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Bile acids are increasingly appearing in the spotlight owing to their novel impacts on various host processes. Similarly, there is growing attention on members of the microbiota that are responsible for bile acid modifications. With recent advances in technology enabling the discovery and continued identification of microbially conjugated bile acids, the chemical complexity of the bile acid landscape in the body is increasing at a rapid pace. In this Review, we summarize our current understanding of how bile acids and the gut microbiota interact to modulate immune responses during homeostasis and disease, with a particular focus on the gut.
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The early microbial colonization of the gastrointestinal tract can have long-term impacts on development and health. Keystone species, including Bacteroides spp., are prominent in early life and play crucial roles in maintaining the structure of the intestinal ecosystem. However, the process by which a resilient community is curated during early life remains inadequately understood. Here, we show that a single sialidase, NanH, in Bacteroides fragilis mediates stable occupancy of the intestinal mucosa in early life and regulates a commensal colonization program. This program is triggered by sialylated glycans, including those found in human milk oligosaccharides and intestinal mucus. NanH is required for vertical transmission from dams to pups and promotes B. fragilis dominance during early life. Furthermore, NanH facilitates commensal resilience and recovery after antibiotic treatment in a defined microbial community. Collectively, our study reveals a co-evolutionary mechanism between the host and microbiota mediated through host-derived glycans to promote stable colonization.
Assuntos
Ecossistema , Neuraminidase , Humanos , Bacteroides fragilis , Mucosa Intestinal/microbiologia , PolissacarídeosRESUMO
Type I interferons (IFNs) exert a broad range of biological effects important in coordinating immune responses, which have classically been studied in the context of pathogen clearance. Yet, whether immunomodulatory bacteria operate through IFN pathways to support intestinal immune tolerance remains elusive. Here, we reveal that the commensal bacterium, Bacteroides fragilis, utilizes canonical antiviral pathways to modulate intestinal dendritic cells (DCs) and regulatory T cell (Treg) responses. Specifically, IFN signaling is required for commensal-induced tolerance as IFNAR1-deficient DCs display blunted IL-10 and IL-27 production in response to B. fragilis. We further establish that IFN-driven IL-27 in DCs is critical in shaping the ensuing Foxp3+ Treg via IL-27Rα signaling. Consistent with these findings, single-cell RNA sequencing of gut Tregs demonstrated that colonization with B. fragilis promotes a distinct IFN gene signature in Foxp3+ Tregs during intestinal inflammation. Altogether, our findings demonstrate a critical role of commensal-mediated immune tolerance via tonic type I IFN signaling.
Assuntos
Interferon Tipo I , Interleucina-27 , Camundongos , Animais , Interleucina-27/metabolismo , Linfócitos T Reguladores , Interferon Tipo I/metabolismo , Tolerância Imunológica , Fatores de Transcrição Forkhead/metabolismo , Bactérias/metabolismo , Células DendríticasRESUMO
Bacteroides fragilis is a Gram-negative commensal bacterium commonly found in the human colon, which differentiates into two genomospecies termed divisions I and II. Through a comprehensive collection of 694 B. fragilis whole genome sequences, we identify novel features distinguishing these divisions. Our study reveals a distinct geographic distribution with division I strains predominantly found in North America and division II strains in Asia. Additionally, division II strains are more frequently associated with bloodstream infections, suggesting a distinct pathogenic potential. We report differences between the two divisions in gene abundance related to metabolism, virulence, stress response, and colonization strategies. Notably, division II strains harbor more antimicrobial resistance (AMR) genes than division I strains. These findings offer new insights into the functional roles of division I and II strains, indicating specialized niches within the intestine and potential pathogenic roles in extraintestinal sites. IMPORTANCE: Understanding the distinct functions of microbial species in the gut microbiome is crucial for deciphering their impact on human health. Classifying division II strains as Bacteroides fragilis can lead to erroneous associations, as researchers may mistakenly attribute characteristics observed in division II strains to the more extensively studied division I B. fragilis. Our findings underscore the necessity of recognizing these divisions as separate species with distinct functions. We unveil new findings of differential gene prevalence between division I and II strains in genes associated with intestinal colonization and survival strategies, potentially influencing their role as gut commensals and their pathogenicity in extraintestinal sites. Despite the significant niche overlap and colonization patterns between these groups, our study highlights the complex dynamics that govern strain distribution and behavior, emphasizing the need for a nuanced understanding of these microorganisms.
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Bacteroides fragilis , Variação Genética , Genoma Bacteriano , Bacteroides fragilis/genética , Bacteroides fragilis/patogenicidade , Bacteroides fragilis/isolamento & purificação , Humanos , Genoma Bacteriano/genética , Microbioma Gastrointestinal/genética , Filogenia , Infecções por Bacteroides/microbiologia , Sequenciamento Completo do Genoma , Farmacorresistência Bacteriana/genéticaRESUMO
Bacteroides fragilis is a prominent member of the human gut microbiota, playing crucial roles in maintaining gut homeostasis and host health. Although it primarily functions as a beneficial commensal, B. fragilis can become pathogenic. To determine the genetic basis of its duality, we conducted a comparative genomic analysis of 813 B. fragilis strains, representing both commensal and pathogenic origins. Our findings reveal that pathogenic strains emerge across diverse phylogenetic lineages, due in part to rapid gene exchange and the adaptability of the accessory genome. We identified 16 phylogenetic groups, differentiated by genes associated with capsule composition, interspecies competition, and host interactions. A microbial genome-wide association study identified 44 genes linked to extra-intestinal survival and pathogenicity. These findings reveal how genomic diversity within commensal species can lead to the emergence of pathogenic traits, broadening our understanding of microbial evolution in the gut.
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microbeMASST, a taxonomically informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbe-derived metabolites and relative producers without a priori knowledge will vastly enhance the understanding of microorganisms' role in ecology and human health.
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Metabolômica , Espectrometria de Massas em Tandem , Humanos , Metabolômica/métodos , Bases de Dados FactuaisRESUMO
Bacteroides fragilis is a Gram-negative commensal bacterium commonly found in the human colon that differentiates into two genomospecies termed division I and II. We leverage a comprehensive collection of 694 B. fragilis whole genome sequences and report differential gene abundance to further support the recent proposal that divisions I and II represent separate species. In division I strains, we identify an increased abundance of genes related to complex carbohydrate degradation, colonization, and host niche occupancy, confirming the role of division I strains as gut commensals. In contrast, division II strains display an increased prevalence of plant cell wall degradation genes and exhibit a distinct geographic distribution, primarily originating from Asian countries, suggesting dietary influences. Notably, division II strains have an increased abundance of genes linked to virulence, survival in toxic conditions, and antimicrobial resistance, consistent with a higher incidence of these strains in bloodstream infections. This study provides new evidence supporting a recent proposal for classifying divisions I and II B. fragilis strains as distinct species, and our comparative genomic analysis reveals their niche-specific roles.