Publications by authors named "Eric J C Gálvez"

20 Publications

  • Page 1 of 1

IL-17 controls central nervous system autoimmunity through the intestinal microbiome.

Sci Immunol 2021 Feb;6(56)

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Interleukin-17A- (IL-17A) and IL-17F-producing CD4 T helper cells (T17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). T17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, T17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in T cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.
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http://dx.doi.org/10.1126/sciimmunol.aaz6563DOI Listing
February 2021

Modulation of inflammatory responses by gastrointestinal Prevotella spp. - From associations to functional studies.

Int J Med Microbiol 2021 Feb 8;311(2):151472. Epub 2021 Jan 8.

Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany; Hannover Medical School, Hannover, Germany; Centre for Individualized Infection Medicine, Hannover, Germany. Electronic address:

Numerous studies have associated alterations in the gut microbiota composition with almost every known inflammatory disease. However, proving the biological relevance of distinct microbial signatures and linking specific microorganisms to host phenotypes, remains a considerable challenge. Correspondingly, increased abundance of members of Prevotella genus within microbial communities colonizing distinct mucosal surfaces has been found in individuals diagnosed with rheumatoid arthritis, periodontitis, metabolic disorders, and intestinal and vaginal dysbiosis. Still, the role of Prevotella spp. in the incidence of these diseases continues to be debated. For many years, poor understanding of Prevotella biology could be in large part attributed to the lack of experimental tools. However, in the recent years significant advances have been made towards overcoming these limitations, including increased number of isolates and improved understanding of genetic diversity. Besides discussing the most relevant associations between Prevotella spp. and inflammatory disorders, in the present review we examine the recent efforts to expand the Prevotella experimental "toolbox" and we highlight remaining experimental challenges that should advance future research and our understanding of Prevotella-host interplay.
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http://dx.doi.org/10.1016/j.ijmm.2021.151472DOI Listing
February 2021

Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury.

Cell Mol Gastroenterol Hepatol 2021 12;11(4):909-933. Epub 2020 Nov 12.

Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany. Electronic address:

Background & Aims: Acute liver failure (ALF) represents an unmet medical need in Western countries. Although the link between intestinal dysbiosis and chronic liver disease is well-established, there is little evidence for a functional role of gut-liver interaction during ALF. Here we hypothesized that intestinal dysbiosis may affect ALF.

Methods: To test this hypothesis, we assessed the association of proton pump inhibitor (PPI) or long-term antibiotics (ABx) intake, which have both been linked to intestinal dysbiosis, and occurrence of ALF in the 500,000 participants of the UK BioBank population-based cohort. For functional studies, male Nlrp6 mice were used as a dysbiotic mouse model and injected with a sublethal dose of acetaminophen (APAP) or lipopolysaccharide (LPS) to induce ALF.

Results: Multivariate Cox regression analyses revealed a significantly increased risk (odds ratio, 2.3-3) for developing ALF in UK BioBank participants with PPI or ABx. Similarly, dysbiotic Nlrp6 mice displayed exacerbated APAP- and LPS-induced liver injury, which was linked to significantly reduced gut and liver tissue microbiota diversity and correlated with increased intestinal permeability at baseline. Fecal microbiota transfer (FMT) from Nlrp6 mice into wild-type (WT) mice augmented liver injury on APAP treatment in recipient WT mice, resembling the inflammatory phenotype of Nlrp6 mice. Specifically, FMT skewed monocyte polarization in WT mice toward a Ly6C inflammatory phenotype, suggesting a critical function of these cells as sensors of gut-derived signals orchestrating the inflammatory response.

Conclusions: Our data show an important yet unknown function of intestinal microbiota during ALF. Intestinal dysbiosis was transferrable to healthy WT mice via FMT and aggravated liver injury. Our study highlights intestinal microbiota as a targetable risk factor for ALF.
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http://dx.doi.org/10.1016/j.jcmgh.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900526PMC
November 2020

Distinct Polysaccharide Utilization Determines Interspecies Competition between Intestinal Prevotella spp.

Cell Host Microbe 2020 12 27;28(6):838-852.e6. Epub 2020 Oct 27.

Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany; Hannover Medical School, Hannover, Germany; Centre for Individualized Infection Medicine, Hannover, Germany. Electronic address:

Prevotella spp. are a dominant bacterial genus within the human gut. Multiple Prevotella spp. co-exist in some individuals, particularly those consuming plant-based diets. Additionally, Prevotella spp. exhibit variability in the utilization of diverse complex carbohydrates. To investigate the relationship between Prevotella competition and diet, we isolated Prevotella species from the mouse gut, analyzed their genomes and transcriptomes in vivo, and performed competition experiments between species in mice. Diverse dominant Prevotella species compete for similar metabolic niches in vivo, which is linked to the upregulation of specific polysaccharide utilization loci (PULs). Complex plant-derived polysaccharides are required for Prevotella spp. expansion, with arabinoxylans having a prominent impact on species abundance. The most dominant Prevotella species encodes a specific tandem-repeat trsusC/D PUL that enables arabinoxylan utilization and is conserved in human Prevotella copri strains, particularly among those consuming a vegan diet. These findings suggest that efficient (arabino)xylan-utilization is a factor contributing to Prevotella dominance.
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http://dx.doi.org/10.1016/j.chom.2020.09.012DOI Listing
December 2020

Perturbation of the gut microbiome by Prevotella spp. enhances host susceptibility to mucosal inflammation.

Mucosal Immunol 2021 01 20;14(1):113-124. Epub 2020 May 20.

Department of Microbial Immune Regulation, Helmholtz Center for Infection Research, Braunschweig, Germany.

Diverse microbial signatures within the intestinal microbiota have been associated with intestinal and systemic inflammatory diseases, but whether these candidate microbes actively modulate host phenotypes or passively expand within the altered microbial ecosystem is frequently not known. Here we demonstrate that colonization of mice with a member of the genus Prevotella, which has been previously associated to colitis in mice, exacerbates intestinal inflammation. Our analysis revealed that Prevotella intestinalis alters composition and function of the ecosystem resulting in a reduction of short-chain fatty acids, specifically acetate, and consequently a decrease in intestinal IL-18 levels during steady state. Supplementation of IL-18 to Prevotella-colonized mice was sufficient to reduce intestinal inflammation. Hence, we conclude that intestinal Prevotella colonization results in metabolic changes in the microbiota, which reduce IL-18 production and consequently exacerbate intestinal inflammation, and potential systemic autoimmunity.
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http://dx.doi.org/10.1038/s41385-020-0296-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790746PMC
January 2021

Variations in microbiota composition of laboratory mice influence Citrobacter rodentium infection via variable short-chain fatty acid production.

PLoS Pathog 2020 03 24;16(3):e1008448. Epub 2020 Mar 24.

Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany.

The composition of the intestinal microbiota influences the outcome of enteric infections in human and mice. However, the role of specific members and their metabolites contributing to disease severity is largely unknown. Using isogenic mouse lines harboring distinct microbiota communities, we observed highly variable disease kinetics of enteric Citrobacter rodentium colonization after infection. Transfer of communities from susceptible and resistant mice into germ-free mice verified that the varying susceptibilities are determined by microbiota composition. The strongest differences in colonization were observed in the cecum and could be maintained in vitro by coculturing cecal bacteria with C. rodentium. Cohousing of animals as well as the transfer of cultivable bacteria from resistant to susceptible mice led to variable outcomes in the recipient mice. Microbiome analysis revealed that a higher abundance of butyrate-producing bacteria was associated with the resistant phenotype. Quantification of short-chain fatty acid (SCFA) levels before and after infection revealed increased concentrations of acetate, butyrate and propionate in mice with delayed colonization. Addition of physiological concentrations of butyrate, but not of acetate and/or propionate strongly impaired growth of C. rodentium in vitro. In vivo supplementation of susceptible, antibiotic-treated and germ-free mice with butyrate led to the same level of protection, notably only when cecal butyrate concentration reached a concentration higher than 50 nmol/mg indicating a critical threshold for protection. In the recent years, commensal-derived primary and secondary bacterial metabolites emerged as potent modulators of hosts susceptibility to infection. Our results provide evidence that variations in SCFA production in mice fed fibre-rich chow-based diets modulate susceptibility to colonization with Enterobacteriaceae not only in antibiotic-disturbed ecosystems but even in undisturbed microbial communities. These findings emphasise the need for microbiota normalization across laboratory mouse lines for infection experiments with the model-pathogen C. rodentium independent of investigations of diet and antibiotic usage.
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http://dx.doi.org/10.1371/journal.ppat.1008448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141690PMC
March 2020

An Integrated Metagenome Catalog Reveals New Insights into the Murine Gut Microbiome.

