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• W2918402014 abstract "•M. restricta is associated with the colonic mucosa in Crohn’s disease (CD) patients•M. restricta exacerbates colitis in wild-type and gnotobiotic mice•M. restricta is found in CD patients with a disease-linked polymorphism in CARD9•Malassezia-exacerbated colitis in mice requires signaling via CARD9 Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal microbiota and altered immune responses to gut microbiota. Evidence is accumulating that IBD is influenced by not only commensal bacteria but also commensal fungi. We characterized fungi directly associated with the intestinal mucosa in healthy people and Crohn’s disease patients and identified fungi specifically abundant in patients. One of these, the common skin resident fungus Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by Crohn’s disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these results suggest that targeting specific commensal fungi may be a therapeutic strategy for IBD. Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal microbiota and altered immune responses to gut microbiota. Evidence is accumulating that IBD is influenced by not only commensal bacteria but also commensal fungi. We characterized fungi directly associated with the intestinal mucosa in healthy people and Crohn’s disease patients and identified fungi specifically abundant in patients. One of these, the common skin resident fungus Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by Crohn’s disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these results suggest that targeting specific commensal fungi may be a therapeutic strategy for IBD. Inflammatory bowel disease (IBD) susceptibility and severity are understood to be influenced by a combination of genetics, microbiota, and environment. The intestinal microbiota includes fungi (the mycobiota), and changes in the mycobiota have been reported in patients with Crohn’s disease (CD) (Chehoud et al., 2015Chehoud C. Albenberg L.G. Judge C. Hoffmann C. Grunberg S. Bittinger K. Baldassano R.N. Lewis J.D. Bushman F.D. Wu G.D. Fungal signature in the gut microbiota of pediatric patients with inflammatory bowel disease.Inflamm. Bowel Dis. 2015; 21: 1948-1956Crossref PubMed Scopus (157) Google Scholar, Hoarau et al., 2016Hoarau G. Mukherjee P.K. Gower-Rousseau C. Hager C. Chandra J. Retuerto M.A. Neut C. Vermeire S. Clemente J. Colombel J.F. et al.Bacteriome and mycobiome interactions underscore microbial dysbiosis in familial Crohn’s disease.MBio. 2016; 7: e01250-16Crossref PubMed Scopus (261) Google Scholar, Lewis et al., 2015Lewis J.D. Chen E.Z. Baldassano R.N. Otley A.R. Griffiths A.M. Lee D. Bittinger K. Bailey A. Friedman E.S. Hoffmann C. et al.Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn’s disease.Cell Host Microbe. 2015; 18: 489-500Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar, Liguori et al., 2016Liguori G. Lamas B. Richard M.L. Brandi G. da Costa G. Hoffmann T.W. Di Simone M.P. Calabrese C. Poggioli G. Langella P. et al.Fungal dysbiosis in Mucosa-associated microbiota of Crohn's disease patients.J. Crohns. Colitis. 2016; 10: 296-305Crossref PubMed Scopus (183) Google Scholar, Sokol et al., 2017Sokol H. Leducq V. Aschard H. Pham H.P. Jegou S. Landman C. Cohen D. Liguori G. Bourrier A. Nion-Larmurier I. et al.Fungal microbiota dysbiosis in IBD.Gut. 2017; 66: 1039-1048Crossref PubMed Scopus (670) Google Scholar), especially increased prevalence of Candida spp., although how this relates to the disease is not yet clear. Circumstantial evidence of a role for commensal fungi in inflammatory diseases of the gut has been accumulating for years. Serological evidence suggests that IBD is associated with changes in how the immune system interacts with commensal fungi. Development of anti-Saccharomyces cerevisiae antibodies (ASCA) that recognize yeast cell wall mannans found in many, but not all, fungi is a clinical biomarker identifying a large portion of CD patients (Joossens et al., 2002Joossens S. Reinisch W. Vermeire S. Sendid B. Poulain D. Peeters M. Geboes K. Bossuyt X. Vandewalle P. Oberhuber G. et al.The value of serologic markers in indeterminate colitis: a prospective follow-up study.Gastroenterology. 