Combinatorial phenotypic landscape enables bacterial resistance to phage infection

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 15, 2025

Success of phage therapies is limited by bacterial defenses against phages. While a large variety anti- defense mechanisms has been characterized, how expression these systems distributed across individual cells and their combined activities translate into protection from phages not studied. Using single-cell RNA sequencing, we profiled the transcriptomes ∼50,000 cultures human pathobiont, Bacteroides fragilis, infected with lytic bacteriophage. We quantified asynchronous progression infection in single reconstructed timeline, characterizing both host transcriptomic changes as unfolded. discovered subpopulation bacteria that remained uninfected determined heterogeneously expressed factors associated protection. Each cell's vulnerability to was defined combinatorial phase-variable multiple genetic loci, including capsular polysaccharide (CPS) biosynthesis pathways, restriction-modification (RM), previously uncharacterized operon likely encoding fimbrial genes. By acting together, anti-phage create phenotypic landscape where distinct protective combinations enable survival re-growth expressing phenotypes without acquiring additional mutations. The emerging model complementary action an isogenic population showcases potent role phase variation stochasticity defenses. Combinatorial states differential fragilis small number super-resistant evade need for

Язык: Английский

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Mutation bias and adaptation in bacteria

Microbiology, Год журнала: 2023, Номер 169(11)

Опубликована: Ноя. 9, 2023

Genetic mutation, which provides the raw material for evolutionary adaptation, is largely a stochastic force. However, there ample evidence showing that mutations can also exhibit strong biases, with some mutation types and certain genomic positions mutating more often than others. It becoming increasingly clear mutational bias play role in determining adaptive outcomes bacteria both laboratory clinic. As such, understanding causes consequences of help microbiologists to anticipate predict outcomes. In this review, we provide an overview mechanisms features bacterial genome cause biases occur. We then describe environmental triggers drive these be potent outline scenarios where synergize natural selection define conclude by describing how mutagenic areas sensitive bias, finish outlining future work will us achieve accurate forecasts.

Язык: Английский

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Gut microbiota mediated T cells regulation and autoimmune diseases

Frontiers in Microbiology, Год журнала: 2024, Номер 15

Опубликована: Дек. 19, 2024

Gut microbiota regulates the immune system, development and progression of autoimmune diseases (AIDs) overall health. Recent studies have played a crucial part in understanding specific role different gut bacterial strains their metabolites AIDs. Microbial signatures AIDs are revealed by advanced sequencing metabolomics studies. Microbes such as Faecalibacterium prausnitzii, Akkermansia muciniphila, Anaerostipes caccae, Bacteroides sp. , Roseburia Blautia faecis Clostridium lavalense Christensenellaceae Coprococcus Firmicutes Ruminococcaceae Lachnospiraceae Megamonas sp., Monoglobus Streptococcus pneumoniae Bifidobacterium help maintain homeostasis; whereas, Prevotella copri, Ruminococcus gnavus, Lactobacillus salivarius, Enterococcus gallinarum, Elizabeth menigoseptica, Collinsella Escherichia Fusobacterium Enterobacter ludwigii, Enterobacteriaceae Proteobacteria Porphyromonas gingivalis nigrescens Dorea cause immuno-pathogenesis. A complex web interactions is influence on cells various T cell subsets CD4+ cells, CD8+ natural killer γδ etc. Certain AIDs, including rheumatoid arthritis, diabetes mellitus, atopic asthma, inflammatory bowel disease non-alcoholic fatty liver exhibit state dysbiosis, characterized alterations microbial diversity relative abundance taxa. This review summarizes recent developments certain composition factors affecting regulatory through also focuses potential application therapeutic significance microbiota-based interventions novel adjunctive therapies for Further research to determine precise association each strain required.

Язык: Английский

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Effects of bacteriophages on gut microbiome functionality

Gut Microbes, Год журнала: 2025, Номер 17(1)

Опубликована: Март 31, 2025

The gut microbiome, composed of bacteria, fungi, and viruses, plays a crucial role in maintaining the delicate balance human health. Emerging evidence suggests that microbiome disruptions can have far-reaching implications, ranging from development inflammatory diseases cancer to metabolic disorders. Bacteriophages, or "phages", are viruses specifically infect bacterial cells, their interactions with receiving increased attention. Despite recently revived interest phageome, it is still considered "dark matter" gut, more than 80% viral genomes remaining uncharacterized. Today, research focused on understanding mechanisms by which phages influence microbiota potential applications. Bacteriophages may regulate relative abundance communities, affect functions various ways, modulate mammalian host immunity. This review explores how functionality, particularly commensals pathogens, emphasizing health disease.

Язык: Английский

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Bacteroides expand the functional versatility of a universal transcription factor and transcribed DNA to program capsule diversity

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 21, 2024

SUMMARY Human gut Bacteroides species encode numerous (eight or more) tightly regulated capsular polysaccharides (CPS). Specialized paralogs of the universal transcription elongation factor NusG, called UpxY (Y), and an anti-Y UpxZ (Z) are encoded by first two genes each CPS operon. The Y-Z regulators combine with promoter inversions to limit a single operon in most cells. Y enhances transcript whereas Z inhibits noncognate Ys. How distinguishes among cognate operons how only Ys unknown. Using in-vivo nascent-RNA sequencing p romoter-less v itr o (PIVoT), we establish that recognizes paused RNA polymerase via sequences both exposed non-template DNA upstream duplex DNA. association is aided novel ‘pause-then-escape’ nascent hairpins. binds non-cognate directly inhibit association. This hierarchical regulatory program allows create subpopulations for optimal fitness.