Cell Rep 2020 03;30(9):2909-2922.e6

Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Hanover Medical School, 30625 Hannover, Germany; RESIST, Cluster of Excellence 2155, Hanover Medical School, 30625 Hanover, Germany. Electronic address:

The complexity of host-associated microbial ecosystems requires host-specific reference catalogs to survey the functions and diversity of these communities. We generate a comprehensive resource, the integrated mouse gut metagenome catalog (iMGMC), comprising 4.6 million unique genes and 660 metagenome-assembled genomes (MAGs), many (485 MAGs, 73%) of which are linked to reconstructed full-length 16S rRNA gene sequences. iMGMC enables unprecedented coverage and taxonomic resolution of the mouse gut microbiota; i.e., more than 92% of MAGs lack species-level representatives in public repositories (<95% ANI match). The integration of MAGs and 16S rRNA gene data allows more accurate prediction of functional profiles of communities than predictions based on 16S rRNA amplicons alone. Accompanying iMGMC, we provide a set of MAGs representing 1,296 gut bacteria obtained through complementary assembly strategies. We envision that integrated resources such as iMGMC, together with MAG collections, will enhance the resolution of numerous existing and future sequencing-based studies.
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http://dx.doi.org/10.1016/j.celrep.2020.02.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059117PMC
March 2020

Bridge helix arginines play a critical role in Cas9 sensitivity to mismatches.

Nat Chem Biol 2020 05 2;16(5):587-595. Epub 2020 Mar 2.

Max Planck Unit for the Science of Pathogens, Berlin, Germany.

The RNA-programmable DNA-endonuclease Cas9 is widely used for genome engineering, where a high degree of specificity is required. To investigate which features of Cas9 determine the sensitivity to mismatches along the target DNA, we performed in vitro biochemical assays and bacterial survival assays in Escherichia coli. We demonstrate that arginines in the Cas9 bridge helix influence guide RNA, and target DNA binding and cleavage. They cluster in two groups that either increase or decrease the Cas9 sensitivity to mismatches. We show that the bridge helix is essential for R-loop formation and that R63 and R66 reduce Cas9 specificity by stabilizing the R-loop in the presence of mismatches. Additionally, we identify Q768 that reduces sensitivity of Cas9 to protospacer adjacent motif-distal mismatches. The Cas9_R63A/Q768A variant showed increased specificity in human cells. Our results provide a firm basis for function- and structure-guided mutagenesis to increase Cas9 specificity for genome engineering.
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http://dx.doi.org/10.1038/s41589-020-0490-4DOI Listing
May 2020

The Role of Ames Dwarfism and Calorie Restriction on Gut Microbiota.

J Gerontol A Biol Sci Med Sci 2020 06;75(7):e1-e8

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando.

The gut microbiome (GM) represents a large and very complex ecosystem of different microorganisms. There is an extensive interest in the potential role of the GM in different diseases including cancer, diabetes, cardiovascular diseases, and aging. The GM changes over the lifespan and is strongly associated with various age-related diseases. Ames dwarf (df/df) mice are characterized by an extended life- and healthspan, and although these mice are protected from many age-related diseases, their microbiome has not been studied. To determine the role of microbiota on longevity animal models, we investigated the changes in the GM of df/df and normal control (N) mice, by comparing parents before mating and littermate mice at three distinct time points during early life. Furthermore, we studied the effects of a 6-month calorie restriction (CR), the most powerful intervention extending the lifespan. Our data revealed significant changes of the GM composition during early life development, and we detected differences in the abundance of some bacteria between df/df and N mice, already in early life. Overall, the variability of the microbiota by genotype, time-point, and breeding pair showed significant differences. In addition, CR caused significant changes in microbiome according to gastrointestinal (GI) location (distal colon, ileum, and cecum), genotype, and diet. However, the overall impact of the genotype was more prominent than that of the CR. In conclusion, our findings suggest that the gut microbiota plays an important role during postnatal development in long-living df/df mice and CR dietary regimen can significantly modulate the GM.
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http://dx.doi.org/10.1093/gerona/glz236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302176PMC
June 2020

Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis.

Gut 2019 08 14;68(8):1477-1492. Epub 2019 Mar 14.

Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.

Objective: There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut-liver crosstalk for CLD in the murine Mdr2 knockout model resembling human primary sclerosing cholangitis (PSC).

Design: Male , crossed with hepatocyte-specific deletion of caspase-8 ( /Casp8) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of -associated intestinal dysbiosis was studied by microbiota transfer experiments.

Results: mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut-liver axis. Intestinal dysbiosis in mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature.

