A report on the first EMBO conference entitled “Next Gen Immunology—From Host Genome to the Microbiome: Immunity in the Genomic Era”, held at the Weizmann Institute of Science, Israel, 14–16 February, 2016

David Zeevi

Eran Segal

Tal Korem

PubMed

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Zeevi et al. Genome Biology  (2016) 17:50 DOI 10.1186/s13059-016-0921-4MEETING REPORT Open AccessTalking about cross-talk: the immunesystem and the microbiomeDavid Zeevi1,2†, Tal Korem1,2† and Eran Segal1,2*AbstractA report on the first EMBO conference entitled “NextGen Immunology—From Host Genome to theMicrobiome: Immunity in the Genomic Era”, held atthe Weizmann Institute of Science, Israel, 14–16February, 2016.physiological and pathological states.The first Next Gen Immunology EMBO conference, heldat the Weizmann Institute of Science in mid-February,touched upon a broad set of topics from host genetics totranscriptomics and microbiome analysis. It specificallydemonstrated the intimate cross-talk between the micro-biome and the immune system and called for a similarlyclose interdisciplinary collaboration between microbiolo-gists and immunologists. Recent years have exhibited anincreasing number of works on the modulation of themicrobiome by the immune system [1–3] and the effectof the microbiome on the healthy development of im-munity [4, 5] as well as on autoimmune disorders [6–8].Groundbreaking research on these topics was presented,along with new research methods, resulting in a broadspectrum of exciting works. Finally, novel therapeutic di-rections were demonstrated that probe and modulatehost–microbiome interactions, and show great promisefor future research. Here, we highlight several researchtopics that are of interest to the scientific and biomedicalcommunities.Microbial signatures of diseaseWith major advances in sequencing came the currentadvent of microbiome research. In the past two decadesthe composition and function of the microbiome havebeen shown to associate with obesity, inflammatory* Correspondence: eran.segal@weizmann.ac.il†Equal contributors1Department of Computer Science and Applied Mathematics, WeizmannInstitute of Science, Rehovot 7610001, Israel2Department of Molecular Cell Biology, Weizmann Institute of Science,Rehovot 7610001, Israel© 2016 Zeevi et al. Open Access This article iInternational License (http://creativecommonsreproduction in any medium, provided you gthe Creative Commons license, and indicate if(http://creativecommons.org/publicdomain/zebowel disease, type II diabetes, liver cirrhosis, host nutri-tional choices, drug treatment, and many other physio-logical and pathological states. The conference discussedtwo major drivers in the field of microbiome research:the better and deeper understanding of the microbialsignatures themselves and applications of this improvedunderstanding to study finer and more complex hostQuite a few novel approaches for microbiome analysiswere presented in the conference. A pioneer in the fieldof microbiome research, Rob Knight (University of Cali-fornia, San Diego, USA) highlighted the importance offollowing the microbiome of individuals over time. Usinga three-dimensional principal coordinate analysis of thecompositions of microbiomes, Knight presented a visualmethod for microbiome diagnostics. He showed thateven though the composition of the microbiome mayfluctuate over time, it remains unique for differentpeople. Julie Segre (National Institutes of Health, USA)presented a computational pipeline for the examinationof the skin microbiome, allowing the exploration ofdifferent strains and of the pangenome versus thecore genome of different species. Sharon Greenblum(University of Washington, USA) presented a differentpipeline, for the detection of strain-level gene copy num-ber variations.Many speakers discussed new insights obtained usingdiverse analysis methods. Knight showed that hisvisualization method can be used to follow the devel-opment of the neonatal microbiome and in the futureidentify risk for allergies and asthma in aberrantly de-veloping microbiomes. Ramnik Xavier (Broad Institute,USA) examined infants genetically predisposed to typeI diabetes and showed that the disease is anticipated bya reduction of diversity in gut microbial species. Hefurther described a difference in bacteria metabolizinghuman milk oligosaccharide (HMO) in different coun-tries, with a possible contribution to host immunity. Aworking hypothesis presented was that bacterialcolonization, followed