Язык: Английский

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The Microbiome in Inflammatory Bowel Disease

Journal of Clinical Medicine, Год журнала: 2024, Номер 13(16), С. 4622 - 4622

Опубликована: Авг. 7, 2024

The management of patients with inflammatory bowel disease (IBD) aims to control inflammation through the use immunosuppressive treatments that target various points in cascade. However, efficacy these therapies long term is limited, and they often are associated severe side effects. Although pathophysiology not completely understood, IBD regarded as a multifactorial occurs due an inappropriate immune response genetically susceptible individuals. gut microbiome considered one main actors development IBD. Gut dysbiosis, characterised by significant changes composition functionality microbiota, leads reduction bacterial diversity anti-inflammatory anaerobic bacteria. At same time, bacteria pro-inflammatory potential increase. upon biological agent usage have been observed, their role biomarkers still unclear. While most studies on focus intestinal population, recent highlighted importance other microbial populations, such viruses fungi, dysbiosis. In order modulate aberrant IBD, researchers developed different players microbiome. These innovative approaches hold promise for future treatment, although safety concerns limitations, effects humans remain unknown.

Язык: Английский

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Epigenetic phase variation in the gut microbiome enhances bacterial adaptation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 12, 2025

Abstract The human gut microbiome within the gastrointestinal tract continuously adapts to variations in diet, medications, and host physiology. A central strategy for genetic adaptation is epigenetic phase variation (ePV) mediated by bacterial DNA methylation, which can regulate gene expression, enhance clonal heterogeneity, enable a single strain exhibit variable phenotypic states. Genome-wide site-specific ePV have been well characterized pathogens’ antigenic virulence factor production. However, role of facilitating remains poorly understood. Here, we comprehensively cataloged genome-wide infant adult microbiomes. First, using long-read metagenomic sequencing, detected complex structural methyltransferases, highlighting ones associated with antibiotics or fecal microbiota transplantation. Second, analyzed an extensive collection public short-read sequencing datasets, uncovering greater prevalence microbiome. Third, quantitatively ePVs single-molecule methylation analysis identify dynamic antibiotic treatment probiotic engraftment. Finally, performed in-depth assessment Akkermansia muciniphila isolate from infant, that expression adaptive capacity employing bet-hedging increase tolerance differing antibiotics. Our findings indicate modifications are common broad used bacteria adapt their environment.

Язык: Английский

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Adaptations in gut Bacteroidales facilitate stable co-existence with their lytic bacteriophages

Gut Microbes, Год журнала: 2025, Номер 17(1)

Опубликована: Май 23, 2025

Bacteriophages (phages) and bacteria within the gut microbiome persist in long-term stable coexistence. These interactions are driven by eco-evolutionary dynamics, where employ a variety of mechanisms to evade phage infection, while phages rely on counterstrategies overcome these defenses. Among most abundant crAss-like that infect members order Bacteroidales, particular, genus Bacteroides. In this study, we explored some enabling co-existence four phage-Bacteroidales host pairs vitro using multi-omics approach (transcriptomics, proteomics metabolomics). included three Bacteroides species paired with (Bacteroides intestinalis фcrAss001, xylanisolvens фcrAss002, an acapsular mutant thetaiotaomicron DAC15), Parabacteroides distasonis siphovirus фPDS1. We show phase variation individual capsular polysaccharides (CPSs) is primary mechanism promoting but not only strategy. Alternative resistance mechanisms, potentially less efficient than CPS variation, can be activated support bacterial survival regulating gene expression resulting metabolic adaptations, particularly amino acid degradation pathways. also likely regulated enable populations presence phages, vice versa. An variant B. demonstrated broader transcriptomic, proteomic, metabolomic changes, supporting involvement additional beyond variation. This study advances our understanding phage-host interaction, offering insights into persistence extending observations other such as Knowledge complexities phage-bacteria essential for designing effective therapies improving human health through targeted interventions.

Язык: Английский

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Regulation of microbial gene expression: the key to understanding our gut microbiome

Trends in Microbiology, Год журнала: 2024, Номер unknown

Опубликована: Авг. 1, 2024

During the past two decades, gut microbiome studies have established significant impact of microbiota and its metabolites on host health. However, molecular mechanisms governing production microbial in environment remain insufficiently investigated thus are poorly understood. Here, we propose that an enhanced understanding gene regulation, which is responsive to dietary components environmental conditions, needed research field essential for our ability effectively promote health prevent diseases through interventions targeting microbiome.

Язык: Английский

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Adaptations in gut Bacteroidales facilitate stable co-existence with their lytic bacteriophages

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 17, 2024

Bacteriophages (phages) and bacteria within the gut microbiome persist in long-term stable coexistence. These interactions are driven by eco-evolutionary dynamics, where employ a variety of mechanisms to evade phage infection, while phages rely on counterstrategies overcome these defences. Among most abundant crAss-like that infect members Bacteroidales, particular

Язык: Английский

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