RESUMEN
How mis-regulated chromatin directly impacts human immune disorders is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing epigenetic "reader," and SP140 loss-of-function mutations associate with Crohn's disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). However, the relevance of these mutations and mechanisms underlying SP140-driven pathogenicity remains unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOPs) that maintains heterochromatin and macrophage fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, de-repression of developmentally silenced genes, and ultimately defective microbe-inducible macrophage transcriptional programs and bacterial killing that drive intestinal pathology. Pharmacological inhibition of TOP1/2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1/2 inhibitors in Sp140-/- mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a TOP repressor and reveal repurposing of TOP inhibition to reverse immune diseases driven by SP140 loss.
Asunto(s)
Enfermedad de Crohn , Animales , Humanos , Ratones , Antígenos Nucleares , Enfermedad de Crohn/genética , Enfermedad de Crohn/patología , Epigénesis Genética , Regulación de la Expresión Génica , Macrófagos/patología , Proteómica , Factores de TranscripciónRESUMEN
Ha and colleagues describe a previously unappreciated diversity of microbes in the mesenteric adipose tissue (MAT) surrounding the GI tract. Viable bacteria that are mislocalized from the gut microbiota and metabolically adapted to the MAT contribute to the "creeping fat" of Crohn's disease.
Asunto(s)
Enfermedad de Crohn , Microbioma Gastrointestinal , Adaptación Fisiológica , Tejido Adiposo , Humanos , MesenterioRESUMEN
A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.
Asunto(s)
Tejido Adiposo/microbiología , Traslocación Bacteriana , Microbioma Gastrointestinal , Mesenterio/microbiología , Tejido Adiposo/patología , Animales , Biodiversidad , Biomarcadores/metabolismo , Polaridad Celular , Células Cultivadas , Colitis Ulcerosa/patología , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/patología , Microbioma Gastrointestinal/genética , Regulación de la Expresión Génica , Vida Libre de Gérmenes , Humanos , Íleon/microbiología , Íleon/patología , Lipopolisacáridos/metabolismo , Macrófagos/metabolismo , Metagenoma , Metagenómica , Ratones , Ratones Endogámicos C57BL , Fenotipo , ARN Ribosómico 16S/genética , Células Madre/metabolismoRESUMEN
Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.
Asunto(s)
Enfermedad de Crohn/microbiología , Células Epiteliales/metabolismo , Microbioma Gastrointestinal , Antígenos de Histocompatibilidad Clase II/metabolismo , Intestino Delgado/inmunología , Intestino Delgado/microbiología , Transcriptoma/genética , Animales , Antibacterianos/farmacología , Relojes Circadianos/fisiología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Dieta , Células Epiteliales/citología , Células Epiteliales/inmunología , Citometría de Flujo , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Perfilación de la Expresión Génica , Antígenos de Histocompatibilidad Clase II/genética , Homeostasis , Hibridación Fluorescente in Situ , Interleucina-10/metabolismo , Interleucina-10/farmacología , Intestino Delgado/fisiología , Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Periodicidad , Linfocitos T/inmunología , Transcriptoma/fisiologíaRESUMEN
Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation landscape of the normal colon. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon, and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR, ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.
Asunto(s)
Evolución Clonal/genética , Colitis/genética , Enfermedades Inflamatorias del Intestino/genética , Tasa de Mutación , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Evolución Clonal/inmunología , Colitis/metabolismo , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/genética , Enfermedad de Crohn/metabolismo , Proteínas de Unión al ADN/genética , Células Epiteliales/metabolismo , Células Epiteliales/patología , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Femenino , Humanos , Mutación INDEL , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Interleucina-17/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Filogenia , Mutación Puntual , Receptores de Superficie Celular/genética , Ribonucleasas/genética , Receptores Toll-Like/genética , Factores de Transcripción/genética , Secuenciación Completa del GenomaRESUMEN
Clinical benefits of cytokine blockade in ileal Crohn's disease (iCD) are limited to a subset of patients. Here, we applied single-cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells, which we named the GIMATS module. Analysis of ligand-receptor interaction pairs identified a distinct network connectivity that likely drives the GIMATS module. Strikingly, the GIMATS module was also present in a subset of patients in four independent iCD cohorts (n = 441), and its presence at diagnosis correlated with failure to achieve durable corticosteroid-free remission upon anti-TNF therapy. These results emphasize the limitations of current diagnostic assays and the potential for single-cell mapping tools to identify novel biomarkers of treatment response and tailored therapeutic opportunities.
