RESUMO
The intestinal microbiota plays a crucial role in influencing the development of host immunity, and in turn the immune system also acts to regulate the microbiota through intestinal barrier maintenance and immune exclusion. Normally, these interactions are homeostatic, tightly controlled, and organized by both innate and adaptive immune responses. However, a combination of environmental exposures and genetic defects can result in a break in tolerance and intestinal homeostasis. The outcomes of these interactions at the mucosal interface have broad, systemic effects on host immunity and the development of chronic inflammatory or autoimmune disease. The underlying mechanisms and pathways the microbiota can utilize to regulate these diseases are just starting to emerge. Here, we discuss the recent evidence in this area describing the impact of microbiota-immune interactions during inflammation and autoimmunity, with a focus on barrier function and CD4+ T cell regulation.
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Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/microbiologia , Microbioma Gastrointestinal/imunologia , Inflamação/microbiologia , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/microbiologia , Animais , Autoimunidade , Diabetes Mellitus Tipo 1/imunologia , Homeostase , Humanos , Tolerância Imunológica , Imunomodulação , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologiaRESUMO
Accumulating evidence suggests that cardiovascular disease (CVD) is associated with an altered gut microbiome. Our understanding of the underlying mechanisms has been hindered by lack of matched multi-omic data with diagnostic biomarkers. To comprehensively profile gut microbiome contributions to CVD, we generated stool metagenomics and metabolomics from 1,429 Framingham Heart Study participants. We identified blood lipids and cardiovascular health measurements associated with microbiome and metabolome composition. Integrated analysis revealed microbial pathways implicated in CVD, including flavonoid, γ-butyrobetaine, and cholesterol metabolism. Species from the Oscillibacter genus were associated with decreased fecal and plasma cholesterol levels. Using functional prediction and in vitro characterization of multiple representative human gut Oscillibacter isolates, we uncovered conserved cholesterol-metabolizing capabilities, including glycosylation and dehydrogenation. These findings suggest that cholesterol metabolism is a broad property of phylogenetically diverse Oscillibacter spp., with potential benefits for lipid homeostasis and cardiovascular health.
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Bactérias , Doenças Cardiovasculares , Colesterol , Microbioma Gastrointestinal , Humanos , Bactérias/metabolismo , Doenças Cardiovasculares/metabolismo , Colesterol/análise , Colesterol/sangue , Colesterol/metabolismo , Fezes/química , Estudos Longitudinais , Metaboloma , Metabolômica , RNA Ribossômico 16S/metabolismoRESUMO
Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.
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Anticorpos Neutralizantes/imunologia , Linfócitos B/metabolismo , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/química , Anticorpos Antivirais/sangue , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Complexo Antígeno-Anticorpo/química , Complexo Antígeno-Anticorpo/metabolismo , Reações Antígeno-Anticorpo , Linfócitos B/citologia , Linfócitos B/virologia , COVID-19/patologia , COVID-19/virologia , Microscopia Crioeletrônica , Cristalografia por Raios X , Perfilação da Expressão Gênica , Humanos , Imunoglobulina A/imunologia , Região Variável de Imunoglobulina/química , Região Variável de Imunoglobulina/genética , Domínios Proteicos/imunologia , Multimerização Proteica , Estrutura Quaternária de Proteína , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Análise de Sequência de RNA , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
CD4+ T cell responses are exquisitely antigen specific and directed toward peptide epitopes displayed by human leukocyte antigen class II (HLA-II) on antigen-presenting cells. Underrepresentation of diverse alleles in ligand databases and an incomplete understanding of factors affecting antigen presentation in vivo have limited progress in defining principles of peptide immunogenicity. Here, we employed monoallelic immunopeptidomics to identify 358,024 HLA-II binders, with a particular focus on HLA-DQ and HLA-DP. We uncovered peptide-binding patterns across a spectrum of binding affinities and enrichment of structural antigen features. These aspects underpinned the development of context-aware predictor of T cell antigens (CAPTAn), a deep learning model that predicts peptide antigens based on their affinity to HLA-II and full sequence of their source proteins. CAPTAn was instrumental in discovering prevalent T cell epitopes from bacteria in the human microbiome and a pan-variant epitope from SARS-CoV-2. Together CAPTAn and associated datasets present a resource for antigen discovery and the unraveling genetic associations of HLA alleles with immunopathologies.