Conclusions: MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.
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http://dx.doi.org/10.1136/gutjnl-2018-316670DOI Listing
August 2019

Sequence and cultivation study of Muribaculaceae reveals novel species, host preference, and functional potential of this yet undescribed family.

Microbiome 2019 02 19;7(1):28. Epub 2019 Feb 19.

ZIEL - Institute for Food & Health, Technical University of Munich, Freising, Germany.

Background: Bacteria within family S24-7 (phylum Bacteroidetes) are dominant in the mouse gut microbiota and detected in the intestine of other animals. Because they had not been cultured until recently and the family classification is still ambiguous, interaction with their host was difficult to study and confusion still exists regarding sequence data annotation.

Methods: We investigated family S24-7 by combining data from large-scale 16S rRNA gene analysis and from functional and taxonomic studies of metagenomic and cultured species.

Results: A total of 685 species was inferred by full-length 16S rRNA gene sequence clustering. While many species could not be assigned ecological habitats (93,045 samples analyzed), the mouse was the most commonly identified host (average of 20% relative abundance and nine co-occurring species). Shotgun metagenomics allowed reconstruction of 59 molecular species, of which 34 were representative of the 16S rRNA gene-derived species clusters. In addition, cultivation efforts allowed isolating five strains representing three species, including two novel taxa. Genome analysis revealed that S24-7 spp. are functionally distinct from neighboring families and versatile with respect to complex carbohydrate degradation.

Conclusions: We provide novel data on the diversity, ecology, and description of bacterial family S24-7, for which the name Muribaculaceae is proposed.
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http://dx.doi.org/10.1186/s40168-019-0637-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381624PMC
February 2019

c-Maf-dependent T cell control of intestinal T17 cells and IgA establishes host-microbiota homeostasis.

Nat Immunol 2019 04 18;20(4):471-481. Epub 2019 Feb 18.

Institute of Immunology, Christian-Albrechts-Universität zu Kiel & Universitätsklinik Schleswig Holstein, Kiel, Germany.

Foxp3 regulatory T cells (T cells) are crucial for the maintenance of immune homeostasis both in lymphoid tissues and in non-lymphoid tissues. Here we demonstrate that the ability of intestinal T cells to constrain microbiota-dependent interleukin (IL)-17-producing helper T cell (T17 cell) and immunoglobulin A responses critically required expression of the transcription factor c-Maf. The terminal differentiation and function of several intestinal T cell populations, including RORγt T cells and follicular regulatory T cells, were c-Maf dependent. c-Maf controlled T cell-derived IL-10 production and prevented excessive signaling via the kinases PI(3)K (phosphatidylinositol-3-OH kinase) and Akt and the metabolic checkpoint kinase complex mTORC1 (mammalian target of rapamycin) and expression of inflammatory cytokines in intestinal T cells. c-Maf deficiency in T cells led to profound dysbiosis of the intestinal microbiota, which when transferred to germ-free mice was sufficient to induce exacerbated intestinal T17 responses, even in a c-Maf-competent environment. Thus, c-Maf acts to preserve the identity and function of intestinal T cells, which is essential for the establishment of host-microbe symbiosis.
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http://dx.doi.org/10.1038/s41590-019-0316-2DOI Listing
April 2019

Chronic d-serine supplementation impairs insulin secretion.

Mol Metab 2018 10 25;16:191-202. Epub 2018 Jul 25.

RG Adipocytes & Metabolism, Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. Electronic address:

Objective: The metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis.

Methods: We apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding. Moreover, we identify SNPs in SRR, the enzyme converting L-to d-serine and two subunits of the NMDA receptor to associate with insulin secretion in humans, based on the analysis of 2760 non-diabetic Caucasian individuals.

Results: We show that chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. Inhibition of alpha 2-adrenergic receptors rapidly restores glycemia and glucose tolerance in d-serine supplemented mice. Moreover, we show that single nucleotide polymorphisms (SNPs) in SRR as well as in individual NMDAR subunits are associated with insulin secretion in humans.

Conclusion: Thus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.
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http://dx.doi.org/10.1016/j.molmet.2018.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157639PMC
October 2018

Shaping of Intestinal Microbiota in Nlrp6- and Rag2-Deficient Mice Depends on Community Structure.

