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Journal of Theoretical Biology Jun 2024The human gut microbiota relies on complex carbohydrates (glycans) for energy and growth, primarily dietary fiber and host-derived mucins. We introduce a mathematical...
The human gut microbiota relies on complex carbohydrates (glycans) for energy and growth, primarily dietary fiber and host-derived mucins. We introduce a mathematical model of a glycan generalist and a mucin specialist in a two-compartment chemostat model of the human colon. Our objective is to characterize the influence of dietary fiber and mucin supply on the abundance of mucin-degrading species within the gut ecosystem. Current mathematical gut reactor models that include the enzymatic degradation of glycans do not differentiate between glycan types and their degraders. The model we present distinguishes between a generalist that can degrade both dietary fiber and mucin, and a specialist species that can only degrade mucin. The integrity of the colonic mucus barrier is essential for overall human health and well-being, with the mucin specialist Akkermanisa muciniphila being associated with a healthy mucus layer. Competition, particularly between the specialist and generalists like Bacteroides thetaiotaomicron, may lead to mucus layer erosion, especially during periods of dietary fiber deprivation. Our model treats the colon as a gut reactor system, dividing it into two compartments that represent the lumen and the mucus of the gut, resulting in a complex system of ordinary differential equations with a large and uncertain parameter space. To understand the influence of model parameters on long-term behavior, we employ a random forest classifier, a supervised machine learning method. Additionally, a variance-based sensitivity analysis is utilized to determine the sensitivity of steady-state values to changes in model parameter inputs. By constructing this model, we can investigate the underlying mechanisms that control gut microbiota composition and function, free from confounding factors.
Topics: Mucins; Dietary Fiber; Humans; Gastrointestinal Microbiome; Mucus; Models, Biological; Colon; Polysaccharides
PubMed: 38604595
DOI: 10.1016/j.jtbi.2024.111824 -
MBio May 2024is a prominent member of the human gut microbiota contributing to nutrient exchange, gut function, and maturation of the host's immune system. This obligate anaerobe...
is a prominent member of the human gut microbiota contributing to nutrient exchange, gut function, and maturation of the host's immune system. This obligate anaerobe symbiont can adopt a biofilm lifestyle, and it was recently shown that biofilm formation is promoted by the presence of bile. This process also requires a extracellular DNase, which is not, however, regulated by bile. Here, we showed that bile induces the expression of several Resistance-Nodulation-Division (RND) efflux pumps and that inhibiting their activity with a global competitive efflux inhibitor impaired bile-dependent biofilm formation. We then showed that, among the bile-induced RND-efflux pumps, only the tripartite BT3337-BT3338-BT3339 pump, re-named BipABC [for Bile Induced Pump A (), B (), and C ()], is required for biofilm formation. We demonstrated that BipABC is involved in the efflux of magnesium to the biofilm extracellular matrix, which leads to a decrease of extracellular DNA concentration. The release of magnesium in the biofilm matrix also impacts biofilm structure, potentially by modifying the electrostatic repulsion forces within the matrix, reducing interbacterial distance and allowing bacteria to interact more closely and form denser biofilms. Our study therefore, identified a new molecular determinant of biofilm formation in response to bile salts and provides a better understanding on how an intestinal chemical cue regulates biofilm formation in a major gut symbiont.IMPORTANCE is a prominent member of the human gut microbiota able to degrade dietary and host polysaccharides, altogether contributing to nutrient exchange, gut function, and maturation of the host's immune system. This obligate anaerobe symbiont can adopt a biofilm community lifestyle, providing protection against environmental factors that might, in turn, protect the host from dysbiosis and dysbiosis-related diseases. It was recently shown that exposure to intestinal bile promotes biofilm formation. Here, we reveal that a specific membrane efflux pump is induced in response to bile, leading to the release of magnesium ions, potentially reducing electrostatic repulsion forces between components of the biofilm matrix. This leads to a reduction of interbacterial distance and strengthens the biofilm structure. Our study, therefore, provides a better understanding of how bile promotes biofilm formation in a major gut symbiont, potentially promoting microbiota resilience to stress and dysbiosis events.