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COVID-19 , Aprendizado Profundo , Humanos , Captana , SARS-CoV-2 , Antígenos HLA , Epitopos de Linfócito T , PeptídeosRESUMO
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.
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Doença de Crohn , Epitopos Imunodominantes , Linfócitos T CD4-Positivos , Epitopos de Linfócito T , Humanos , Interleucina-10 , Interleucina-17RESUMO
Mucus production by goblet cells of the large intestine serves as a crucial antimicrobial protective mechanism at the interface between the eukaryotic and prokaryotic cells of the mammalian intestinal ecosystem. However, the regulatory pathways involved in goblet cell-induced mucus secretion remain largely unknown. Here, we demonstrate that the NLRP6 inflammasome, a recently described regulator of colonic microbiota composition and biogeographical distribution, is a critical orchestrator of goblet cell mucin granule exocytosis. NLRP6 deficiency leads to defective autophagy in goblet cells and abrogated mucus secretion into the large intestinal lumen. Consequently, NLRP6 inflammasome-deficient mice are unable to clear enteric pathogens from the mucosal surface, rendering them highly susceptible to persistent infection. This study identifies an innate immune regulatory pathway governing goblet cell mucus secretion, linking nonhematopoietic inflammasome signaling to autophagy and highlighting the goblet cell as a critical innate immune player in the control of intestinal host-microbial mutualism. PAPERCLIP:
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Colo/imunologia , Células Caliciformes/imunologia , Inflamassomos/imunologia , Mucosa Intestinal/imunologia , Receptores de Superfície Celular/imunologia , Animais , Autofagia , Colite/imunologia , Colite/microbiologia , Colo/microbiologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Caliciformes/citologia , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Camundongos , Muco/metabolismoRESUMO
The mammalian intestinal tract harbors a diverse community of trillions of microorganisms, which have co-evolved with the host immune system for millions of years. Many of these microorganisms perform functions critical for host physiology, but the host must remain vigilant to control the microbial community so that the symbiotic nature of the relationship is maintained. To facilitate homeostasis, the immune system ensures that the diverse microbial load is tolerated and anatomically contained, while remaining responsive to microbial breaches and invasion. Although the microbiota is required for intestinal immune development, immune responses also regulate the structure and composition of the intestinal microbiota. Here we discuss recent advances in our understanding of these complex interactions and their implications for human health and disease.
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Intestinos/microbiologia , Metagenoma/imunologia , Animais , Homeostase/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/imunologia , Intestinos/imunologiaRESUMO
Active inflammatory bowel disease (IBD) often coincides with increases of Ruminococcus gnavus, a gut microbe found in nearly everyone. It was not known how, or if, this correlation contributed to disease. We investigated clinical isolates of R. gnavus to identify molecular mechanisms that would link R. gnavus to inflammation. Here, we show that only some isolates of R. gnavus produce a capsular polysaccharide that promotes a tolerogenic immune response, whereas isolates lacking functional capsule biosynthetic genes elicit robust proinflammatory responses in vitro. Germ-free mice colonized with an isolate of R. gnavus lacking a capsule show increased measures of gut inflammation compared to those colonized with an encapsulated isolate in vivo. These observations in the context of our earlier identification of an inflammatory cell-wall polysaccharide reveal how some strains of R. gnavus could drive the inflammatory responses that characterize IBD.