Cell Rep 2017 12;21(13):3914-3926

Research Group Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany. Electronic address:

Contradicting observations have been made regarding the relative contributions of immune sensors to shaping the microbiome, yet the reasons for these discrepancies are not fully understood. Here, we investigated the contribution of environmental factors in shaping the microbiome in mice deficient in adaptive immunity (Rag2) and Nlrp6, an immune sensor proposed to be involved in regulation of microbiota composition. In conventionally housed Nlrp6 mice, familial transmission has a significant effect on microbiota composition, complicating the analysis of genotype-dependent effects. Notably, after rederivation into standardized specific pathogen-free (SPF) conditions devoid of pathobionts, microbiota composition was indistinguishable between WT, Rag2, and Nlrp6 mice. However, upon reintroduction of a pathobiont-containing community host, genotype-dependent differences reappear, specifically affecting the relative abundance of pathobionts such as Helicobacter spp. Our results show that the impact of Nlrp6 and also of adaptive immunity on microbiota composition depends on community structure and primarily influences pathobionts but not commensals.
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http://dx.doi.org/10.1016/j.celrep.2017.12.027DOI Listing
December 2017

Distinct Microbial Communities Trigger Colitis Development upon Intestinal Barrier Damage via Innate or Adaptive Immune Cells.

Cell Rep 2017 Oct;21(4):994-1008

Microbial Immune Regulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany. Electronic address:

Inflammatory bowel disease comprises a group of heterogeneous diseases characterized by chronic and relapsing mucosal inflammation. Alterations in microbiota composition have been proposed to contribute to disease development, but no uniform signatures have yet been identified. Here, we compare the ability of a diverse set of microbial communities to exacerbate intestinal inflammation after chemical damage to the intestinal barrier. Strikingly, genetically identical wild-type mice differing only in their microbiota composition varied strongly in their colitis susceptibility. Transfer of distinct colitogenic communities in gene-deficient mice revealed that they triggered disease via opposing pathways either independent or dependent on adaptive immunity, specifically requiring antigen-specific CD4 T cells. Our data provide evidence for the concept that microbial communities may alter disease susceptibility via different immune pathways despite eventually resulting in similar host pathology. This suggests a potential benefit for personalizing IBD therapies according to patient-specific microbiota signatures.
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http://dx.doi.org/10.1016/j.celrep.2017.09.097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668567PMC
October 2017

A flagellum-specific chaperone facilitates assembly of the core type III export apparatus of the bacterial flagellum.

PLoS Biol 2017 Aug 3;15(8):e2002267. Epub 2017 Aug 3.

Junior Research Group Infection Biology of Salmonella, Helmholtz Centre for Infection Research, Braunschweig, Germany.

Many bacteria move using a complex, self-assembling nanomachine, the bacterial flagellum. Biosynthesis of the flagellum depends on a flagellar-specific type III secretion system (T3SS), a protein export machine homologous to the export machinery of the virulence-associated injectisome. Six cytoplasmic (FliH/I/J/G/M/N) and seven integral-membrane proteins (FlhA/B FliF/O/P/Q/R) form the flagellar basal body and are involved in the transport of flagellar building blocks across the inner membrane in a proton motive force-dependent manner. However, how the large, multi-component transmembrane export gate complex assembles in a coordinated manner remains enigmatic. Specific for most flagellar T3SSs is the presence of FliO, a small bitopic membrane protein with a large cytoplasmic domain. The function of FliO is unknown, but homologs of FliO are found in >80% of all flagellated bacteria. Here, we demonstrate that FliO protects FliP from proteolytic degradation and promotes the formation of a stable FliP-FliR complex required for the assembly of a functional core export apparatus. We further reveal the subcellular localization of FliO by super-resolution microscopy and show that FliO is not part of the assembled flagellar basal body. In summary, our results suggest that FliO functions as a novel, flagellar T3SS-specific chaperone, which facilitates quality control and productive assembly of the core T3SS export machinery.
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http://dx.doi.org/10.1371/journal.pbio.2002267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542435PMC
August 2017

Enhancement of IFNγ Production by Distinct Commensals Ameliorates Salmonella-Induced Disease.