Asunto(s)
Enfermedad de Crohn/terapia , Citocinas/inmunología , Intestinos/patología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/patología , Humanos , Inmunoterapia/métodos , Fagocitos/patología , Análisis de la Célula Individual , Células del Estroma/patología , Linfocitos T/patologíaRESUMEN
Delineating ecologically meaningful populations among microbes is important for identifying their roles in environmental and host-associated microbiomes. Here, we introduce a metric of recent gene flow, which when applied to co-existing microbes, identifies congruent genetic and ecological units separated by strong gene flow discontinuities from their next of kin. We then develop a pipeline to identify genome regions within these units that show differential adaptation and allow mapping of populations onto environmental variables or host associations. Using this reverse ecology approach, we show that the human commensal bacterium Ruminococcus gnavus breaks up into sharply delineated populations that show different associations with health and disease. Defining populations by recent gene flow in this way will facilitate the analysis of bacterial and archaeal genomes using ecological and evolutionary theory developed for plants and animals, thus allowing for testing unifying principles across all biology.
Asunto(s)
Clostridiales/genética , Flujo Génico , Microbiota/genética , Adaptación Fisiológica/genética , Alelos , Colitis Ulcerosa/microbiología , Enfermedad de Crohn/microbiología , Transferencia de Gen Horizontal , Genoma Bacteriano , Humanos , Modelos Genéticos , Tasa de Mutación , Filogenia , Polimorfismo de Nucleótido Simple , Prochlorococcus/genética , Sulfolobus/genética , Vibrio/genéticaRESUMEN
The diversity of regulatory T (Treg) cells in health and in disease remains unclear. Individuals with colorectal cancer harbor a subpopulation of RORγt+ Treg cells with elevated expression of ß-catenin and pro-inflammatory properties. Here we show progressive expansion of RORγt+ Treg cells in individuals with inflammatory bowel disease during inflammation and early dysplasia. Activating Wnt-ß-catenin signaling in human and murine Treg cells was sufficient to recapitulate the disease-associated increase in the frequency of RORγt+ Treg cells coexpressing multiple pro-inflammatory cytokines. Binding of the ß-catenin interacting partner, TCF-1, to DNA overlapped with Foxp3 binding at enhancer sites of pro-inflammatory pathway genes. Sustained Wnt-ß-catenin activation induced newly accessible chromatin sites in these genes and upregulated their expression. These findings indicate that TCF-1 and Foxp3 together limit the expression of pro-inflammatory genes in Treg cells. Activation of ß-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.
Asunto(s)
Proliferación Celular , Reprogramación Celular , Colitis Ulcerosa/metabolismo , Neoplasias Asociadas a Colitis/metabolismo , Enfermedad de Crohn/metabolismo , Epigénesis Genética , Activación de Linfocitos , Linfocitos T Reguladores/metabolismo , Vía de Señalización Wnt , Animales , Estudios de Casos y Controles , Células Cultivadas , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Neoplasias Asociadas a Colitis/genética , Neoplasias Asociadas a Colitis/inmunología , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Humanos , Ratones Endogámicos C57BL , Ratones Transgénicos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Fenotipo , Factor 1 de Transcripción de Linfocitos T , Linfocitos T Reguladores/inmunologíaRESUMEN
Inflammatory bowel diseases (IBDs), e.g., Crohn's disease (CD) and ulcerative colitis (UC), are chronic immune-mediated inflammatory diseases. A comprehensive overview of an IBD-specific antibody epitope repertoire is, however, lacking. Using high-throughput phage-display immunoprecipitation sequencing (PhIP-Seq), we identified antibodies against 344,000 antimicrobial, immune, and food antigens in 497 individuals with IBD compared with 1,326 controls. IBD was characterized by 373 differentially abundant antibody responses (202 overrepresented and 171 underrepresented), with 17% shared by both IBDs, 55% unique to CD, and 28% unique to UC. Antibody reactivities against bacterial flagellins dominated in CD and were associated with ileal involvement, fibrostenotic disease, and anti-Saccharomyces cerevisiae antibody positivity, but not with fecal microbiome composition. Antibody epitope repertoires accurately discriminated CD from controls (area under the curve [AUC] = 0.89), and similar discrimination was achieved when using only ten antibodies (AUC = 0.87). Individuals with IBD thus show a distinct antibody repertoire against selected peptides, allowing clinical stratification and discovery of immunological targets.
Asunto(s)
Bacteriófagos , Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Anticuerpos , EpítoposRESUMEN
Fungi are consistently enriched in inflamed intestines, with elusive effects on host immunity. In a recent issue of Nature Medicine, Martini et al. identify a subset of Th1 cells able to lyse the epithelium, enriched in Crohn's disease patient samples after fungal exposure.
