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Gut Microbes 2021The functional diversity of the mammalian intestinal microbiome far exceeds that of the host organism, and microbial genes contribute substantially to the well-being of... (Review)
Review
The functional diversity of the mammalian intestinal microbiome far exceeds that of the host organism, and microbial genes contribute substantially to the well-being of the host. However, beneficial gut organisms can also be pathogenic when present in the gut or other locations in the body. Among dominant beneficial bacteria are several species of , which metabolize polysaccharides and oligosaccharides, providing nutrition and vitamins to the host and other intestinal microbial residents. These topics and the specific organismal and molecular interactions that are known to be responsible for the beneficial and detrimental effects of species in humans comprise the focus of this review. The complexity of these interactions will be revealed.
Topics: Animals; Bacteroides; Extracellular Vesicles; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Microbial Interactions; Polysaccharides; Virulence Factors
PubMed: 33535896
DOI: 10.1080/19490976.2020.1848158 -
Nature Microbiology Mar 2019The gut microbiota affects many important host functions, including the immune response and the nervous system. However, while substantial progress has been made in...
The gut microbiota affects many important host functions, including the immune response and the nervous system. However, while substantial progress has been made in growing diverse microorganisms of the microbiota, 23-65% of species residing in the human gut remain uncultured, which is an obstacle for understanding their biological roles. A likely reason for this unculturability is the absence in artificial media of key growth factors that are provided by neighbouring bacteria in situ. In the present study, we used co-culture to isolate KLE1738, which required the presence of Bacteroides fragilis to grow. Bioassay-driven purification of B. fragilis supernatant led to the isolation of the growth factor, which, surprisingly, is the major inhibitory neurotransmitter GABA (γ-aminobutyric acid). GABA was the only tested nutrient that supported the growth of KLE1738, and a genome analysis supported a GABA-dependent metabolism mechanism. Using growth of KLE1738 as an indicator, we isolated a variety of GABA-producing bacteria, and found that Bacteroides ssp. produced large quantities of GABA. Genome-based metabolic modelling of the human gut microbiota revealed multiple genera with the predicted capability to produce or consume GABA. A transcriptome analysis of human stool samples from healthy individuals showed that GABA-producing pathways are actively expressed by Bacteroides, Parabacteroides and Escherichia species. By coupling 16S ribosmal RNA sequencing with functional magentic resonance imaging in patients with major depressive disorder, a disease associated with an altered GABA-mediated response, we found that the relative abundance levels of faecal Bacteroides are negatively correlated with brain signatures associated with depression.
Topics: Adult; Aged; Bacteria; Bacteroides; Brain; Cohort Studies; Depression; Depressive Disorder, Major; Feces; Female; Gastrointestinal Microbiome; