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Microbiota-induced IL-17 production mediates CNS processes and animal behavior. However, its role on the peripheral nervous system (PNS) remains largely unknown. Enamorado et al. demonstrate that commensal-specific Th17 cells are recalled following tissue injury to support local nerve regeneration, a process orchestrated by IL-17 signaling on peripheral neurons.
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Sistema Nervoso Central , Interleucina-17 , Animais , Sistema Nervoso Periférico , Regeneração Nervosa/fisiologia , Transdução de Sinais , Nervos Periféricos , Axônios/fisiologiaRESUMO
Fungal microorganisms (mycobiota) comprise a small but immunoreactive component of the human microbiome, yet little is known about their role in human cancers. Pan-cancer analysis of multiple body sites revealed tumor-associated mycobiomes at up to 1 fungal cell per 104 tumor cells. In lung cancer, Blastomyces was associated with tumor tissues. In stomach cancers, high rates of Candida were linked to the expression of pro-inflammatory immune pathways, while in colon cancers Candida was predictive of metastatic disease and attenuated cellular adhesions. Across multiple GI sites, several Candida species were enriched in tumor samples and tumor-associated Candida DNA was predictive of decreased survival. The presence of Candida in human GI tumors was confirmed by external ITS sequencing of tumor samples and by culture-dependent analysis in an independent cohort. These data implicate the mycobiota in the pathogenesis of GI cancers and suggest that tumor-associated fungal DNA may serve as diagnostic or prognostic biomarkers.
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Neoplasias Pulmonares , Micobioma , Biomarcadores , Candida/genética , DNA Fúngico , Fungos/genética , HumanosRESUMO
Fungal communities (the mycobiota) are an integral part of the gut microbiota, and the disruption of their integrity contributes to local and gut-distal pathologies. Yet, the mechanisms by which intestinal fungi promote homeostasis remain unclear. We characterized the mycobiota biogeography along the gastrointestinal tract and identified a subset of fungi associated with the intestinal mucosa of mice and humans. Mucosa-associated fungi (MAF) reinforced intestinal epithelial function and protected mice against intestinal injury and bacterial infection. Notably, intestinal colonization with a defined consortium of MAF promoted social behavior in mice. The gut-local effects on barrier function were dependent on IL-22 production by CD4+ T helper cells, whereas the effects on social behavior were mediated through IL-17R-dependent signaling in neurons. Thus, the spatial organization of the gut mycobiota is associated with host-protective immunity and epithelial barrier function and might be a driver of the neuroimmune modulation of mouse behavior through complementary Type 17 immune mechanisms.
Assuntos
Microbioma Gastrointestinal , Micobioma , Receptores de Interleucina-17/metabolismo , Comportamento Social , Animais , Fungos , Imunidade nas Mucosas , Mucosa Intestinal , Camundongos , MucosaRESUMO
Antibodies mediate natural and vaccine-induced immunity against viral and bacterial pathogens, whereas fungi represent a widespread kingdom of pathogenic species for which neither vaccine nor neutralizing antibody therapies are clinically available. Here, using a multi-kingdom antibody profiling (multiKAP) approach, we explore the human antibody repertoires against gut commensal fungi (mycobiota). We identify species preferentially targeted by systemic antibodies in humans, with Candida albicans being the major inducer of antifungal immunoglobulin G (IgG). Fungal colonization of the gut induces germinal center (GC)-dependent B cell expansion in extraintestinal lymphoid tissues and generates systemic antibodies that confer protection against disseminated C. albicans or C. auris infection. Antifungal IgG production depends on the innate immunity regulator CARD9 and CARD9+CX3CR1+ macrophages. In individuals with invasive candidiasis, loss-of-function mutations in CARD9 are associated with impaired antifungal IgG responses. These results reveal an important role of gut commensal fungi in shaping the human antibody repertoire through CARD9-dependent induction of host-protective antifungal IgG.