Asunto(s)
Agaricales , Enfermedad de Crohn , Humanos , Células TH1 , Intestinos/microbiologíaRESUMEN
Crohn's disease (CD) is a chronic gastrointestinal disease that is increasing in prevalence worldwide. CD is multifactorial, involving the complex interplay of genetic, immune, and environmental factors, necessitating a system-level understanding of its etiology. To characterize cell-type-specific transcriptional heterogeneity in active CD, we profiled 720,633 cells from the terminal ileum and colon of 71 donors with varying inflammation status. Our integrated datasets revealed organ- and compartment-specific responses to acute and chronic inflammation; most immune changes were in cell composition, whereas transcriptional changes dominated among epithelial and stromal cells. These changes correlated with endoscopic inflammation, but small and large intestines exhibited distinct responses, which were particularly apparent when focusing on IBD risk genes. Finally, we mapped markers of disease-associated myofibroblast activation and identified CHMP1A, TBX3, and RNF168 as regulators of fibrotic complications. Altogether, our results provide a roadmap for understanding cell-type- and organ-specific differences in CD and potential directions for therapeutic development.
Asunto(s)
Enfermedad de Crohn , Humanos , Transcriptoma , Colon , Íleon , Inflamación/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis are characterized by uncontrolled activation of intestinal immune cells in a genetically susceptible host. Due to the progressive and destructive nature of the inflammatory process in IBD, complications such as fibrosis, stenosis or cancer are frequently observed, which highlights the need for effective anti-inflammatory therapy. Studies have identified altered trafficking of immune cells and pathogenic immune cell circuits as crucial drivers of mucosal inflammation and tissue destruction in IBD. A defective gut barrier and microbial dysbiosis induce such accumulation and local activation of immune cells, which results in a pro-inflammatory cytokine loop that overrides anti-inflammatory signals and causes chronic intestinal inflammation. This Review discusses pathogenic cytokine responses of immune cells as well as immune cell trafficking as a rational basis for new translational therapies in IBD.
Asunto(s)
Colitis Ulcerosa/inmunología , Enfermedad de Crohn/inmunología , Citocinas/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Animales , Movimiento Celular/inmunología , Colitis Ulcerosa/terapia , Enfermedad de Crohn/terapia , Disbiosis , Humanos , Inflamación/patología , Mucosa Intestinal/citología , Activación de Linfocitos/inmunología , Ratones , Linfocitos T/inmunologíaRESUMEN
Reciprocal interactions between host T helper cells and gut microbiota enforce local immunological tolerance and modulate extra-intestinal immunity. However, our understanding of antigen-specific tolerance to the microbiome is limited. Here, we developed a systematic approach to predict HLA class-II-specific epitopes using the humanized bacteria-originated T cell antigen (hBOTA) algorithm. We identified a diverse set of microbiome epitopes spanning all major taxa that are compatible with presentation by multiple HLA-II alleles. In particular, we uncovered an immunodominant epitope from the TonB-dependent receptor SusC that was universally recognized and ubiquitous among Bacteroidales. In healthy human subjects, SusC-reactive T cell responses were characterized by IL-10-dominant cytokine profiles, whereas in patients with active Crohn's disease, responses were associated with elevated IL-17A. Our results highlight the potential of targeted antigen discovery within the microbiome to reveal principles of tolerance and functional transitions during inflammation.
Asunto(s)
Enfermedad de Crohn , Epítopos Inmunodominantes , Linfocitos T CD4-Positivos , Epítopos de Linfocito T , Humanos , Interleucina-10 , Interleucina-17RESUMEN
Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161+ regulatory T (Treg) cells as a distinct, highly suppressive population of Treg cells that mediate wound healing. These Treg cells were enriched in intestinal lamina propria, particularly in Crohn's disease. CD161+ Treg cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on Treg cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORγt, FOSL2, AP-1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161+ Treg cell signature in Crohn's disease mucosa associated with reduced inflammation. These findings identify CD161+ Treg cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut.
Asunto(s)
Mucosa Intestinal/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Tretinoina/inmunología , Cicatrización de Heridas/inmunología , Enfermedad de Crohn/inmunología , HumanosRESUMEN
Defective autophagy is linked to diseases such as rheumatoid arthritis, lupus and inflammatory bowel disease (IBD). However, the mechanisms by which autophagy limits inflammation remain poorly understood. Here we found that loss of the autophagy-related gene Atg16l1 promoted accumulation of the adaptor TRIF and downstream signaling in macrophages. Multiplex proteomic profiling identified SQSTM1 and Tax1BP1 as selective autophagy-related receptors that mediated the turnover of TRIF. Knockdown of Tax1bp1 increased production of the cytokines IFN-ß and IL-1ß. Mice lacking Atg16l1 in myeloid cells succumbed to lipopolysaccharide-mediated sepsis but enhanced their clearance of intestinal Salmonella typhimurium in an interferon receptor-dependent manner. Human macrophages with the Crohn's disease-associated Atg16l1 variant T300A exhibited more production of IFN-ß and IL-1ß. An elevated interferon-response gene signature was observed in patients with IBD who were resistant to treatment with an antibody to the cytokine TNF. These findings identify selective autophagy as a key regulator of signaling via the innate immune system.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/inmunología , Autofagia/inmunología , Inmunidad Innata/inmunología , Inflamación/inmunología , Animales , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/inmunología , Enfermedad de Crohn/inmunología , Femenino , Humanos , Macrófagos/inmunología , Masculino , Ratones , Ratones Transgénicos , Transducción de Señal/inmunologíaRESUMEN
Intestinal microbiome perturbation characterizes Crohn's disease (CD), though specific contributors to pathophysiology remain elusive. In a recent issue of Science, Jain et al. show that Debaryomyces hansenii impairs intestinal healing in mice via effects on type I interferon signaling and chemokine CCL5 expression in macrophages and that it is also prevalent in the inflamed mucosa of CD patients.