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Cápsulas Bacterianas/imunologia , Clostridiales/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade/imunologia , Doenças Inflamatórias Intestinais/imunologia , Polissacarídeos/imunologia , Adulto , Animais , Antibacterianos/farmacologia , Cápsulas Bacterianas/química , Cápsulas Bacterianas/ultraestrutura , Células Cultivadas , Criança , Clostridiales/classificação , Clostridiales/genética , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Humanos , Íleo/imunologia , Íleo/metabolismo , Íleo/microbiologia , Doenças Inflamatórias Intestinais/microbiologia , Camundongos Endogâmicos C57BL , Família Multigênica/genética , FilogeniaRESUMO
Fecal-oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL-BG). The MAL-BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non-neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal-oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL-BG mice. Unexpectedly, these changes occurred independently from significant cytokine-induced inflammation or blood-brain barrier (BBB) disruption, key gut-brain pathways. Metabolomic profiling of the MAL-BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant-associated diet (PAO) mitigated cognitive deficits within the MAL-BG model. These findings provide valued insight into the malnourished gut microbiota-brain axis, highlighting PUFA metabolism as a potential therapeutic target.
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Microbioma Gastrointestinal , Desnutrição , Animais , Cognição , Microbioma Gastrointestinal/fisiologia , Desnutrição/complicações , Camundongos , Camundongos Endogâmicos C57BL , MicrogliaRESUMO
Intestinal helminth infections occur predominantly in regions where exposure to enteric bacterial pathogens is also common. Helminth infections inhibit host immunity against microbial pathogens, which has largely been attributed to the induction of regulatory or type 2 (Th2) immune responses. Here we demonstrate an additional 3-way interaction in which helminth infection alters the metabolic environment of the host intestine to enhance bacterial pathogenicity. We show that an ongoing helminth infection increased colonization by Salmonella independently of T regulatory or Th2 cells. Instead, helminth infection altered the metabolic profile of the intestine, which directly enhanced bacterial expression of Salmonella pathogenicity island 1 (SPI-1) genes and increased intracellular invasion. These data reveal a novel mechanism by which a helminth-modified metabolome promotes susceptibility to bacterial coinfection.
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Coinfecção/imunologia , Helmintíase/imunologia , Enteropatias Parasitárias/imunologia , Mucosa Intestinal/metabolismo , Metaboloma , Infecções por Salmonella/imunologia , Células Th2/imunologia , Animais , Coinfecção/microbiologia , Coinfecção/parasitologia , Células HeLa , Humanos , Intestinos/microbiologia , Intestinos/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Salmonella typhimurium/genéticaRESUMO
Studies of the relationship between the microbiome and the development and function of the immune system are demonstrating novel concepts that could significantly alter the way we treat disease and promote wellness. Several diseases, including inflammatory bowel disease, allergy/asthma, and diabetes, are associated with changes in composition of the microbiome. Recent findings suggest novel complex mechanisms by which the microbiome impacts immune cell development and differentiation. A major implication of these findings is that the composition of microbiome may ultimately affect vaccine efficacy. We explore here the potential role of the microbiome in vaccine responses in the context of our growing understanding of the relationship between the gastrointestinal microbiota, resident immune cell populations, and systemic immunity.
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Sistema Imunitário/fisiologia , Intestinos/imunologia , Intestinos/microbiologia , Microbiota , Vacinas/imunologia , Fatores Etários , Animais , Biodiversidade , Exposição Ambiental , Humanos , Estado Nutricional , Prebióticos , ProbióticosRESUMO
There currently is no consensus on which immunological mechanisms can best explain the rise in atopic disease post industrialization. The hygiene hypothesis lays groundwork for our understanding of how altered microbial exposures can drive atopy; yet since its introduction increasing evidence suggests the exposure of our immune system to the intestinal microbiota plays a key role in development of atopic disease. As societal change shifts our microbial exposure, concordant shifts in the tolerant and effector functions of our immune systems give rise to more hypersensitive responses to external antigens. This is contrasted with the greater immune tolerant capabilities of individuals still living in regions with lifestyles more representative of our evolutionary history. Recent findings, buoyed by technological advances in the field, suggest a direct role for the intestinal microbiota-immune system interplay in the development of atopic disease mechanisms. Overall, harnessing current mechanistic studies for translational research into microbiota composition and function in relation to atopy have potential for the design of therapeutics that could moderate these diseases.