2002; 122: 1242-1247Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, Reese et al., 2006Reese G.E. Constantinides V.A. Simillis C. Darzi A.W. Orchard T.R. Fazio V.W. Tekkis P.P. Diagnostic precision of anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease.Am. J. Gastroenterol. 2006; 101: 2410-2422Crossref PubMed Scopus (196) Google Scholar). Serological markers including ASCA have proven useful in defining IBD subtypes and predicting responses to therapies. Anti-tumor necrosis factor-α biologics (e.g., infliximab) are useful in treating IBD; however, the presence or absence of ASCA together with other markers is linked to failure of infliximab therapy in CD and ulcerative colitis (Esters et al., 2002Esters N. Vermeire S. Joossens S. Noman M. Louis E. Belaiche J. De Vos M. Van Gossum A. Pescatore P. Fiasse R. et al.Serological markers for prediction of response to anti-tumor necrosis factor treatment in Crohn's disease.Am. J. Gastroenterol. 2002; 97: 1458-1462Crossref PubMed Scopus (7) Google Scholar, Ferrante et al., 2007Ferrante M. Vermeire S. Katsanos K.H. Noman M. Van Assche G. Schnitzler F. Arijs I. De Hertogh G. Hoffman I. Geboes J.K. et al.Predictors of early response to infliximab in patients with ulcerative colitis.Inflamm. Bowel Dis. 2007; 13: 123-128Crossref PubMed Scopus (165) Google Scholar, Taylor et al., 2001Taylor K.D. Plevy S.E. Yang H. Landers C.J. Barry M.J. Rotter J.I. Targan S.R. ANCA pattern and LTA haplotype relationship to clinical responses to anti-TNF antibody treatment in Crohn's disease.Gastroenterology. 2001; 120: 1347-1355Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Genome-wide association studies have identified a common polymorphism in the gene for CARD9, a signaling adapter protein that is essential for anti-fungal innate immunity in mice and humans, as among the strongest genetic risk factors linked to CD and ulcerative colitis (Jostins et al., 2012Jostins L. Ripke S. Weersma R.K. Duerr R.H. McGovern D.P. Hui K.Y. Lee J.C. Schumm L.P. Sharma Y. Anderson C.A. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3255) Google Scholar, Rivas et al., 2011Rivas M.A. Beaudoin M. Gardet A. Stevens C. Sharma Y. Zhang C.K. Boucher G. Ripke S. Ellinghaus D. Burtt N. et al.Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.Nat. Genet. 2011; 43: 1066-1073Crossref PubMed Scopus (588) Google Scholar). CARD9 is required for inflammatory signaling by C-type lectin receptors involved in innate sensing of fungi including Dectin-1, Dectin-2, and Mincle (Pérez de Diego et al., 2015Pérez de Diego R. Sánchez-Ramón S. López-Collazo E. Martínez-Barricarte R. Cubillos-Zapata C. Ferreira Cerdán A. Casanova J.L. Puel A. Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: molecular, immunologic, and clinical heterogeneity.J. Allergy Clin. Immunol. 2015; 136: 1139-1149Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, Roth and Ruland, 2013Roth S. Ruland J. Caspase recruitment domain-containing protein 9 signaling in innate immunity and inflammation.Trends Immunol. 2013; 34: 243-250Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). The primary phenotype in people with rare loss-of-function mutations in CARD9 is susceptibility to fungal infection (Glocker et al., 2009Glocker E.O. Hennigs A. Nabavi M. Schäffer A.A. Woellner C. Salzer U. Pfeifer D. Veelken H. Warnatz K. Tahami F. et al.A homozygous CARD9 mutation in a family with susceptibility to fungal infections.N. Engl. J. Med. 2009; 361: 1727-1735Crossref PubMed Scopus (638) Google Scholar). The common disease-associated risk allele confers an amino acid change in CARD9 (S12N) that has recently been shown in a mouse model to alter rather than ablate signaling (Xu et al., 2018Xu X. Xu J.F. Zheng G. Lu H.W. Duan J.L. Rui W. Guan J.H. Cheng L.Q. Yang D.D. Wang M.C. et al.CARD9S12N facilitates the production of IL-5 by alveolar macrophages for the induction of type 2 immune responses.Nat. Immunol. 