Asunto(s)
Enfermedad de Crohn/inmunología , Enfermedad de Crohn/microbiología , Mucosa Intestinal/microbiología , Cicatrización de Heridas/inmunología , Animales , Quimiocina CCL5/inmunología , Microbioma Gastrointestinal/inmunología , Humanos , Interferón Tipo I/inmunología , Mucosa Intestinal/inmunología , Macrófagos/inmunología , Ratones , Micosis/inmunología , Micosis/microbiología , Saccharomycetales/inmunología , Transducción de Señal/inmunologíaRESUMEN
Inflammatory bowel disease (IBD) mainly includes Crohn's disease (CD) and ulcerative colitis (UC). Immune disorders play an essential role in the pathogenesis of these two IBDs, but the differences in the immune microenvironment of the colon and their underlying mechanisms remain poorly investigated. Here we examined the immunological features and metabolic microenvironment of untreated individuals with IBD by multiomics analyses. Modulation of CD-specific metabolites, particularly reduced selenium, can obviously shape type 1 T helper (Th1) cell differentiation, which is specifically enriched in CD. Selenium supplementation suppressed the symptoms and onset of CD and Th1 cell differentiation via selenoprotein W (SELW)-mediated cellular reactive oxygen species scavenging. SELW promoted purine salvage pathways and inhibited one-carbon metabolism by recruiting an E3 ubiquitin ligase, tripartite motif-containing protein 21, which controlled the stability of serine hydroxymethyltransferase 2. Our work highlights selenium as an essential regulator of T cell responses and potential therapeutic targets in CD.
Asunto(s)
Antioxidantes/farmacología , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/inmunología , Selenio/farmacología , Selenoproteína W/metabolismo , Células TH1/citología , Diferenciación Celular/inmunología , Polaridad Celular , Colon/inmunología , Colon/patología , Glicina Hidroximetiltransferasa/metabolismo , Humanos , Especies Reactivas de Oxígeno/metabolismo , Ribonucleoproteínas/metabolismo , Células TH1/inmunología , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNFΔARE mice, a model of ileitis, revealed TLO formation at valves of CLVs. TLOs obstructed cellular and molecular outflow from the gut and were sites of lymph leakage and backflow. Tumor necrosis factor (TNF) neutralization begun at early stages of TLO formation restored lymph transport. However, robustly developed, chronic TLOs resisted regression and restoration of flow after TNF neutralization. TNF stimulation of cultured lymphatic endothelial cells reprogrammed responses to oscillatory shear stress, preventing the induction of valve-associated genes. Disrupted transport of immune cells, driven by loss of valve integrity and TLO formation, may contribute to the pathology of Crohn's disease.
Asunto(s)
Enfermedad de Crohn/inmunología , Células Endoteliales/inmunología , Íleon/inmunología , Linfa/metabolismo , Vasos Linfáticos/inmunología , Mesenterio/inmunología , Estructuras Linfoides Terciarias/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Movimiento Celular , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Ileítis , Linfangitis , Ratones , Ratones Noqueados , Estrés MecánicoRESUMEN
Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn's disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease and cohort specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.
Asunto(s)
Caudovirales/aislamiento & purificación , Colitis Ulcerosa/virología , Enfermedad de Crohn/virología , Disbiosis/virología , Microviridae/aislamiento & purificación , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Estudios de Casos y Controles , Caudovirales/genética , Estudios de Cohortes , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/patología , Colitis Ulcerosa/terapia , Enfermedad de Crohn/microbiología , Enfermedad de Crohn/patología , Enfermedad de Crohn/terapia , Disbiosis/microbiología , Disbiosis/patología , Disbiosis/terapia , Heces/microbiología , Heces/virología , Humanos , Metagenoma , Microviridae/genéticaRESUMEN
Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.