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Xavier, Ramnik

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Xavier, Ramnik
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    Multi-Omics of the Gut Microbial Ecosystem in Inflammatory Bowel Diseases
    (Springer Science and Business Media LLC, 2019-05) Lloyd-Price, Jason; Arze, Cesar; Schirmer, Melanie; Andrews, Elizabeth; Ajami, Nadim J.; Brislawn, Colin J.; Courtney, Holly; Gonzalez, Antonio; Graeber, Thomas G.; Hall, A. Brantley; Mallick, Himel; Rahnavard, Gholamali; Sauk, Jenny; Shungin, Dmitry; Vázquez-Baeza, Yoshiki; White, Richard A.; Braun, Jonathan; Denson, Lee A.; Jansson, Janet K.; Knight, Robert; Kugathasan, Subra; McGovern, Dermot P. B.; Stappenbeck, Thaddeus S.; Vlamakis, Hera; Huttenhower, Curtis; Ananthakrishnan, Ashwin; Avila-Pacheco, Julian; Poon, Tiffany; Bonham, Kevin; Casero, David; Lake, Kathleen; Landers, Carol; Plichta, Damian; Prasad, Mahadev; Winter, Harland; Clish, Clary; Franzosa, Eric; Xavier, Ramnik; Petrosino, Joseph
    Inflammatory bowel diseases (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), affect several million individuals worldwide. CD and UC are complex diseases and heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Extensive study has focused on individual contributing factors. As part of the Integrative Human Microbiome Project (HMP2), 132 subjects were followed one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each, in total 2,965 stool, biopsy, and blood specimens). These provide a comprehensive view of the gut microbiome’s functional dysbiosis during IBD activity, showing a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (e.g. among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and host serum antibody levels. Disease was also marked by greater temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to the dysregulation. The study’s infrastructure resources, results, and data, available through the Inflammatory Bowel Disease Multi'omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in IBD.
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    Genome-Wide Enhancer Maps Link Risk Variants to Disease Genes
    (Springer Science and Business Media LLC, 2021-04-07) Nasser, Joseph; Bergman, Drew T.; Fulco, Charles P.; Guckelberger, Philine; Doughty, Benjamin; Patwardhan, Tejal A.; Jones, Thouis; Nguyen, Tung; Ulirsch, Jacob; Lekschas, Fritz; Mualim, Kristy; Natri, Heini M.; Weeks, Elle M.; Munson, Glen; Kane, Michael; Kang, Helen Y.; Cui, Ang; Ray, John P.; Eisenhaure, Thomas M.; Collins, Ryan; Dey, Kushal; Pfister, Hanspeter; Price, Alkes; Epstein, Charles; Kundaje, Anshul; Xavier, Ramnik; Daly, Mark; Huang, Hailiang; Finucane, Hilary; Hacohen, Nir; Lander, Eric; Engreitz, Jesse
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    Metagenomic Characterization of Microbial Communities In Situ Within the Deeper Layers of the Ileum in Crohn’s Disease
    (Elsevier, 2016) Pedamallu, Chandra Sekhar; Bhatt, Ami S.; Bullman, Susan; Fowler, Sharyle; Freeman, Sam; Durand, Jacqueline; Jung, Joonil; Duke, Fujiko; Manzo, Veronica; Cai, Diana; Ananthakrishnan, Ashwin; Ojesina, Akinyemi I.; Ramachandran, Aruna; Gevers, Dirk; Xavier, Ramnik; Bhan, Atul; Meyerson, Matthew; Yajnik, Vijay
    Background & Aims Microbial dysbiosis and aberrant host–microbe interactions in the gut are believed to contribute to the development and progression of Crohn’s disease (CD). Microbiome studies in CD typically have focused on microbiota in feces or superficial mucosal layers of the colon because accessing DNA from deeper layers of the bowel is challenging. In this study, we analyzed the deep tissue microbiome in patients who underwent surgical resection of the small intestine. Methods: Paraffin blocks were obtained from 12 CD patients undergoing ileocecal resection, and healthy ileum samples (inflammatory bowel disease–free controls) were obtained from 12 patients undergoing surgery for right-sided colon cancer. Diseased and healthy-appearing ileum was identified using microscopy, and paraffin blocks were macrodissected using a core needle to specifically isolate DNA. Illumina Whole Genome Sequencing was used for microbial sequence identification and subsequent taxonomic classification using the PathSeq tool. Results: We observed significant differences between the microbiome of CD samples vs inflammatory bowel disease–free controls, including depletion of Bacteroidetes and Clostridia. Notably, microbial composition at the phyla level did not differ markedly between healthy and diseased areas of CD patients. However, we observed enrichment of potentially pathogenic organisms at the species level. Conclusions: Our study showed dysbiosis within deeper layers of the ileum of CD patients, specifically enrichment of enterotoxigenic Staphylococcus aureus and an environmental Mycobacterium species not described previously. Future studies with larger cohort sizes are warranted to confirm these findings. Studies would benefit from effective microbial DNA extraction methods from paraffin sections and host nucleic acid depletion approaches to increase microbial read coverage.
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    IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
    (Nature Publishing Group UK, 2018) Momozawa, Yukihide; Dmitrieva, Julia; Théâtre, Emilie; Deffontaine, Valérie; Rahmouni, Souad; Charloteaux, Benoît; Crins, François; Docampo, Elisa; Elansary, Mahmoud; Gori, Ann-Stephan; Lecut, Christelle; Mariman, Rob; Mni, Myriam; Oury, Cécile; Altukhov, Ilya; Alexeev, Dmitry; Aulchenko, Yuri; Amininejad, Leila; Bouma, Gerd; Hoentjen, Frank; Löwenberg, Mark; Oldenburg, Bas; Pierik, Marieke J.; vander Meulen-de Jong, Andrea E.; Janneke van der Woude, C.; Visschedijk, Marijn C.; Abraham, Clara; Achkar, Jean-Paul; Ahmad, Tariq; Ananthakrishnan, Ashwin; Andersen, Vibeke; Anderson, Carl A.; Andrews, Jane M.; Annese, Vito; Aumais, Guy; Baidoo, Leonard; Baldassano, Robert N.; Bampton, Peter A.; Barclay, Murray; Barrett, Jeffrey C.; Bayless, Theodore M.; Bethge, Johannes; Bitton, Alain; Boucher, Gabrielle; Brand, Stephan; Brandt, Berenice; Brant, Steven R.; Büning, Carsten; Chew, Angela; Cho, Judy H.; Cleynen, Isabelle; Cohain, Ariella; Croft, Anthony; Daly, Mark; D’Amato, Mauro; Danese, Silvio; Jong, Dirk De; Denapiene, Goda; Denson, Lee A.; Devaney, Kathy L.; Dewit, Olivier; D’Inca, Renata; Dubinsky, Marla; Duerr, Richard H.; Edwards, Cathryn; Ellinghaus, David; Essers, Jonah; Ferguson, Lynnette R.; Festen, Eleonora A.; Fleshner, Philip; Florin, Tim; Franke, Andre; Fransen, Karin; Gearry, Richard; Gieger, Christian; Glas, Jürgen; Goyette, Philippe; Green, Todd; Griffiths, Anne M.; Guthery, Stephen L.; Hakonarson, Hakon; Halfvarson, Jonas; Hanigan, Katherine; Haritunians, Talin; Hart, Ailsa; Hawkey, Chris; Hayward, Nicholas K.; Hedl, Matija; Henderson, Paul; Hu, Xinli; Huang, Hailiang; Hui, Ken Y.; Imielinski, Marcin; Ippoliti, Andrew; Jonaitis, Laimas; Jostins, Luke; Karlsen, Tom H.; Kennedy, Nicholas A.; Khan, Mohammed Azam; Kiudelis, Gediminas; Krishnaprasad, Krupa; Kugathasan, Subra; Kupcinskas, Limas; Latiano, Anna; Laukens, Debby; Lawrance, Ian C.; Lee, James C.; Lees, Charlie W.; Leja, Marcis; Limbergen, Johan Van; Lionetti, Paolo; Liu, Jimmy Z.; Mahy, Gillian; Mansfield, John; Massey, Dunecan; Mathew, Christopher G.; McGovern, Dermot P. B.; Milgrom, Raquel; Mitrovic, Mitja; Montgomery, Grant W.; Mowat, Craig; Newman, William; Ng, Aylwin; Ng, Siew C.; Ng, Sok Meng Evelyn; Nikolaus, Susanna; Ning, Kaida; Nöthen, Markus; Oikonomou, Ioannis; Palmieri, Orazio; Parkes, Miles; Phillips, Anne; Ponsioen, Cyriel