Topics: Biofilms; Bacteroides thetaiotaomicron; Magnesium; Bacterial Proteins; Bile; Humans; Membrane Transport Proteins; Gastrointestinal Microbiome; Gene Expression Regulation, Bacterial
PubMed: 38534200
DOI: 10.1128/mbio.03488-23 -
Nature Microbiology Apr 2024Plasticity in gene expression allows bacteria to adapt to diverse environments. This is particularly relevant in the dynamic niche of the human intestinal tract;...
Plasticity in gene expression allows bacteria to adapt to diverse environments. This is particularly relevant in the dynamic niche of the human intestinal tract; however, transcriptional networks remain largely unknown for gut-resident bacteria. Here we apply differential RNA sequencing (RNA-seq) and conventional RNA-seq to the model gut bacterium Bacteroides thetaiotaomicron to map transcriptional units and profile their expression levels across 15 in vivo-relevant growth conditions. We infer stress- and carbon source-specific transcriptional regulons and expand the annotation of small RNAs (sRNAs). Integrating this expression atlas with published transposon mutant fitness data, we predict conditionally important sRNAs. These include MasB, which downregulates tetracycline tolerance. Using MS2 affinity purification and RNA-seq, we identify a putative MasB target and assess its role in the context of the MasB-associated phenotype. These data-publicly available through the Theta-Base web browser ( http://micromix.helmholtz-hiri.de/bacteroides/ )-constitute a valuable resource for the microbiome community.
Topics: Humans; Bacteroides thetaiotaomicron; Transcriptome; RNA; Protein Synthesis Inhibitors; Tetracyclines
PubMed: 38528147
DOI: 10.1038/s41564-024-01642-9 -
Cell Reports Nov 2023Industrialization has transformed the gut microbiota, reducing the prevalence of relative to . Here, we isolate and strains from the microbiota of Hadza...
Industrialization has transformed the gut microbiota, reducing the prevalence of relative to . Here, we isolate and strains from the microbiota of Hadza hunter-gatherers in Tanzania, a population with high levels of . We demonstrate that plant-derived microbiota-accessible carbohydrates (MACs) are required for persistence of but not . Differences in carbohydrate metabolism gene content, expression, and growth reveal that Hadza strains specialize in degrading plant carbohydrates, while Hadza isolates use both plant and host-derived carbohydrates, a difference mirrored in from non-Hadza populations. When competing directly, requires plant-derived MACs to maintain colonization in the presence of , as a no-MAC diet eliminates colonization. 's reliance on plant-derived MACs and ' ability to use host mucus carbohydrates could explain the reduced prevalence of in populations consuming a low-MAC, industrialized diet.
Topics: Animals; Mice; Microbiota; Diet; Gastrointestinal Microbiome; Carbohydrates; Bacteroides; Prevotella
PubMed: 38510311
DOI: 10.1016/j.celrep.2023.113233 -
American Journal of Physiology.... May 2024Fecal microbiota transplantation (FMT) is a promising therapy for inflammatory bowel disease (IBD) via rectifying gut microbiota. The aim of this study was to identify a...
Fecal microbiota transplantation (FMT) is a promising therapy for inflammatory bowel disease (IBD) via rectifying gut microbiota. The aim of this study was to identify a mechanism of how specific bacteria-associated immune response contributes to alleviated colitis. Forty donors were divided into high () and low () groups according to the diversity and the abundance of and by 16S rRNA sequencing. FMT was performed on dextran sulfate sodium (DSS)-induced colitis in mice. Mice with colitis showed significant improvement in intestinal injury and immune imbalance after FMT with ( < 0.05). and were identified as targeted strains in donor feces by real-time PCR and droplet digital PCR. Mice with colitis were treated with mono- or dual-bacterial gavage therapy. Dual-bacterial therapy significantly ameliorated intestinal injury compared with mono-bacterial therapy ( < 0.05). Dual-bacterial therapy increased the M2/M1 macrophage polarization and improved the Th17/Treg imbalance and elevated IL-10 production by Tregs compared with the DSS group ( < 0.05). Metabolomics showed increased abundance of lecithin in the glycerophospholipid metabolism pathway. In conclusion, , as the key bacteria in donor feces, alleviate colitis in mice. The mechanism may involve increasing lecithin and regulating IL-10 production of intestinal Tregs. We demonstrate that donors with high abundance of and ameliorate dextran sulfate sodium (DSS)-induced colitis in mice by fecal microbiota transplantation (FMT). The combination therapy of and is superior to mono-bacterial therapy in ameliorating colitis in mice, of which mechanism may involve promoting lecithin and inducing IL-10 production of intestinal Tregs.