Assuntos
Anticorpos Antifúngicos/imunologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Imunidade , Imunoglobulina G/imunologia , Micobioma/imunologia , Animais , Linfócitos B/imunologia , Candida albicans/imunologia , Candidíase/imunologia , Candidíase/microbiologia , Fezes/microbiologia , Centro Germinativo/imunologia , Humanos , Camundongos Endogâmicos C57BL , Fagócitos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica , Transdução de SinaisRESUMO
Gastrointestinal fungal dysbiosis is a hallmark of several diseases marked by systemic immune activation. Whether persistent pathobiont colonization during immune alterations and impaired gut barrier function has a durable impact on host immunity is unknown. We found that elevated levels of Candida albicans immunoglobulin G (IgG) antibodies marked patients with severe COVID-19 (sCOVID-19) who had intestinal Candida overgrowth, mycobiota dysbiosis and systemic neutrophilia. Analysis of hematopoietic stem cell progenitors in sCOVID-19 revealed transcriptional changes in antifungal immunity pathways and reprogramming of granulocyte myeloid progenitors (GMPs) for up to a year. Mice colonized with C. albicans patient isolates experienced increased lung neutrophilia and pulmonary NETosis during severe acute respiratory syndrome coronavirus-2 infection, which were partially resolved with antifungal treatment or by interleukin-6 receptor blockade. sCOVID-19 patients treated with tocilizumab experienced sustained reductions in C. albicans IgG antibodies titers and GMP transcriptional changes. These findings suggest that gut fungal pathobionts may contribute to immune activation during inflammatory diseases, offering potential mycobiota-immune therapeutic strategies for sCOVID-19 with prolonged symptoms.
Assuntos
COVID-19 , Micobioma , Humanos , Animais , Camundongos , Antifúngicos , Disbiose , Neutrófilos , Candida albicans , Imunoglobulina GRESUMO
The colon is primarily responsible for absorbing fluids. It contains a large number of microorganisms including fungi, which are enriched in its distal segment. The colonic mucosa must therefore tightly regulate fluid influx to control absorption of fungal metabolites, which can be toxic to epithelial cells and lead to barrier dysfunction. How this is achieved remains unknown. Here, we describe a mechanism by which the innate immune system allows rapid quality check of absorbed fluids to avoid intoxication of colonocytes. This mechanism relies on a population of distal colon macrophages that are equipped with "balloon-like" protrusions (BLPs) inserted in the epithelium, which sample absorbed fluids. In the absence of macrophages or BLPs, epithelial cells keep absorbing fluids containing fungal products, leading to their death and subsequent loss of epithelial barrier integrity. These results reveal an unexpected and essential role of macrophages in the maintenance of colon-microbiota interactions in homeostasis. VIDEO ABSTRACT.
Assuntos
Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/metabolismo , Macrófagos/metabolismo , Animais , Colo/metabolismo , Células Epiteliais/metabolismo , Epitélio , Feminino , Homeostase , Imunidade Inata/imunologia , Mucosa Intestinal/microbiologia , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microbiota , Transdução de SinaisRESUMO
Regulation of neutrophil activation is critical for disease control. Neutrophil extracellular traps (NETs), which are web-like structures composed of DNA and neutrophil-derived proteins, are formed following pro-inflammatory signals; however, if this process is uncontrolled, NETs contribute to disease pathogenesis, exacerbating inflammation and host tissue damage1,2. Here we show that myeloid inhibitory C-type lectin-like (MICL), an inhibitory C-type lectin receptor, directly recognizes DNA in NETs; this interaction is vital to regulate neutrophil activation. Loss or inhibition of MICL functionality leads to uncontrolled NET formation through the ROS-PAD4 pathway and the development of an auto-inflammatory feedback loop. We show that in the context of rheumatoid arthritis, such dysregulation leads to exacerbated pathology in both mouse models and in human patients, where autoantibodies to MICL inhibit key functions of this receptor. Of note, we also detect similarly inhibitory anti-MICL autoantibodies in patients with other diseases linked to aberrant NET formation, including lupus and severe COVID-19. By contrast, dysregulation of NET release is protective during systemic infection with the fungal pathogen Aspergillus fumigatus. Together, we show that the recognition of NETs by MICL represents a fundamental autoregulatory pathway that controls neutrophil activity and NET formation.