by HMO metabolism by immune-s distributed under the terms of the Creative Commons Attribution 4.0.org/licenses/by/4.0/), which permits unrestricted use, distribution, andive appropriate credit to the original author(s) and the source, provide a link tochanges were made. The Creative Commons Public Domain Dedication waiverro/1.0/) applies to the data made available in this article, unless otherwise stated.Zeevi et al. Genome Biology  (2016) 17:50 Page 2 of 4silent bacteria, may attenuate immune education and leadto autoimmunity. Moran Yassour (Broad Institute, USA)presented results from a longitudinal cohort of 40 childrenwho consumed or abstained from antibiotic consumption,and showed a prolonged reduction of microbial diversityin children that are prescribed repeated courses of antibi-otics, also resulting in less stable communities, reducedintraspecies diversity, and transient increase in antibioticresistance genes.Segre showed surprising figures of viral and fungalcontent in the skin microbiome and a shift in its com-position going through puberty. She presented her workon atopic dermatitis, showing that two bacterial species,Staphylococcus aureus and Staphylococcus epidermidis,rise in abundance during flares of the disease. Eran Elinav(Weizmann Institute of Science, Israel) presented a collab-orative project with our lab that addressed the issue of re-current obesity, which may be linked to the microbiome,thereby impeding dieting and weight management.The microbiome as an immunomodulatorAnother central theme of the conference was the recog-nition of the important role of the microbiome in hostimmune maturation and in immunological health anddisease. The microbiome was shown to affect many im-mune pathways, including innate immunity, inflamma-somes, and regulatory T cells.Andrew MacPherson (University of Bern, Switzerland)showed that the microbiota in pregnancy shapes neonateimmunity, and specifically that innate immunity can betransferred between mother and offspring in the absenceof the immunomodulating agent. Macpherson colonizedpregnant germ-free mice with an Escherichia coli strainwhich infects the host transiently, thus decoupling theeffect of gestational and postnatal maternal microbiome.Finally, he showed that such colonization initiates thetransfer of microbial molecules to the offspring, causingthem to develop innate immunity to the same E. coli.The effect of the maternal microbiome on offspringhealth was underlined by Dan Littman (Skirball Instituteof Biomolecular Medicine, New York University, USA)who showed that simulating a viral infection with polyI:C at gestational day 12.5 leads to autism spectrum dis-order (ASD)-like symptoms in mice offspring. Thisprocess is blocked with anti-interleukin (IL)-6 or anti-IL-17 antibodies which affect maternal T-cell differenti-ation. Since T-cell differentiation is also modulated bygut microbiota, this work shows a possible role for thematernal microbiome in offspring ASD.Fiona Powrie (Oxford University, UK) showed that apolysaccharide derived from Helicobacter hepaticusregulates IL-10 and Treg response in the gut but notIL-6 and tumor necrosis factor-alpha, modulating theimmune response and allowing the bacteria to prosperin the resulting niche. Such discoveries hold promisefor future therapies modulating host immunity usingmicrobiome modulation and microbiome-derivedmetabolites.Technological advancesMany new methodological and technological advanceswere presented in the meeting. Feng Zhang (MassachusettsInstitute of Technology, USA) discussed the CRISPR tech-nology, and presented his efforts to improve its specificityby introducing mutations that reduce the ability of Cas9 tostabilize incorrect guide matches. He also presented theprocess of identifying “new” CRISPR systems, and specific-ally the FnCpf1 system, which has a simple RNA guide,cuts with sticky end, and is independent of the RNA poly-merase III enzyme of the host—allowing for a simpler sys-tem which is more efficient in many cases. The potential ofthe CRISPR technology is just starting to unfold, withworks such as that of Jonathan Schmid-Burgk (Universityof Bonn, Germany) who used it to knockout multiplegenes, identifying key genes to NLRP3 inflammasome acti-vation, such as NEK7. A complementary approach wastaken by Nobel laureate Bruce Beutler (University of TexasSouthwestern, USA), who found the dominant role ofNEK7 in the activation of the NLRP3 inflammasome,enforcing mutual exclusivity of cell division and theinflammasome