2018; 19: 547-560Crossref PubMed Scopus (42) Google Scholar). A polymorphic haplotype of the gene for Dectin-1, an innate receptor for fungal β-glucan that signals via CARD9, has been linked to severe disease in patients with ulcerative colitis, and we have observed that mice lacking the gene for Dectin-1 are more susceptible to experimental colitis (Iliev et al., 2012Iliev I.D. Funari V.A. Taylor K.D. Nguyen Q. Reyes C.N. Strom S.P. Brown J. Becker C.A. Fleshner P.R. Dubinsky M. et al.Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis.Science. 2012; 336: 1314-1317Crossref PubMed Scopus (732) Google Scholar). Recent studies suggest that changes in the mycobiota may be observed in IBD (Lewis et al., 2015Lewis J.D. Chen E.Z. Baldassano R.N. Otley A.R. Griffiths A.M. Lee D. Bittinger K. Bailey A. Friedman E.S. Hoffmann C. et al.Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn’s disease.Cell Host Microbe. 2015; 18: 489-500Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar, Ott et al., 2008Ott S.J. Kühbacher T. Musfeldt M. Rosenstiel P. Hellmig S. Rehman A. Drews O. Weichert W. Timmis K.N. Schreiber S. Fungi and inflammatory bowel diseases: alterations of composition and diversity.Scand. J. Gastroenterol. 2008; 43: 831-841Crossref PubMed Scopus (319) Google Scholar). Sequencing of highly variable regions in bacterial rDNA (16S sequencing) has proven to be a powerful and widely adopted approach for in-depth characterization of complex bacterial communities. The analogous approach for fungi is based on sequencing the “internal transcribed spacer” (ITS) regions of fungal rDNA. A recent study of fecal samples from pediatric IBD patients and controls using this approach suggested that the disease may be associated with a decrease in overall fungal diversity and an increase in the presence of Candida spp. (Chehoud et al., 2015Chehoud C. Albenberg L.G. Judge C. Hoffmann C. Grunberg S. Bittinger K. Baldassano R.N. Lewis J.D. Bushman F.D. Wu G.D. Fungal signature in the gut microbiota of pediatric patients with inflammatory bowel disease.Inflamm. Bowel Dis. 2015; 21: 1948-1956Crossref PubMed Scopus (157) Google Scholar), an idea that has some history and may suggest that Candida could be a factor in a subset of CD patients (Pineton de Chambrun et al., 2008Pineton de Chambrun G. Colombel J.F. Poulain D. Darfeuille-Michaud A. Pathogenic agents in inflammatory bowel diseases.Curr. Opin. Gastroenterol. 2008; 24: 440-447Crossref PubMed Scopus (46) Google Scholar). Subsequent studies with adult patients investigating fecal or biopsy samples have described similar associations with Candida and, to a lesser and more variable degree, other fungi (Chehoud et al., 2015Chehoud C. Albenberg L.G. Judge C. Hoffmann C. Grunberg S. Bittinger K. Baldassano R.N. Lewis J.D. Bushman F.D. Wu G.D. Fungal signature in the gut microbiota of pediatric patients with inflammatory bowel disease.Inflamm. Bowel Dis. 2015; 21: 1948-1956Crossref PubMed Scopus (157) Google Scholar, Hoarau et al., 2016Hoarau G. Mukherjee P.K. Gower-Rousseau C. Hager C. Chandra J. Retuerto M.A. Neut C. Vermeire S. Clemente J. Colombel J.F. et al.Bacteriome and mycobiome interactions underscore microbial dysbiosis in familial Crohn’s disease.MBio. 2016; 7: e01250-16Crossref PubMed Scopus (261) Google Scholar, Liguori et al., 2016Liguori G. Lamas B. Richard M.L. Brandi G. da Costa G. Hoffmann T.W. Di Simone M.P. Calabrese C. Poggioli G. Langella P. et al.Fungal dysbiosis in Mucosa-associated microbiota of Crohn's disease patients.J. Crohns. Colitis. 2016; 10: 296-305Crossref PubMed Scopus (183) Google Scholar, Sokol et al., 2017Sokol H. Leducq V. Aschard H. Pham H.P. Jegou S. Landman C. Cohen D. Liguori G. Bourrier A. Nion-Larmurier I. et al.Fungal microbiota dysbiosis in IBD.Gut. 2017; 66: 1039-1048Crossref PubMed Scopus (670) Google Scholar). However, accurately identifying fungi in ITS sequencing projects is still a challenge, and how detection of fungal DNA relates to host-microbe interactions at mucosal surfaces is still unclear (Limon et al., 2018Limon J.J. Kershaw K.M. Underhill D.M. Mucosal immune responses to fungi and the implications for inflammatory bowel disease.Curr. Opin. Gastroenterol. 