Topics: Animals; Fecal Microbiota Transplantation; Colitis; Faecalibacterium prausnitzii; Mice; Gastrointestinal Microbiome; Male; Humans; Bacteroides thetaiotaomicron; Dextran Sulfate; Mice, Inbred C57BL; Interleukin-10; Adult; Female; Feces; Disease Models, Animal; Middle Aged
PubMed: 38502145
DOI: 10.1152/ajpgi.00303.2023 -
Nature Communications Mar 2024Synthetic biologists seek to engineer intelligent living systems capable of decision-making, communication, and memory. Separate technologies exist for each tenet of...
Synthetic biologists seek to engineer intelligent living systems capable of decision-making, communication, and memory. Separate technologies exist for each tenet of intelligence; however, the unification of all three properties in a living system has not been achieved. Here, we engineer completely intelligent Escherichia coli strains that harbor six orthogonal and inducible genome-integrated recombinases, forming Molecularly Encoded Memory via an Orthogonal Recombinase arraY (MEMORY). MEMORY chassis cells facilitate intelligence via the discrete multi-input regulation of recombinase functions enabling inheritable DNA inversions, deletions, and genomic insertions. MEMORY cells can achieve programmable and permanent gain (or loss) of functions extrachromosomally or from a specific genomic locus, without the loss or modification of the MEMORY platform - enabling the sequential programming and reprogramming of DNA circuits within the cell. We demonstrate all three tenets of intelligence via a probiotic (Nissle 1917) MEMORY strain capable of information exchange with the gastrointestinal commensal Bacteroides thetaiotaomicron.
Topics: Recombinases; Escherichia coli; DNA; Genomics
PubMed: 38499601
DOI: 10.1038/s41467-024-46755-1 -
Microbiome Research Reports 2024The infant gut microbiome is a complex community that influences short- and long-term health. Its assembly and composition are governed by variables such as the feeding...
The infant gut microbiome is a complex community that influences short- and long-term health. Its assembly and composition are governed by variables such as the feeding type. Breast milk provides infants an important supply of human milk oligosaccharides (HMO), a broad family of carbohydrates comprising neutral, fucosylated, and sialylated molecules. There is a positive association between HMOs and the overrepresentation of species in the infant gut, which is sustained by multiple molecular determinants present in the genomes of these species. Infant-gut-associated species usually share a similar niche and display similar HMO inclinations, suggesting they compete for these resources. There is also strong evidence of cross-feeding interactions between HMO-derived molecules and bifidobacteria. In this study, we screened for unidirectional and bidirectional interactions between and other species using individual HMO. and increased the growth of several other species when their supernatants were used, probably mediated by the partial degradation of HMO. In contrast, subsp. . supernatants did not exhibit positive growth. species compete for lacto--tetraose, which is associated with reduced bidirectional growth. The outcome of these interactions was HMO-dependent, in which the two species could compete for one substrate but cross-feed on another. 2'-fucosyllactose and lacto--neotetraose are associated with several positive interactions that generally originate from the partial degradation of these HMOs. This study presents evidence for complex interactions during HMO utilization, which can be cooperative or competitive, depending on the nature of the HMO. This information could be useful for understanding how breast milk supports the growth of some species, shaping the ecology of this important microbial community.
PubMed: 38455082
DOI: 10.20517/mrr.2023.61 -
Nature Communications Mar 2024Sophisticated gene circuits built by synthetic biology can enable bacteria to sense their environment and respond predictably. Engineered biosensing bacteria outfitted...