response, by assaying the phenotypic effectin a forward genetic analysis of N-ethyl-N-nitrosourea-induced mutagenesis in mice.Timm Schroeder (ETH Zurich, Switzerland) made aclaim for continuously following and quantifying the fateof stem cells at the single-cell level. He presented his ap-proach, by combining time-lapse microscopy, cellularmarkers, and computational analysis. This allows him toidentify decision-making points and combine them withsingle-cell approaches to descend into molecularmechanisms. Ilana Kolodkin-Gal (Weizmann Instituteof Science, Israel) utilized X-ray for the study of biofilms,arguing for a dominant role for minerals in their forma-tion and function. She showed that three-dimensionalbiofilm formation is associated with and dependent oncrystalline calcium carbonate deposition, which allowsfor control of diffusion, potentiating antibiotic resist-ance within the biofilm.Michael Fischbach (University of California, SanFrancisco, USA) presented his methodology for novelbiocompound discovery, which involves prediction ofmolecular products of genetic sequences, instead ofthe common course of first finding a molecule of inter-est and then looking for the biosynthesizing enzymes.This is a much needed approach, as even the best-studied organisms have many genes whose productsare unknown. The same idea applies to gene clusters inthe human microbiome, as most are not characterized,Zeevi et al. Genome Biology  (2016) 17:50 Page 3 of 4yet appear in over 90 % of the Human MicrobiomeProject samples. A striking example is indoxyl sulfate,which is created in a manner that is dependent uponmicrobial metabolism of diet-derived molecules and istoxic to kidney patients.Transcription regulation in host immune responseOne way by which exogenic compounds exert their effecton the host is by altering transcription, and the topic oftranscription regulation was widely discussed during themeeting. Nobel laureate David Baltimore (Caltech, USA)discussed the dynamics of mRNA transcription followinginflammation and described how the temporal order ofthe immune response is regulated by splicing, by measur-ing the accumulation of unspliced mRNA. Baltimoreshowed that the splice sites of late-response genes harborintrons that contain conserved noncanonical sequenceswhich serve as “bottlenecks”.Amos Tanay (Weizmann Institute of Science, Israel)discussed new ways to study topologically associatingdomains (TADs) and gene regulation within them. Tanayintroduced algorithms and new single-cell and single-molecule assays to capture “walks” between physicallylinked genomic loci. He then argued that multiway con-tacts between enhancers can be explained by independentpairwise interactions within the context of TADs, while si-lenced domains can form rosette-like hubs. Ido Amit(Weizmann Institute of Science, Israel) presented a collab-oration with Tanay where they examined the transcriptomeof single hematopoietic progenitors and used transcrip-tional sorting to delineate progenitor subgroups, as op-posed to contemporary surface markers and functionalassays, and found early transcriptional priming of differen-tiation lines, with no mixed-state progenitors. Further-more, he demonstrated that comprehensive single-cellanalysis of bone marrow progenitors can be used to revisethe current hematopoietic tree model, defining new pro-genitors, markers, signaling pathways, and transcriptionallineage regulators.Microbiome as a basis for therapeuticsThe microbiome has been implicated as a target fortherapy as it affects human health, but, unlike humangenetics, it is easier to manipulate. Recurrent Clostrid-ium difficile colitis is now commonly treated with stooltransplants, and the effect of microbial transplants onobesity and insulin sensitivity has also been shown.However, although probiotic and prebiotic supplementa-tion, along with stool transplants and diet-based micro-biome alterations, are some of the tools readily availablein the clinic, little is known about the mechanisms lead-ing to their desired effects. Host immunity, the presenceor absence of certain metabolites, bacterial compositionand bacterial genetics are all important players in thecomplex environment of the gut, and were all addressedat the conference.Addressing the effect of host immunity, Richard Flavell(Yale University, USA) observed the fraction of the gutmicrobiome that is coated by immunoglobulin A (IgA),postulating that it acts as an initiator of immune re-sponses. In a healthy gut, IgA normally coats