2018; 34: 398-403Crossref PubMed Scopus (7) Google Scholar). Together, the data suggest that immune responses to intestinal fungi may influence intestinal inflammation in a subset of patients with IBD. Using a fungal ITS sequencing approach and a custom-curated database of fungal ITS sequences (Tang et al., 2015Tang J. Iliev I.D. Brown J. Underhill D.M. Funari V.A. Mycobiome: approaches to analysis of intestinal fungi.J. Immunol. Methods. 2015; 421: 112-121Crossref PubMed Scopus (108) Google Scholar), we have examined in depth the mucosa-associated intestinal mycobiota of healthy people and patients with CD. We found several mucosa-associated fungi that were significantly more abundant in CD patients, and we found that one of these, Malassezia restricta, was especially present in patients carrying the IBD CARD9 risk allele and that ASCA can recognize this yeast. Indeed, we found that the CARD9S12N variant caused human immune cells to more potently produce inflammatory cytokines in response to M. restricta. M. restricta is known as a common member of the skin microbiome, but a role for M. restricta in the gut has not been previously established. We found that M. restricta exacerbates colitis in mice, even in gnotobiotic mice in which M. restricta is the only fungus present and that it elicits its inflammatory responses via CARD9. To focus our mycobiota analysis on fungi that are associated with intestinal mucosal surfaces (as opposed to those found in fecal material), we obtained water-lavage samples from CD patients and healthy controls undergoing screening colonic endoscopy (McHardy et al., 2013McHardy I.H. Goudarzi M. Tong M. Ruegger P.M. Schwager E. Weger J.R. Graeber T.G. Sonnenburg J.L. Horvath S. Huttenhower C. et al.Integrative analysis of the microbiome and metabolome of the human intestinal mucosal surface reveals exquisite inter-relationships.Microbiome. 2013; 1: 17Crossref PubMed Scopus (192) Google Scholar). The patient preparation associated with endoscopy clears out fecal material, selectively leaving behind microbes capable of sticking firmly to the gut mucosa or otherwise evading the general flushing of the gut. We isolated and sequenced fungal ITS1 regions from 166 samples representing the sigmoid colon and cecum (Tables S1 and S2). Three samples were excluded from further analysis because of obtaining too few sequences for sufficiently deep analysis (Figure S1A). For the remaining samples, an average of ≈100,000 sequences per sample were assessed. Of these sequences, 77%–83% were identified by comparison to a custom-curated fungal ITS database, an approach designed to mitigate current challenges associated with inaccurate and non-specific data in public repositories (Figure S1B) (Tang et al., 2015Tang J. Iliev I.D. Brown J. Underhill D.M. Funari V.A. Mycobiome: approaches to analysis of intestinal fungi.J. Immunol. Methods. 2015; 421: 112-121Crossref PubMed Scopus (108) Google Scholar). For 28 patients, we had paired sigmoid and cecum samples collected at the same time. Analysis demonstrated that these samples are more closely related to each other than they were to the sites from which they were collected (Figure S1C), suggesting that heterogeneity between samples is a reliable measure of the source of the samples and not due to technical variations in sample handling. Overall, of the two major fungal phyla Ascomycota were substantially more common than Basidiomycota in all groups, consistent with previous studies surveying the human intestinal mycobiota (Figure S1D) (Chehoud et al., 2015Chehoud C. Albenberg L.G. Judge C. Hoffmann C. Grunberg S. Bittinger K. Baldassano R.N. Lewis J.D. Bushman F.D. Wu G.D. Fungal signature in the gut microbiota of pediatric patients with inflammatory bowel disease.Inflamm. Bowel Dis. 2015; 21: 1948-1956Crossref PubMed Scopus (157) Google Scholar, Hoarau et al., 2016Hoarau G. Mukherjee P.K. Gower-Rousseau C. Hager C. Chandra J. Retuerto M.A. Neut C. Vermeire S. Clemente J. Colombel J.F. et al.Bacteriome and mycobiome interactions underscore microbial dysbiosis in familial Crohn’s disease.MBio. 2016; 7: e01250-16Crossref PubMed Scopus (261) Google Scholar, Lewis et al., 2015Lewis J.D. Chen E.Z. Baldassano R.N. Otley A.R. Griffiths A.M. Lee D. Bittinger K. Bailey A. Friedman E.S. Hoffmann C. et al.Inflammation, antibiotics, and diet as environmental stressors of the gut microbiome in pediatric Crohn’s disease.Cell Host Microbe. 