Cell Host Microbe 2017 Jun;21(6):682-694.e5

Research Group Microbial Immune Regulation, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany. Electronic address:

The microbiota contributes to colonization resistance against invading pathogens by competing for metabolites, producing inhibitory substances, and priming protective immune responses. However, the specific commensal bacteria that promote host resistance and immune-mediated protection remain largely elusive. Using isogenic mouse lines with distinct microbiota profiles, we demonstrate that severity of disease induced by enteric Salmonella Typhimurium infection is strongly modulated by microbiota composition in individual lines. Transferring a restricted community of cultivable intestinal commensals from protected into susceptible mice decreases S. Typhimurium tissue colonization and consequently disease severity. This reduced tissue colonization, along with ameliorated weight loss and prolonged survival, depends on microbiota-enhanced IFNγ production, as IFNγ-deficient mice do not exhibit protective effects. Innate cells and CD4 T cells increase in number and show high levels of IFNγ after transfer of the commensal community. Thus, distinct microbiota members prevent intestinal Salmonella infection by enhancing antibacterial IFNγ responses.
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http://dx.doi.org/10.1016/j.chom.2017.05.005DOI Listing
June 2017

Microbiota Normalization Reveals that Canonical Caspase-1 Activation Exacerbates Chemically Induced Intestinal Inflammation.

Cell Rep 2017 06;19(11):2319-2330

Microbial Immune Regulation Research Group, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany. Electronic address:

Inflammasomes play a central role in regulating intestinal barrier function and immunity during steady state and disease. Because the discoveries of a passenger mutation and a colitogenic microbiota in the widely used caspase-1-deficient mouse strain have cast doubt on previously identified direct functions of caspase-1, we reassessed the role of caspase-1 in the intestine. To this end, we generated Casp1 and Casp11 mice and rederived them into an enhanced barrier facility to standardize the microbiota. We found that caspase-11 does not influence caspase-1-dependent processing of IL-18 in homeostasis and during DSS colitis. Deficiency of caspase-1, but not caspase-11, ameliorated the severity of DSS colitis independent of microbiota composition. Ablation of caspase-1 in intestinal epithelial cells was sufficient to protect mice against DSS colitis. Moreover, Casp1 mice developed fewer inflammation-induced intestinal tumors than control mice. These data show that canonical inflammasome activation controls caspase-1 activity, contributing to exacerbation of chemical-induced colitis.
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http://dx.doi.org/10.1016/j.celrep.2017.05.058DOI Listing
June 2017

Draft Genome Sequence of Bacillus licheniformis CG-B52, a Highly Virulent Bacterium of Pacific White Shrimp (Litopenaeus vannamei), Isolated from a Colombian Caribbean Aquaculture Outbreak.

Genome Announc 2016 May 12;4(3). Epub 2016 May 12.

RG Microbial Ecology: Metabolism, Genomics & Evolution, Div Ecogenomics & Holobionts, Microbiomas Foundation, Chía, Colombia

Bacillus licheniformis strain CG-B52 was isolated as the etiological agent producing a self-limited outbreak of high mortalities in commercial Litopenaeus vannamei culture ponds on the Colombian Caribbean coast in 2005. Here, we report its draft genome and three novel extrachromosomal elements that it harbors.
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http://dx.doi.org/10.1128/genomeA.00321-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866838PMC
May 2016

Distinct composition signatures of archaeal and bacterial phylotypes in the Wanda Glacier forefield, Antarctic Peninsula.

FEMS Microbiol Ecol 2015 Jan 5;91(1):1-10. Epub 2014 Dec 5.

Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Avenida Bento Gonçalves, 9500 - Agronomia, Porto Alegre - RS, 91501-970, Brazil Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Avenida Ipiranga, 2752 - Azenha, Porto Alegre - RS, 90610-000, Brazil.

Several studies have shown that microbial communities in Antarctic environments are highly diverse. However, considering that the Antarctic Peninsula is among the regions with the fastest warming rates, and that regional climate change has been linked to an increase in the mean rate of glacier retreat, the microbial diversity in Antarctic soil is still poorly understood. In this study, we analysed more than 40 000 sequences of the V5-V6 hypervariable region of the 16S rRNA gene obtained by 454 pyrosequencing from four soil samples from the Wanda Glacier forefield, King George Island, Antarctic Peninsula. Phylotype diversity and richness were surprisingly high, and taxonomic assignment of sequences revealed that communities are dominated by Proteobacteria, Bacteroidetes and Euryarchaeota, with a high frequency of archaeal and bacterial phylotypes unclassified at the genus level and without cultured representative strains, representing a distinct microbial community signature. Several phylotypes were related to marine microorganisms, indicating the importance of the marine environment as a source of colonizers for this recently deglaciated environment. Finally, dominant phylotypes were related to different microorganisms possessing a large array of metabolic strategies, indicating that early successional communities in Antarctic glacier forefield can be also functionally diverse.
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http://dx.doi.org/10.1093/femsec/fiu005DOI Listing
January 2015