RESUMO
The study of the intestinal microbiota has begun to shift from cataloging individual members of the commensal community to understanding their contributions to the physiology of the host organism in health and disease. Here, we review the effects of the microbiome on innate and adaptive immunological players from epithelial cells and antigen-presenting cells to innate lymphoid cells and regulatory T cells. We discuss recent studies that have identified diverse microbiota-derived bioactive molecules and their effects on inflammation within the intestine and distally at sites as anatomically remote as the brain. Finally, we highlight new insights into how the microbiome influences the host response to infection, vaccination and cancer, as well as susceptibility to autoimmune and neurodegenerative disorders.
Assuntos
Microbioma Gastrointestinal/imunologia , Infecções/imunologia , Inflamação/imunologia , Neoplasias/imunologia , Imunidade Adaptativa/imunologia , Células Apresentadoras de Antígenos/imunologia , Doenças Autoimunes/imunologia , Humanos , Imunidade Inata/imunologia , Imunidade nas Mucosas/imunologia , Linfócitos/imunologia , Doenças Neurodegenerativas/imunologia , Simbiose , Linfócitos T Reguladores/imunologia , VacinaçãoRESUMO
The mammalian intestine is colonized by a wealth of microorganisms-including bacteria, viruses, protozoa, and fungi-that are all integrated into a functional trans-kingdom community. Characterization of the composition of the fungal community-the mycobiota-has advanced further than the much-needed mechanistic studies. Recent findings have revealed roles for the gut mycobiota in the regulation of host immunity and in the development and progression of human diseases of inflammatory origin. We review these findings here while placing them in the context of the current understanding of the pathways and cellular networks that induce local and systemic immune responses to fungi in the gastrointestinal tract. We discuss gaps in knowledge and argue for the importance of considering bacteria-fungal interactions as we aim to define the roles of mycobiota in immune homeostasis and immune-associated pathologies.
Assuntos
Suscetibilidade a Doenças , Gastroenterite/etiologia , Microbioma Gastrointestinal/imunologia , Imunidade , Imunidade Adaptativa , Animais , Suscetibilidade a Doenças/imunologia , Gastroenterite/metabolismo , Homeostase , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade InataRESUMO
The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation1-6. Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease3-9, it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR-Cas9-based fungal strain editing system, in vitro functional immunoreactivity assays and in vivo models, this platform enables the examination of host-fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1ß-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (TH17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans-secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host-fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin.
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Fungos , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Microbiota , Micobioma , Animais , Sistemas CRISPR-Cas , Candida albicans , Fungos/genética , Fungos/patogenicidade , Variação Genética , Humanos , Imunidade , Inflamação , MamíferosRESUMO
Diverse innate lymphoid cell (ILC) subtypes have been defined on the basis of effector function and transcription factor expression. ILCs derive from common lymphoid progenitors, although the transcriptional pathways that lead to ILC-lineage specification remain poorly characterized. Here we found that the transcriptional regulator TOX was required for the in vivo differentiation of common lymphoid progenitors into ILC lineage-restricted cells. In vitro modeling demonstrated that TOX deficiency resulted in early defects in the survival or proliferation of progenitor cells, as well as ILC differentiation at a later stage. In addition, comparative transcriptome analysis of bone marrow progenitors revealed that TOX-deficient cells failed to upregulate many genes of the ILC program, including genes that are targets of Notch, which indicated that TOX is a key determinant of early specification to the ILC lineage.