Y.; Potocnik, Urõs; Prescott, Natalie J.; Proctor, Deborah D.; Radford-Smith, Graham; Rahier, Jean-Francois; Raychaudhuri, Soumya; Regueiro, Miguel; Rieder, Florian; Rioux, John D.; Ripke, Stephan; Roberts, Rebecca; Russell, Richard K.; Sanderson, Jeremy D.; Sans, Miquel; Satsangi, Jack; Schadt, Eric E.; Schreiber, Stefan; Schulte, Dominik; Schumm, L. Philip; Scott, Regan; Seielstad, Mark; Sharma, Yashoda; Silverberg, Mark S.; Simms, Lisa A.; Skieceviciene, Jurgita; Spain, Sarah L.; Steinhart, A. Hillary; Stempak, Joanne M.; Stronati, Laura; Sventoraityte, Jurgita; Targan, Stephan R.; Taylor, Kirstin M.; ter Velde, Anje; Torkvist, Leif; Tremelling, Mark; Sommeren, Suzanne van; Vasiliauskas, Eric; Verspaget, Hein W.; Walters, Thomas; Wang, Kai; Wang, Ming-Hsi; Wei, Zhi; Whiteman, David; Wijmenga, Cisca; Wilson, David C.; Winkelmann, Juliane; Xavier, Ramnik; Zhang, Bin; Zhang, Clarence K.; Zhang, Hu; Zhang, Wei; Zhao, Hongyu; Zhao, Zhen Z.; Lathrop, Mark; Hugot, Jean-Pierre; Weersma, Rinse K.; De Vos, Martine; Franchimont, Denis; Vermeire, Severine; Kubo, Michiaki; Louis, Edouard; Georges, Michel
    GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
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    The Human Cell Atlas
    (eLife Sciences Publications, Ltd, 2017) Regev, Aviv; Teichmann, Sarah A; Lander, Eric; Amit, Ido; Benoist, Christophe; Birney, Ewan; Bodenmiller, Bernd; Campbell, Peter; Carninci, Piero; Clatworthy, Menna; Clevers, Hans; Deplancke, Bart; Dunham, Ian; Eberwine, James; Eils, Roland; Enard, Wolfgang; Farmer, Andrew; Fugger, Lars; Göttgens, Berthold; Hacohen, Nir; Haniffa, Muzlifah; Hemberg, Martin; Kim, Seung; Klenerman, Paul; Kriegstein, Arnold; Lein, Ed; Linnarsson, Sten; Lundberg, Emma; Lundeberg, Joakim; Majumder, Partha; Marioni, John C; Merad, Miriam; Mhlanga, Musa; Nawijn, Martijn; Netea, Mihai; Nolan, Garry; Pe'er, Dana; Phillipakis, Anthony; Ponting, Chris P; Quake, Stephen; Reik, Wolf; Rozenblatt-Rosen, Orit; Sanes, Joshua; Satija, Rahul; Schumacher, Ton N; Shalek, Alex; Shapiro, Ehud; Sharma, Padmanee; Shin, Jay W; Stegle, Oliver; Stratton, Michael; Stubbington, Michael J T; Theis, Fabian J; Uhlen, Matthias; van Oudenaarden, Alexander; Wagner, Allon; Watt, Fiona; Weissman, Jonathan; Wold, Barbara; Xavier, Ramnik; Yosef, Nir
    The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.