Sophisticated gene circuits built by synthetic biology can enable bacteria to sense their environment and respond predictably. Engineered biosensing bacteria outfitted with such circuits can potentially probe the human gut microbiome to prevent, diagnose, or treat disease. To provide robust biocontainment for engineered bacteria, we devised a Cas9-assisted auxotrophic biocontainment system combining thymidine auxotrophy, an Engineered Riboregulator (ER) for controlled gene expression, and a CRISPR Device (CD). The CD prevents the engineered bacteria from acquiring thyA via horizontal gene transfer, which would disrupt the biocontainment system, and inhibits the spread of genetic elements by killing bacteria harboring the gene cassette. This system tunably controlled gene expression in the human gut commensal bacterium Bacteroides thetaiotaomicron, prevented escape from thymidine auxotrophy, and blocked transgene dissemination. These capabilities were validated in vitro and in vivo. This biocontainment system exemplifies a powerful strategy for bringing genetically engineered microorganisms safely into biomedicine.
Topics: Humans; CRISPR-Cas Systems; Containment of Biohazards; Genetic Engineering; Bacteria; Thymidine
PubMed: 38453913
DOI: 10.1038/s41467-024-45893-w -
MSystems Apr 2024The microbial utilization of dietary carbohydrates is closely linked to the pivotal role of the gut microbiome in human health. Inherent to the modulation of complex...
UNLABELLED
The microbial utilization of dietary carbohydrates is closely linked to the pivotal role of the gut microbiome in human health. Inherent to the modulation of complex microbial communities, a prebiotic implies the selective utilization of a specific substrate, relying on the metabolic capacities of targeted microbes. In this study, we investigated the metabolic capacities of 17 commensal bacteria of the human gut microbiome toward dietary carbohydrates with prebiotic potential. First, experiments allowed the classification of bacterial growth and fermentation profiles in response to various carbon sources, including agave inulin, corn fiber, polydextrose, and citrus pectin. The influence of phylogenetic affiliation appeared to statistically outweigh carbon sources in determining the degree of carbohydrate utilization. Second, we narrowed our focus on six commensal bacteria representative of the and phyla to perform an untargeted high-resolution liquid chromatography-mass spectrometry metabolomic analysis: , , , , and exhibited distinct metabolomic profiles in response to different carbon sources. The relative abundance of bacterial metabolites was significantly influenced by dietary carbohydrates, with these effects being strain-specific and/or carbohydrate-specific. Particularly, the findings indicated an elevation in short-chain fatty acids and other metabolites, including succinate, gamma-aminobutyric acid, and nicotinic acid. These metabolites were associated with putative health benefits. Finally, an RNA-Seq transcriptomic approach provided deeper insights into the underlying mechanisms of carbohydrate metabolization. Restricting our focus on four commensal bacteria, including , and , carbon sources did significantly modulate the level of bacterial genes related to the enzymatic machinery involved in the metabolization of dietary carbohydrates. This study provides a holistic view of the molecular strategies induced during the dynamic interplay between dietary carbohydrates with prebiotic potential and gut commensal bacteria.
IMPORTANCE
This study explores at a molecular level the interactions between commensal health-relevant bacteria and dietary carbohydrates holding prebiotic potential. We showed that prebiotic breakdown involves the specific activation of gene expression related to carbohydrate metabolism. We also identified metabolites produced by each bacteria that are potentially related to our digestive health. The characterization of the functional activities of health-relevant bacteria toward prebiotic substances can yield a better application of prebiotics in clinical interventions and personalized nutrition. Overall, this study highlights the importance of identifying the impact of prebiotics at a low resolution of the gut microbiota to characterize the activities of targeted bacteria that can play a crucial role in our health.
Topics: Humans; Prebiotics; Dietary Carbohydrates; Phylogeny; Bacteria; Carbon
PubMed: 38441031
DOI: 10.1128/msystems.01401-23 -
Pharmacological Research Apr 2024
peu-MIR2916-p3-enriched garlic exosomes ameliorate murine colitis by reshaping gut microbiota, especially by boosting the anti-colitic Bacteroides thetaiotaomicron - Correspondence.
Topics: Mice; Humans; Animals; Bacteroides thetaiotaomicron; Garlic; Gastrointestinal Microbiome; Exosomes; Colitis
PubMed: 38438088
DOI: 10.1016/j.phrs.2024.107131