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Hipótese da Higiene , Hipersensibilidade/imunologia , Intestinos/imunologia , Intestinos/microbiologia , Animais , Humanos , MicrobiotaRESUMO
As a result of participating in the Centers for Disease Control and Prevention's Private Well Initiative and Environmental Public Health Tracking Network (Tracking), the Colorado Department of Public Health and Environment was able to inventory private well water quality data, prioritize potential health concerns associated with drinking water from these wells, and create a Web portal for sharing public health information regarding private well water. The Colorado Department of Public Health and Environment collaborated with a local health department to pilot the project prior to a public implementation. Approximately 18 data sets were identified and inventoried. The Colorado Department of Public Health and Environment also participated in development and pilot testing of best practices for display of well water quality data with other Tracking states. Available data sets were compiled and summarized, and the data made available on the Colorado Tracking portal using geographic information system technology to support public health outreach regarding private wells.
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Bases de Dados Factuais/normas , Água Potável/análise , Saúde Pública/métodos , Qualidade da Água , Poços de Água , Centers for Disease Control and Prevention, U.S. , Colorado , Comportamento Cooperativo , Humanos , Estados UnidosRESUMO
The strong association of the human leukocyte antigen B∗27 alleles (HLA-B∗27) with spondyloarthritis and related rheumatic conditions has long fascinated researchers, yet the precise mechanisms underlying its pathogenicity remain elusive. Here, we review how interplay between the microbiome, the immune system, and the enigmatic HLA-B∗27 could trigger spondyloarthritis, with a focus on whether HLA-B∗27 presents an arthritogenic peptide. We propose mechanisms by which the unique biochemical characteristics of the HLA-B∗27 protein structure, particularly its peptide binding groove, could dictate its propensity to induce pathological T cell responses. We further provide new insights into how TRBV9+ CD8+ T cells are implicated in the disease process, as well as how the immunometabolism of T cells modulates tissue-specific inflammatory responses in spondyloarthritis. Finally, we present testable models and suggest approaches to this problem in future studies given recent advances in computational biology, chemical biology, structural biology, and small-molecule therapeutics.
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OBJECTIVE: The present study explored rates of burnout and racial trauma among 182 Black mental health professionals (BMHPs) and utilized racial-cultural theory to explore potential protective factors against burnout and racial trauma. METHOD: We collected data from 182 Black psychologists and counselors who were active mental health professionals during 2020. Descriptive statistics, multivariate analyses of variance, follow-up univariate analyses of variance, bivariate correlations, and multiple regression analyses were used. RESULTS: Both burnout and racial trauma were considerably higher among BMHPs than has been reported across general samples of helping professionals and across a sample of Black participants across the United States. Differences among rates of burnout and racial trauma existed across genders and specialties (i.e., counseling and psychology). Higher levels of social support and an external locus of control significantly predicted lower levels of burnout and racial trauma. In addition, higher levels of resilient coping predicted lower levels of burnout. Last, more frequent meetings with a mentor significantly predicted lower levels of racial trauma. CONCLUSIONS: Results from this study suggest that BMHPs may be more susceptible to burnout and race-based traumatic stress as a result of their work. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Understanding the role of the microbiome in inflammatory diseases requires the identification of microbial effector molecules. We established an approach to link disease-associated microbes to microbial metabolites by integrating paired metagenomics, stool and plasma metabolomics, and culturomics. We identified host-microbial interactions correlated with disease activity, inflammation, and the clinical course of ulcerative colitis (UC) in the Predicting Response to Standardized Colitis Therapy (PROTECT) pediatric inception cohort. In severe disease, metabolite changes included increased dipeptides and tauro-conjugated bile acids (BAs) and decreased amino-acid-conjugated BAs in stool, whereas in plasma polyamines (N-acetylputrescine and N1-acetylspermidine) increased. Using patient samples and Veillonella parvula as a model, we uncovered nitrate- and lactate-dependent metabolic pathways, experimentally linking V. parvula expansion to immunomodulatory tryptophan metabolite production. Additionally, V. parvula metabolizes immunosuppressive thiopurine drugs through xdhA xanthine dehydrogenase, potentially impairing the therapeutic response. Our findings demonstrate that the microbiome contributes to disease-associated metabolite changes, underscoring the importance of these interactions in disease pathology and treatment.