2015; 18: 489-500Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar, Liguori et al., 2016Liguori G. Lamas B. Richard M.L. Brandi G. da Costa G. Hoffmann T.W. Di Simone M.P. Calabrese C. Poggioli G. Langella P. et al.Fungal dysbiosis in Mucosa-associated microbiota of Crohn's disease patients.J. Crohns. Colitis. 2016; 10: 296-305Crossref PubMed Scopus (183) Google Scholar, Sokol et al., 2017Sokol H. Leducq V. Aschard H. Pham H.P. Jegou S. Landman C. Cohen D. Liguori G. Bourrier A. Nion-Larmurier I. et al.Fungal microbiota dysbiosis in IBD.Gut. 2017; 66: 1039-1048Crossref PubMed Scopus (670) Google Scholar). 70 genera of fungi were identified, with the most prevalent 8 genera accounting for more than 60% of the sequences (Figures 1A and 1B ; Table S3). Candida and Pichia were the most highly detected, although there was considerable heterogeneity, even among healthy control samples. While many samples were dominated by Candida, other groups of samples were dominated by Pichia or Fusarium. In healthy control samples (sigmoid or cecum), almost half were dominated by a single genus (48%/48%), while in the CD samples, this number fell to less than a quarter (15%/23%). To determine whether there are disease-associated alterations in fungi we applied the MaAsLin (Multivariate Association with Linear Models) method developed by Huttenhower and coworkers (Morgan et al., 2012Morgan X.C. Tickle T.L. Sokol H. Gevers D. Devaney K.L. Ward D.V. Reyes J.A. Shah S.A. LeLeiko N. Snapper S.B. et al.Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment.Genome Biol. 2012; 13: R79Crossref PubMed Scopus (1742) Google Scholar). This is a multivariate statistical framework specifically designed to be used to discover associations between clinical metadata (here being gender, age, diagnosis, and site) and microbial community abundance. Similar to a previous study, we observed that CD samples are associated with a significant loss of Ascomycota and an associated gain in Basidiomycota (Figure 1C) (Sokol et al., 2017Sokol H. Leducq V. Aschard H. Pham H.P. Jegou S. Landman C. Cohen D. Liguori G. Bourrier A. Nion-Larmurier I. et al.Fungal microbiota dysbiosis in IBD.Gut. 2017; 66: 1039-1048Crossref PubMed Scopus (670) Google Scholar). Specifically, we found that several fungal genera (Malassezia, Cladosporium, Aureobasidium, and Fusarium) stand out as associated with CD (Figure 1D; Table S4A). The first three are more common in samples taken from patients with CD and are rarely found in samples from healthy controls. Malassezia (identified as 65% M. restricta and 34% M. globosa) is responsible for the increase in basidiomycetes in CD patients. Fusarium, an ascomycete, is significantly reduced in CD patients. Other ascomycete fungi commonly of interest such as Candida and Pichia were not distributed unequally between samples from healthy controls and patients with CD (Figure S1E). CD is characterized by diverse clinical characteristics including the primary location of the disease. We observed that the CD-associated increases in detection of Malassezia and Cladosporium were mainly in patients with ileocolonic disease, while the decrease in Fusarium was mainly in patients with colonic disease (Figure 1E; Table S4B). The CD risk variant of CARD9 is a non-synonymous single nucleotide polymorphism (SNP) leading to a serine to asparagine change at codon 12 (S12N) that may alter the function of the protein (Xu et al., 2018Xu X. Xu J.F. Zheng G. Lu H.W. Duan J.L. Rui W. Guan J.H. Cheng L.Q. Yang D.D. Wang M.C. et al.CARD9S12N facilitates the production of IL-5 by alveolar macrophages for the induction of type 2 immune responses.Nat. Immunol. 