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    Helminth-Induced Alterations Of The Gut Microbiota Exacerbate Bacterial Colitis
    (2017) Su, Chienwen; Su, Libo; Li, Yali; Chang, Jeffrey; Zhang, Wei; Walker, W.A.; Xavier, Ramnik; Cherayil, Bobby; Shi, Hai
    Infection with the intestinal helminth parasite Heligmosomoides polygyrus exacerbates the colitis caused by the bacterial enteropathogen Citrobacter rodentium. To clarify the underlying mechanism, we analyzed fecal microbiota composition of control and helminth-infected mice and evaluated the functional role of compositional differences by microbiota transplantation experiments. Our results showed that infection of Balb/c mice with H. polygyrus resulted in significant changes in the composition of the gut microbiota, characterized by a marked increase in the abundance of Bacteroidetes and decreases in Firmicutes and Lactobacillales. Recipients of the gut microbiota from helminth-infected wide-type, but not STAT 6-deficient, Balb/c donors had increased fecal pathogen shedding and significant worsening of Citrobacter-induced colitis compared to recipients of microbiota from control donors. Recipients of helminth-altered microbiota also displayed increased regulatory T cells and IL-10 expression. Depletion of CD4+CD25+ T cells and neutralization of IL-10 in recipients of helminth-altered microbiota led to reduced stool C. rodentium numbers and attenuated colitis. These results indicate that alteration of the gut microbiota is a significant contributor to the H. polygyrus-induced exacerbation of C. rodentium colitis. The helminth-induced alteration of the microbiota is Th2-dependent and acts by promoting regulatory T cells that suppress protective responses to bacterial enteropathogens.
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    Host genetic variation and its microbiome interactions within the Human Microbiome Project
    (BioMed Central, 2018) Kolde, Raivo; Franzosa, Eric; Rahnavard, Gholamali; Hall, Andrew Brantley; Vlamakis, Hera; Stevens, Christine; Daly, Mark; Xavier, Ramnik; Huttenhower, Curtis
    Background: Despite the increasing recognition that microbial communities within the human body are linked to health, we have an incomplete understanding of the environmental and molecular interactions that shape the composition of these communities. Although host genetic factors play a role in these interactions, these factors have remained relatively unexplored given the requirement for large population-based cohorts in which both genotyping and microbiome characterization have been performed. Methods: We performed whole-genome sequencing of 298 donors from the Human Microbiome Project (HMP) healthy cohort study to accompany existing deep characterization of their microbiomes at various body sites. This analysis yielded an average sequencing depth of 32x, with which we identified 27 million (M) single nucleotide variants and 2.3 M insertions-deletions. Results: Taxonomic composition and functional potential of the microbiome covaried significantly with genetic principal components in the gastrointestinal tract and oral communities, but not in the nares or vaginal microbiota. Example associations included validation of known associations between FUT2 secretor status, as well as a variant conferring hypolactasia near the LCT gene, with Bifidobacterium longum abundance in stool. The associations of microbial features with both high-level genetic attributes and single variants were specific to particular body sites, highlighting the opportunity to find unique genetic mechanisms controlling microbiome properties in the microbial communities from multiple body sites. Conclusions: This study adds deep sequencing of host genomes to the body-wide microbiome sequences already extant from the HMP healthy cohort, creating a unique, versatile, and well-controlled reference for future studies seeking to identify host genetic modulators of the microbiome. Electronic supplementary material The online version of this article (10.1186/s13073-018-0515-8) contains supplementary material, which is available to authorized users.