pathogens,but individuals with inflammatory bowel diseases exhibitaberrant IgA coating of microbes. Flavell introduced thefraction of microbes coated with IgA to germ-free mice,showing their ability to induce dysbiosis and colitis. Fi-nally, as a prospective therapeutic avenue, Flavell showedthat immunizing against one of the aberrantly coatedspecies was enough to protect mice against dextran sul-fate sodium (DSS)-induced colitis.The importance of certain metabolites for the healthyfunction of the gut microbiome was shown by Powrie.Tying metabolite composition with host immunity, shediscussed how the short-chain fatty acid butyrate pro-motes bone marrow-derived macrophage activity withimproved Salmonella killing. She ended with a thera-peutic promise, showing that treating mice with butyratepromoted host defense against Citrobacter rodentium in-fection. Using an analysis of the compositions of micro-biomes, Knight showed that applying a vaginal swab toneonates born by cesarean section promoted a healthierdevelopment of infant microbiomes. In patients with aClostridium difficile infection, Knight showed that stoolsamples cluster outside the normal range of healthy hu-man stool microbiota composition, but that a stooltransplant can induce a favorable change within a day.We (presented by Eran Segal) showed a collaborativeproject with Elinav in which we measured the compos-ition and genetic function of the microbiomes of over800 people and found them to be associated with an effecton human glucose metabolism. We further showed thatthese microbial markers are utilized in the prediction ofpersonal response to meals, and that the microbiomechanges in a manner that was consistent across differentindividuals when the host is put on a diet designed tolower postmeal blood glucose responses. This intricateinterplay between host diet, host health, and microbiomecompositional dynamics holds promise for the design ofnew diet-based microbiome modulating therapeutics.Concluding remarksThis meeting covered many new and exciting develop-ments in microbiome research, immunology, and thecross-talk between them. Due to the large number of ex-citing and interesting talks presented in the meeting, thisreport only provides a small glimpse of these topics ratherthan a comprehensive view of the entire conference. Manyunpublished works were presented and we can expectsome innovative research to be published very soon.Zeevi et al. Genome Biology  (2016) 17:50 Page 4 of 4AbbreviationsASD: Autism spectrum disorder; DSS: Dextran sulfate sodium; HMO: Humanmilk oligosaccharide; IgA: Immunoglobulin A; IL: Interleukin;TAD: Topologically associating domain.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsDZ, TK and ES prepared the manuscript. DZ and TK contributed equally tothis work. All authors read and approved the final manuscript.References1. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R.Recognition of commensal microflora by toll-like receptors is required forintestinal homeostasis. Cell. 2004;118:229–41.2. Levy M, Thaiss CA, Zeevi D, Dohnalová L, Zilberman-Schapira G, Mahdi JA,et al. Microbiota-modulated metabolites shape the intestinalmicroenvironment by regulating NLRP6 inflammasome signaling. Cell.2015;163:1428–43.3. Kubinak JL, Petersen C, Stephens WZ, Soto R, Bake E, O’Connell RM, et al.MyD88 signaling in T cells directs IgA-mediated control of the microbiotato promote health. Cell Host Microbe. 2015;17:153–63.4. Hooper LV, Littman DR, Macpherson AJ. Interactions between themicrobiota and the immune system. Science. 2012;336:1268–73.5. An D, Oh SF, Olszak T, Neves JF, Avci FY, Erturk-Hasdemir D, et al.Sphingolipids from a symbiotic microbe regulate homeostasis of hostintestinal natural killer T cells. Cell. 2014;156:123–33.6. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC,et al. Innate immunity and intestinal microbiota in the development ofType 1 diabetes. Nature. 2008;455:1109–13.7. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, et al. NLRP6inflammasome regulates colonic microbial ecology and risk for colitis. Cell.2011;145:745–57.8. Sano T, Huang W, Hall JA, Yang Y, Chen A, Gavzy SJ, et al. An IL-23R/IL-22circuit regulates epithelial serum amyloid a to promote local effector Th17responses. Cell. 2015;163:381–93.

Talking about cross-talk: the immune system and the microbiome

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Talking about cross-talk: the immune system and the microbiome

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