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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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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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Bacterias , Enfermedades Cardiovasculares , Colesterol , Microbioma Gastrointestinal , Humanos , Bacterias/metabolismo , Enfermedades Cardiovasculares/metabolismo , Colesterol/análisis , Colesterol/sangre , Colesterol/metabolismo , Heces/química , Estudios Longitudinales , Metaboloma , Metabolómica , ARN Ribosómico 16S/metabolismoRESUMEN
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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Colitis Ulcerosa , Microbioma Gastrointestinal , Humanos , Niño , Colitis Ulcerosa/tratamiento farmacológico , Interacciones Microbiota-Huesped , Microbioma Gastrointestinal/genética , Progresión de la Enfermedad , Genes MicrobianosRESUMEN
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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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 , Aprendizaje Profundo , Humanos , Captano , SARS-CoV-2 , Antígenos HLA , Epítopos de Linfocito T , PéptidosRESUMEN
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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Colitis Ulcerosa , Humanos , Colitis Ulcerosa/genética , Células Plasmáticas , Colon , Inflamación/metabolismo , Antígenos Bacterianos , Bacterias , Inmunoglobulina A/metabolismo , Mucosa IntestinalRESUMEN
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 , Animales , Microbioma Gastrointestinal/fisiología , Metabolismo de los Lípidos , Sistema Inmunológico , Lípidos , MamíferosRESUMEN
Colonization of the intestine by oral microbes has been linked to multiple diseases such as inflammatory bowel disease and colon cancer, yet mechanisms allowing expansion in this niche remain largely unknown. Veillonella parvula, an asaccharolytic, anaerobic, oral microbe that derives energy from organic acids, increases in abundance in the intestine of patients with inflammatory bowel disease. Here we show that nitrate, a signature metabolite of inflammation, allows V. parvula to transition from fermentation to anaerobic respiration. Nitrate respiration, through the narGHJI operon, boosted Veillonella growth on organic acids and also modulated its metabolic repertoire, allowing it to use amino acids and peptides as carbon sources. This metabolic shift was accompanied by changes in carbon metabolism and ATP production pathways. Nitrate respiration was fundamental for ectopic colonization in a mouse model of colitis, because a V. parvula narG deletion mutant colonized significantly less than a wild-type strain during inflammation. These results suggest that V. parvula harness conditions present during inflammation to colonize in the intestine.
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Enfermedades Inflamatorias del Intestino , Veillonella , Adenosina Trifosfato/metabolismo , Aminoácidos/metabolismo , Animales , Carbono/metabolismo , Inflamación , Intestinos , Ratones , Nitratos/metabolismo , Veillonella/genética , Veillonella/metabolismoRESUMEN
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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Enfermedad de Crohn , Epítopos Inmunodominantes , Linfocitos T CD4-Positivos , Epítopos de Linfocito T , Humanos , Interleucina-10 , Interleucina-17RESUMEN
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.
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Hígado Graso , Microbiota , Animales , Bacteroides , Hígado , Ratones , EsfingolípidosRESUMEN
Trisulfides and higher polysulfides are important in the body due to their function as key reservoirs of sulfane sulfur and their rapid reactions to release persulfides. Recent work has shown that persulfides act as powerful antioxidants and release hydrogen sulfide, an emerging gasotransmitter with numerous therapeutic effects. Despite the important role of polysulfides, there is a lack of understanding of their stabilities in aqueous systems. To investigate the reactivity of trisulfides and polysulfides, three key biologically important trisulfides were synthesized from cysteine, glutathione, and N-acetylcysteine, and the tetrasulfide of N-acetylcysteine was synthesized as a representative polysulfide. The stabilities of sulfides were monitored in buffered D2O using 1H NMR spectroscopy under a range of conditions including high temperatures and acidic and alkaline environments. The tri- and tetrasulfides degraded rapidly in the presence of primary and tertiary amines to the corresponding disulfide and elemental sulfur. The half-lives of N-acetylcysteine tri- and tetrasulfides in the presence of butylamine were 53 and 1.5 min, respectively. These results were important because they suggest that tri- and tetrasulfide linkages are short-lived species in vivo due to the abundance of amines in the body. Under basic conditions, cysteine and glutathione trisulfides were unstable due to the deprotonation of the ammonium group, exposing an amine; however, N-acetylcysteine trisulfide was stable at all pH values tested. Hydrogen sulfide release of each polysulfide in the presence of cysteine was quantified using a hydrogen sulfide-sensitive electrode and 1H NMR spectroscopy.