2018; 19: 547-560Crossref PubMed Scopus (42) Google Scholar, Zhernakova et al., 2008Zhernakova A. Festen E.M. Franke L. Trynka G. van Diemen C.C. Monsuur A.J. Bevova M. Nijmeijer R.M. van 't Slot R. Heijmans R. et al.Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP.Am. J. Hum. Genet. 2008; 82: 1202-1210Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). We examined whether the CARD9 genotype was specifically linked to the presence of any fungi. Of the fungi we identified, Malassezia spp. was the most strongly linked to CARD9S12N (Figure 2A). This association is strikingly illustrated in samples from the sigmoid colon of all CD patients or selectively in CD patients with ileocolonic disease in which Malassezia spp. was increasingly present as the number of CARD9S12N alleles increased (AA; Figure 2B). In contrast, Pichia was nearly absent in patients homozygous for the CARD9S12N risk allele. As noted above, ASCA are common in CD patients, so we investigated whether patient sera with high ASCA reactivity also recognize Malassezia restricta, the primary species of Malassezia found associated with CD. We observed that ASCA-high patient sera are substantially more reactive against M. restricta than ASCA-low sera (Figure 2C). Together, the data support a link between CD, CARD9, and Malassezia. Malassezia restricta is a common fungus that is a natural commensal colonizer of the skin of many animals including humans (Findley et al., 2013Findley K. Oh J. Yang J. Conlan S. Deming C. Meyer J.A. Schoenfeld D. Nomicos E. Park M. NIH Intramural Sequencing Center Comparative Sequencing Program et al.Topographic diversity of fungal and bacterial communities in human skin.Nature. 2013; 498: 367-370Crossref PubMed Scopus (735) Google Scholar). It can grow aerobically as well as anaerobically and requires long chain fatty acids for growth (and is thus commonly associated with oilier regions of the skin). Diseases associated with Malassezia spp. range from benign (dandruff) to life-threatening sepsis (typically associated with indwelling catheters). To experimentally determine whether M. restricta might exacerbate colitis, we treated specific pathogen-free (SPF) mice by oral gavage with M. restricta and examined its effect on DSS-induced colitis (Figure S2A). Under these conditions, M. restricta levels were modestly elevated in feces compared to control mice (Figure S2B). Oral gavage with M. restricta by itself had no apparent adverse effects, but it exacerbated DSS-induced colitis as measured by a shortening of the colon (Figures 3A and 3B), a worsening of disease activity (Figure 3C), increased lipocalin-2 levels in the feces (Figure 3D), and more severe intestinal inflammation characterized by increased mucosal erosion, crypt destruction, and inflammatory cell infiltration in the colon (Figures 3E and 3F). Consistent with the histology, restimulation of colonic lamina propria T cells revealed stronger production of IL-17A- and IFN-γ-producing CD4+ cells, which correlated with higher numbers of inflammatory Th1 and Th17 cells (Figures 3G, 3H, and S2C). Further, we detected increased activated CD4+ T cells in the lamina propria and mesenteric lymph nodes (Figure S2D). The effects of M. restricta were consistently more pronounced than C. albicans, which had little effect in these experiments. S. cerevisiae has also been reported to exacerbate disease in mouse models of colitis (Chiaro et al., 2017Chiaro T.R. Soto R. Zac Stephens W. Kubinak J.L. Petersen C. Gogokhia L. Bell R. Delgado J.C. Cox J. Voth W. et al.A member of the gut mycobiota modulates host purine metabolism exacerbating colitis in mice.Sci. Transl. Med. 2017; 9: eaaf9044Crossref PubMed Scopus (120) Google Scholar), so we also compared the effects of M. restricta to S. cerevisiae. M. restricta promoted more severe disease compared to S. cerevisiae (Figure