Assuntos
Proteínas de Homeodomínio/metabolismo , Células Matadoras Naturais/fisiologia , Subpopulações de Linfócitos/fisiologia , Células Progenitoras Linfoides/fisiologia , Receptores Notch/metabolismo , Animais , Células da Medula Óssea/fisiologia , Diferenciação Celular/genética , Linhagem da Célula/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Feminino , Proteínas de Homeodomínio/genética , Imunidade Inata/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores Notch/genética , TranscriptomaRESUMO
The dynamic and complex community of microbes that colonizes the intestines is composed of bacteria, fungi, and viruses. At the mucosal surfaces, immunoglobulins play a key role in protection against bacterial and fungal pathogens, and their toxins. Secretory immunoglobulin A (sIgA) is the most abundantly produced antibody at the mucosal surfaces, while Immunoglobulin G (IgG) isotypes play a critical role in systemic protection. IgA and IgG antibodies with reactivity to commensal fungi play an important role in shaping the mycobiota and host antifungal immunity. In this article, we review the latest evidence that establishes a connection between commensal fungi and B cell-mediated antifungal immunity as an additional layer of protection against fungal infections and inflammation.
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Antifúngicos , Imunoglobulina A Secretora , Humanos , Imunoglobulina G , Bactérias , Imunidade nas Mucosas , ImunoglobulinasRESUMO
The intestinal microbiota comprises diverse fungal and viral components, in addition to bacteria. These microbes interact with the immune system and affect human physiology. Advances in metagenomics have associated inflammatory and autoimmune diseases with alterations in fungal and viral species in the gut. Studies of animal models have found that commensal fungi and viruses can activate host-protective immune pathways related to epithelial barrier integrity, but can also induce reactions that contribute to events associated with inflammatory bowel disease. Changes in our environment associated with modernization and the COVID-19 pandemic have exposed humans to new fungi and viruses, with unknown consequences. We review the lessons learned from studies of animal viruses and fungi commonly detected in the human gut and how these might affect health and intestinal disease.
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Microbioma Gastrointestinal/fisiologia , Imunidade/imunologia , Doenças Inflamatórias Intestinais/etiologia , Micobioma/fisiologia , Viroma/fisiologia , Animais , COVID-19/complicações , Transplante de Microbiota Fecal , Humanos , Lectinas Tipo C/fisiologia , SARS-CoV-2 , Células Th1/imunologiaRESUMO
The human gastrointestinal tract is home to a vibrant, diverse ecosystem of prokaryotic and eukaryotic microorganisms. The gut fungi (mycobiota) have recently risen to prominence due to their ability to modulate host immunity. Colonization of the gut occurs through a combination of vertical transmission from the maternal mycobiota and environmental and dietary exposure. Data from human and animal studies demonstrate that nutrition strongly affects the mycobiota composition and that changes in the fungal communities can aggravate metabolic diseases. The mechanisms pertaining to the mycobiota's influence on host health, pathology, and resident gastrointestinal communities through intrakingdom, transkingdom, and immune cross talk are beginning to come into focus, setting the stage for a new chapter in microbiota-host interactions. Herein, we examine the inception, maturation, and dietary modulation of gastrointestinal and nutritional fungal communities and inspect their impact on metabolic diseases in humans.
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Fungos/fisiologia , Microbioma Gastrointestinal/fisiologia , Estado Nutricional , Interações entre Hospedeiro e Microrganismos , HumanosRESUMO
Gut mycobiota dysbiosis can negatively impact the outcome of several diseases of inflammatory origin, suggesting a role of the mycobiota in influencing the host immunity. However, it is unknown whether the gut mycobiota composition can create an immune environment that would influence the immune response to a newly introduced intestinal fungus. Using ITS1 deep sequencing, we evaluated the mycobiome structure of C57BL/6J mice acquired from Jackson (JAX) or bred in a controlled environment at a dedicated room in our own mouse facility (WCM-CE) for several generations. We found that C57BL/6J mice from these segregated mouse colonies harbor dramatically different mycobiota. To assess whether the mycobiota make up can influence immune responses to colonization with a fungus foreign to the murine GI tract, we colonized JAX and WCM-CE mice with the human commensal C. albicans and measured Th17 responses in the gut. We found that independent of mycobiota composition, mice produced strong Th17 responses to gastrointestinal C. albicans colonization. Our data suggest that different mouse colonies can carry dramatically different mycobiota. Nevertheless, strong Th17 responses to a newly introduced opportunistic commensal fungus are potently induced independent of the mycobiota background in this experimental setting.