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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 , Desnutrición , Animales , Cognición , Microbioma Gastrointestinal/fisiología , Desnutrición/complicaciones , Ratones , Ratones Endogámicos C57BL , MicroglíaRESUMEN
The slow release of hydrogen sulfide has been shown to be beneficial to plants by protecting them from environmental stressors, increasing germination, and extending the lifetime of harvested fruits. A major challenge in this field is controlling the amount and location of release of hydrogen sulfide so that it is available for use by plants at optimal amounts. This article reports a dual method to release hydrogen sulfide near the roots of plants by controlling its release using the hydrolysis of a dithiophosphate and the degradation of poly(lactic acid) [PLA]. Di(t-butanol)dithiophosphate phenylethylamine (tBDPA) was dissolved in a solution of PLA, and the solvent was allowed to evaporate. The resulting solid was crushed in a blender and separated into microparticles with two different size distributions of 250-500 or 500-2000 µm. The microparticles were characterized by powder X-ray diffraction to measure the presence of microcrystals of tBDPA within PLA, and images obtained using scanning electron microscopy with energy dispersive X-ray analysis confirmed the presence of these crystals. Microparticles of tBDPA loaded within PLA were characterized for their release of phosphorus and hydrogen sulfide, which both showed a burst release within 3 days, followed by a steady release. Radish plants grown with microparticles of PLA loaded with tBDPA had up to a 141% increase in harvest yield compared to plants grown in the presence of free tBDPA not loaded into PLA, PLA microparticles without tBDPA, and control plants grown without PLA or tBDPA. These experiments showed that loading hydrogen sulfide-releasing chemicals into PLA is a promising method to improve the effect of hydrogen sulfide on plants.
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The development of chemicals to slowly release hydrogen sulfide would aid the survival of plants under environmental stressors as well as increase harvest yields. We report a series of dialkyldithiophosphates and disulfidedithiophosphates that slowly degrade to release hydrogen sulfide in the presence of water. Kinetics of the degradation of these chemicals were obtained at 85 °C and room temperature, and it was shown that the identity of the alkyl or sulfide group had a large impact on the rate of hydrolysis, and the rate constant varied by more than 104×. For example, using tert-butanol as the nucleophile yielded a dithiophosphate (8) that hydrolyzed 13,750× faster than the dithiophosphate synthesized from n-butanol (1), indicating that the rate of hydrolysis is structure-dependent. The rates of hydrolysis at 85 °C varied from a low value of 6.9 × 10-4 h-1 to a high value of 14.1 h-1. Hydrogen sulfide release in water was also quantified using a hydrogen sulfide-sensitive electrode. Corn was grown on an industrial scale and dosed with dibutyldithiophosphate to show that these dithiophosphates have potential applications in agriculture. At a loading of 2 kg per acre, a 6.4% increase in the harvest yield of corn was observed.
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Sulfuro de Hidrógeno , Hidrólisis , Cinética , Sulfuros , Zea maysRESUMEN
Bacterial ADP-ribosyltransferases (ADPRTs) have been described as toxins involved in pathogenesis through the modification of host proteins. Here, we report that ADPRTs are not pathogen restricted but widely prevalent in the human gut microbiome and often associated with phage elements. We validated their biochemical activity in a large clinical isolate collection and further examined Bxa, a highly abundant ADPRT in Bacteroides. Bxa is expressed, secreted, and enzymatically active in Bacteroides and can ADP-ribosylate non-muscle myosin II proteins. Addition of Bxa to epithelial cells remodeled the actin cytoskeleton and induced secretion of inosine. Bxa-encoding B. stercoris can use inosine as a carbon source and colonizes the gut to significantly greater numbers than a bxa-deleted strain in germ-free and altered Schaedler flora (ASF) mice. Colonization correlated with increased inosine concentrations in the feces and tissues. Altogether, our results show that ADPRTs are abundant in the microbiome and act as bacterial fitness factors.