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    Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population
    (Public Library of Science, 2018) Rivas, Manuel A.; Avila, Brandon E.; Koskela, Jukka; Huang, Hailiang; Stevens, Christine; Pirinen, Matti; Haritunians, Talin; Neale, Benjamin; Kurki, Mitja; Ganna, Andrea; Graham, Daniel; Glaser, Benjamin; Peter, Inga; Atzmon, Gil; Barzilai, Nir; Levine, Adam P.; Schiff, Elena; Pontikos, Nikolas; Weisburd, Ben; Lek, Monkol; Karczewski, Konrad; Bloom, Jonathan; Minikel, Eric; Petersen, Britt-Sabina; Beaugerie, Laurent; Seksik, Philippe; Cosnes, Jacques; Schreiber, Stefan; Bokemeyer, Bernd; Bethge, Johannes; Heap, Graham; Ahmad, Tariq; Plagnol, Vincent; Segal, Anthony W.; Targan, Stephan; Turner, Dan; Saavalainen, Paivi; Farkkila, Martti; Kontula, Kimmo; Palotie, Aarno; Brant, Steven R.; Duerr, Richard H.; Silverberg, Mark S.; Rioux, John D.; Weersma, Rinse K.; Franke, Andre; Jostins, Luke; Anderson, Carl A.; Barrett, Jeffrey C.; MacArthur, Daniel; Jalas, Chaim; Sokol, Harry; Xavier, Ramnik; Pulver, Ann; Cho, Judy H.; McGovern, Dermot P. B.; Daly, Mark
    As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10–100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10−16). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC (sites VCF available via FTP at ftp.broadinstitute.org/pub/ExAC_release/release0.3/) to pinpoint genetic variation that contributes to variable disease predisposition across populations.
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    A single-cell survey of the small intestinal epithelium
    (2018) Haber, Adam L.; Biton, Moshe; Rogel, Noga; Herbst, Rebecca; Shekhar, Karthik; Smillie, Christopher; Burgin, Grace; Delorey, Toni M.; Howitt, Michael R.; Katz, Yarden; Tirosh, Itay; Beyaz, Semir; Dionne, Danielle; Zhang, Mei; Raychowdhury, Raktima; Garrett, Wendy; Rozenblatt-Rosen, Orit; Shi, Hai; Yilmaz, Omer; Xavier, Ramnik; Regev, Aviv
    Intestinal epithelial cells (IECs) absorb nutrients, respond to microbes, provide barrier function and help coordinate immune responses. We profiled 53,193 individual epithelial cells from mouse small intestine and organoids, and characterized novel subtypes and their gene signatures. We showed unexpected diversity of hormone-secreting enteroendocrine cells and constructed their novel taxonomy. We distinguished between two tuft cell subtypes, one of which expresses the epithelial cytokine TSLP and CD45 (Ptprc), the pan-immune marker not previously associated with non-hematopoietic cells. We also characterized how cell-intrinsic states and cell proportions respond to bacterial and helminth infections. Salmonella infection caused an increase in Paneth cells and enterocytes abundance, and broad activation of an antimicrobial program. In contrast, Heligmosomoides polygyrus caused an expansion of goblet and tuft cell populations. Our survey highlights new markers and programs, associates sensory molecules to cell types, and uncovers principles of gut homeostasis and response to pathogens.
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    Intestinal epithelial cell-specific RARα depletion results in aberrant epithelial cell homeostasis and underdeveloped immune system
    (2017) Jijon, Humberto B.; Suarez-Lopez, Lucia; Diaz, Oscar E.; Das, Srustidhar; De Calisto, Jaime; Yaffe, Michael; Pittet, Mikael; Mora, J. Rodrigo; Belkaid, Yasmine; Xavier, Ramnik; Villablanca, Eduardo J.
    Retinoic acid (RA), a dietary vitamin A metabolite, is crucial in maintaining intestinal homeostasis. RA acts on intestinal leukocytes to modulate their lineage commitment and function. Although the role of RA has been characterized in immune cells, whether intestinal epithelial cells (IECs) rely on RA signaling to exert their immune-regulatory function has not been examined. Here we demonstrate that lack of retinoic acid receptor alpha (RARα) signaling in IECs results in deregulated epithelial lineage specification, leading to increased numbers of goblet cells and Paneth cells. Mechanistically, lack or RARα resulted in increased KLF4+ goblet cell precursors in the distal bowel, whereas RA treatment inhibited klf4 expression and goblet cell differentiation in zebrafish. These changes in secretory cells are associated with increased reg3g, reduced luminal bacterial detection and an underdeveloped intestinal immune system, as evidenced by an almost complete absence of lymphoid follicles and gut resident mononuclear phagocytes. This underdeveloped intestinal immune system shows a decreased ability to clear infection with Citrobacter rodentium. Collectively, our findings indicate that epithelial cell-intrinsic RARα signaling is critical to the global development of the intestinal immune system.