Assuntos
Fungos/classificação , Trato Gastrointestinal/microbiologia , Micobioma , Simbiose , Células Th17/imunologia , Animais , DNA Intergênico/genética , DNA Ribossômico/genética , Fungos/fisiologia , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Patógeno , Camundongos , Camundongos Endogâmicos C57BLRESUMO
PURPOSE OF REVIEW: In this review, we discuss recent advances into delineating the dual role of intestinal phagocytes in health and during intestinal disease. We further discuss the key role of gut-resident macrophages in recognition of bacterial and fungal microbiota in the gut. RECENT FINDINGS: Inflammatory bowel disease (IBD) commonly manifests with pathologic changes in the composition of gut bacterial and fungal microbiota. Intestinal macrophages are key regulators of the balance between tolerogenic immunity and inflammation. Recent studies have highlighted the role of resident intestinal macrophages in the control of commensal fungi and bacteria in the steady state and during dysbiosis. The dual role of these cells in maintaining intestinal homeostasis and responding to microbiota dysbiosis during inflammation is being increasingly studied. SUMMARY: It is becoming increasingly clear that an aberrant proinflammatory response to microbiota by infiltrating monocytes plays a role in the development of intestinal inflammation. Intestinal mononuclear phagocytes with characteristics of macrophages play an important role in limiting fungal and bacterial overgrowth under these conditions, but can be influenced by the inflammatory environment to further propel inflammation. Better understanding of the interaction of intestinal macrophages with host microbiota including commensal fungi and bacteria, provides an opportunity for the development of more targeted therapies for IBD.
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Bactérias/imunologia , Fungos/imunologia , Microbioma Gastrointestinal/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Macrófagos/imunologia , Disbiose/imunologia , Disbiose/microbiologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Doenças Inflamatórias Intestinais/imunologiaRESUMO
The intestine and liver are thought to metabolize dietary nutrients and regulate host nutrient homeostasis. Here, we find that the gut microbiota also reshapes the host amino acid (aa) landscape via efficiently metabolizing intestinal aa. To identify the responsible microbes/genes, we developed a metabolomics-based assay to screen 104 commensals and identified candidates that efficiently utilize aa. Using genetics, we identified multiple responsible metabolic genes in phylogenetically diverse microbes. By colonizing germ-free mice with the wild-type strain and their isogenic mutant deficient in individual aa-metabolizing genes, we found that these genes regulate the availability of gut and circulatory aa. Notably, microbiota genes for branched-chain amino acids (BCAAs) and tryptophan metabolism indirectly affect host glucose homeostasis via peripheral serotonin. Collectively, at single-gene level, this work characterizes a microbiota-encoded metabolic activity that affects host nutrient homeostasis and provides a roadmap to interrogate microbiota-dependent activity to improve human health.
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Aminoácidos de Cadeia Ramificada , Aminoácidos , Microbioma Gastrointestinal , Homeostase , Triptofano , Animais , Microbioma Gastrointestinal/fisiologia , Camundongos , Aminoácidos/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Triptofano/metabolismo , Camundongos Endogâmicos C57BL , Nutrientes/metabolismo , Intestinos/microbiologia , Humanos , Metabolômica , Glucose/metabolismo , Serotonina/metabolismo , Vida Livre de Germes , Bactérias/metabolismo , Bactérias/genética , Bactérias/classificação , MasculinoRESUMO
Recent work suggests that dendritic cells (DCs) in mucosal tissues are "educated" by intestinal epithelial cells (IECs) to suppress inflammation and promote immunological tolerance. After attack by pathogenic microorganisms, however, "non-educated" DCs are recruited from nearby areas, such as the dome of Peyer's patches (PPs) and the blood, to initiate inflammation and the ensuing immune response to the invader. Differential epithelial cell (EC) responses to commensals and pathogens may control these two tolorogenic and immunogenic functions of DCs.
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Células Dendríticas/imunologia , Células Epiteliais/imunologia , Intestinos/imunologia , Yin-Yang , Animais , Humanos , Inflamação/imunologia , Inflamação/patologia , Intestinos/patologiaRESUMO
Specialized epithelium secretes an antifungal peptide.