887012PMC
September 2014

The gut microbiota--masters of host development and physiology.

Nat Rev Microbiol 2013 Apr 25;11(4):227-38. Epub 2013 Feb 25.

Wallenberg Laboratory for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Department of Molecular and Clinical Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden.

Establishing and maintaining beneficial interactions between the host and its associated microbiota are key requirements for host health. Although the gut microbiota has previously been studied in the context of inflammatory diseases, it has recently become clear that this microbial community has a beneficial role during normal homeostasis, modulating the host's immune system as well as influencing host development and physiology, including organ development and morphogenesis, and host metabolism. The underlying molecular mechanisms of host-microorganism interactions remain largely unknown, but recent studies have begun to identify the key signalling pathways of the cross-species homeostatic regulation between the gut microbiota and its host.
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http://dx.doi.org/10.1038/nrmicro2974DOI Listing
April 2013