S3). Mechanistically, M. restricta might exacerbate disease directly, or its presence might alter other bacterial or fungal members of the microbiota to exacerbate disease. To better understand whether increased levels of M. restricta alone are sufficient to exacerbate colitis, we made use of germ-free mice colonized with altered Schaedler flora (ASF). Being colonized with a defined set of 8 bacteria, ASF mice are healthier than germ-free mice, have more mature immune systems, and are fungal-free (Figure 4A) (Wymore Brand et al., 2015Wymore Brand M. Wannemuehler M.J. Phillips G.J. Proctor A. Overstreet A.M. Jergens A.E. Orcutt R.P. Fox J.G. The altered Schaedler flora: continued applications of a defined murine microbial community.ILAR J. 2015; 56: 169-178Crossref PubMed Scopus (110) Google Scholar). Oral gavage with M. restricta makes M. restricta the only fungus present, and we found that this does not alter relative levels of any of the ASF bacteria (Figure 4B). As in SPF mice, M. restricta exacerbated DSS-induced colitis in ASF mice as measured by a shortening of the colon (Figures 4C and 4D), a worsening of disease activity (Figure 4E), increased lipocalin-2 levels in the feces (Figure 4F), and stronger production of IL-17A- and IFN-γ-producing lamina propria CD4+ cells (Figures 4G and 4H). To further investigate this, we evaluated the response to DSS-induced colitis in germ-free animals exposed to M. restricta. Like the ASF mice, disease was more severe when M. restricta was present (Figure S4). These data suggest that M. restricta is sufficient to directly exacerbate disease. Given the ability of M. restricta to exacerbate colitis in mice, we sought a better understanding of how it activates inflammatory immune responses compared to other common budding yeasts. Although M. restricta is substantially smaller than C. albicans or S. cerevisiae yeasts (Figure 5A), it evokes a stronger pro-inflammatory response per organism from human monocyte-derived dendritic cells (Figure 5B) and mouse bone-marrow-derived dendritic cells and macrophages (Figures 5C and 5D). M. restricta is also particularly potent at inducing expression of co-stimulatory molecules on mouse dendritic cells, (Figure 5E) and when co-cultured with naive T cells and anti-CD3ɛ antibodies, these cells induce proliferation and Th1/Th17 polarization more potently than C. albicans yeast (Figures 5F and 5G). Consistent with prior reports that Malassezia pachydermatis and Malassezia furfur are recognized by Dectin-2 and Mincle (Ishikawa et al., 2013Ishikawa T. Itoh F. Yoshida S. Saijo S. Matsuzawa T. Gonoi T. Saito T. Okawa Y. Shibata N. Miyamoto T. et al.Identification of distinct ligands for the C-type lectin receptors Mincle and Dectin-2 in the pathogenic fungus Malassezia.Cell Host Microbe. 2013; 13: 477-488Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, Yamasaki et al., 2009Yamasaki S. Matsumoto M. Takeuchi O. Matsuzawa T. Ishikawa E. Sakuma M. Tateno H. Uno J. Hirabayashi J. Mikami Y. et al.C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia.Proc. Natl. Acad. Sci. USA. 2009; 106: 1897-1902Crossref PubMed Scopus (329) Google Scholar), receptors that signal through CARD9 (Plato et al., 2015Plato A. Hardison S.E. Brown G.D. Pattern recognition receptors in antifungal immunity.Semin. Immunopathol. 2015; 37: 97-106Crossref PubMed Scopus (144) Google Scholar), the inflammatory response of mouse bone-marrow-derived dendritic cells and neutrophils to M. restricta was highly dependent on CARD9 (Figures 6A and 6B ). We further found that Dectin-2 was especially important for responses to M. restricta, while Dectin-1 and Mincle did not contribute significantly (Figure 6C). To investigate the consequences of the IBD-associated CARD9S12N polymorphism on host responses to M. restricta, we generated human peripheral blood monocyte-derived dendritic cells from healthy donors homozygous for the S (GG) or N (AA) alleles and stimulated them with fungi. AA dendritic cells produced signi" @default.
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