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ADP Ribosa Transferasas/metabolismo , Citoesqueleto de Actina/metabolismo , Bacteroides thetaiotaomicron/metabolismo , Bacteroides/metabolismo , Células Epiteliales/metabolismo , Inosina/metabolismo , ADP Ribosa Transferasas/genética , Animales , Bacteriófagos/genética , Células CACO-2 , Línea Celular Tumoral , Heces/química , Heces/microbiología , Femenino , Microbioma Gastrointestinal/genética , Vida Libre de Gérmenes , Células HT29 , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Cadenas Pesadas de Miosina/metabolismoRESUMEN
An estimated 3.5 billion people are colonized by intestinal parasites worldwide. Intestinal parasitic eukaryotes interact not only with the host but also with the intestinal microbiota. In this work, we studied the relationship between the presence of multiple enteric parasites and the community structures of gut bacteria and eukaryotes in an asymptomatic mother-child cohort from a semirural community in Mexico. Fecal samples were collected from 46 mothers and their respective children, with ages ranging from 2 to 20 months. Mothers and infants were found to be multiparasitized by Blastocystis hominis, Entamoeba dispar, Endolimax nana, Chilomastix mesnili, Iodamoeba butshlii, Entamoeba coli, Hymenolepis nana, and Ascaris lumbricoides. Sequencing of bacterial 16S rRNA and eukaryotic 18S rRNA genes showed a significant effect of parasite exposure on bacterial beta-diversity, which explained between 5.2% and 15.0% of the variation of the bacterial community structure in the cohort. Additionally, exposure to parasites was associated with significant changes in the relative abundances of multiple bacterial taxa, characterized by an increase in Clostridiales and decreases in Actinobacteria and Bacteroidales. Parasite exposure was not associated with changes in intestinal eukaryote relative abundances. However, we found several significant positive correlations between intestinal bacteria and eukaryotes, including Oscillospira with Entamoeba coli and Prevotella stercorea with Entamoeba hartmanni, as well as the co-occurrence of the fungus Candida with Bacteroides and Actinomyces, Bifidobacterium, and Prevotella copri and the fungus Pichia with Oscillospira. The parasitic exposure-associated changes in the bacterial community structure suggest effects on microbial metabolic routes, host nutrient uptake abilities, and intestinal immunity regulation in host-parasite interactions. IMPORTANCE The impact of intestinal eukaryotes on the prokaryotic microbiome composition of asymptomatic carriers has not been extensively explored, especially in infants and mothers with multiple parasitic infections. In this work, we studied the relationship between protist and helminth parasite colonization and the intestinal microbiota structure in an asymptomatic population of mother-child binomials from a semirural community in Mexico. We found that the presence of parasitic eukaryotes correlated with changes in the bacterial gut community structure in the intestinal microbiota in an age-dependent way. Parasitic infection was associated with an increase in the relative abundance of the class Clostridia and decreases of Actinobacteria and Bacteroidia. Parasitic infection was not associated with changes in the eukaryote community structure. However, we observed strong positive correlations between bacterial and other eukaryote taxa, identifying novel relationships between prokaryotes and fungi reflecting interkingdom interactions within the human intestine.
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Bacterias/genética , Heces/parasitología , Microbioma Gastrointestinal/genética , Helmintos/fisiología , Parasitosis Intestinales/epidemiología , Parásitos/fisiología , Adolescente , Adulto , Animales , Bacterias/clasificación , Estudios de Cohortes , Femenino , Microbioma Gastrointestinal/fisiología , Helmintos/genética , Interacciones Huésped-Parásitos , Humanos , Lactante , México/epidemiología , Persona de Mediana Edad , Modelos Estadísticos , Madres , Parásitos/clasificación , Parásitos/genética , ARN Ribosómico 16S/genética , Población Rural/estadística & datos numéricos , Adulto JovenRESUMEN
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/inmunología , Clostridiales/inmunología , Microbioma Gastrointestinal/inmunología , Inmunidad/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Polisacáridos/inmunología , Adulto , Animales , Antibacterianos/farmacología , Cápsulas Bacterianas/química , Cápsulas Bacterianas/ultraestructura , Células Cultivadas , Niño , Clostridiales/clasificación , Clostridiales/genética , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Humanos , Íleon/inmunología , Íleon/metabolismo , Íleon/microbiología , Enfermedades Inflamatorias del Intestino/microbiología , Ratones Endogámicos C57BL , Familia de Multigenes/genética , FilogeniaRESUMEN
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.