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Colite Ulcerativa , Microbioma Gastrointestinal , Humanos , Criança , Colite Ulcerativa/tratamento farmacológico , Interações entre Hospedeiro e Microrganismos , Microbioma Gastrointestinal/genética , Progressão da Doença , Genes MicrobianosRESUMO
Metabolites produced by commensal gut microbes impact host health through their recognition by the immune system and their influence on numerous metabolic pathways. Notably, the gut microbiota can both transform and synthesize lipids as well as break down dietary lipids to generate secondary metabolites with host modulatory properties. Although lipids have largely been consigned to structural roles, particularly in cell membranes, recent research has led to an increased appreciation of their signaling activities, with potential impacts on host health and physiology. This review focuses on studies that highlight the functions of bioactive lipids in mammalian physiology, with a special emphasis on immunity and metabolism.
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Microbioma Gastrointestinal , Animais , Microbioma Gastrointestinal/fisiologia , Metabolismo dos Lipídeos , Sistema Imunitário , Lipídeos , MamíferosRESUMO
Hydrogen sulfide has emerged as a key gasotransmitter in humans and in plants, and the addition of exogenous hydrogen sulfide has many beneficial effects in vivo and in vitro. A challenge in investigating the effect of exogenous hydrogen sulfide is tracking the location of exogenous hydrogen sulfide on an organism and cellular level. In this article, we report the synthesis of three key chemicals (cysteine trisulfide, glutathione trisulfide, and GYY-4137) that release radiolabeled 35S as hydrogen sulfide. The synthesis started with the reduction of Na235SO4 mixed with Na2SO4 to generate hydrogen sulfide gas that was trapped with aq NaOH to yield radiolabeled Na2S. The Na2S was converted in one step to GYY-4137 at 65% yield. It was also converted to bis(tributyltin) sulfide that readily reacted with N-bromophthalimide to yield a monosulfur transfer reagent. Trisulfides were synthesized by reaction with the monosulfur transfer reagent and the corresponding thiols. The levels of radioactivity of the final products could be varied on a per gram basis to alter the radioactivity for applications that require different loadings of hydrogen sulfide donors.
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Plasma cells (PCs) constitute a significant fraction of colonic mucosal cells and contribute to inflammatory infiltrates in ulcerative colitis (UC). While gut PCs secrete bacteria-targeting IgA antibodies, their role in UC pathogenesis is unknown. We performed single-cell V(D)J- and RNA-seq on sorted B cells from the colon of healthy individuals and patients with UC. A large fraction of B cell clones is shared between different colon regions, but inflammation in UC broadly disrupts this landscape, causing transcriptomic changes characterized by an increase in the unfolded protein response (UPR) and antigen presentation genes, clonal expansion, and isotype skewing from IgA1 and IgA2 to IgG1. We also directly expressed and assessed the specificity of 152 mAbs from expanded PC clones. These mAbs show low polyreactivity and autoreactivity and instead target both shared bacterial antigens and specific bacterial strains. Altogether, our results characterize the microbiome-specific colon PC response and how its disruption might contribute to inflammation in UC.
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Colite Ulcerativa , Humanos , Colite Ulcerativa/genética , Plasmócitos , Colo , Inflamação/metabolismo , Antígenos de Bactérias , Bactérias , Imunoglobulina A/metabolismo , Mucosa IntestinalRESUMO
In this issue of Cell Host & Microbe, Le et al. discover that addition of exogenous Bacteroides sphingolipids can reverse lipid accumulation in the liver in a mouse model of hepatic steatosis. An elegant labeling strategy also revealed a unique microbially produced sphingolipid that was able to transit to the liver.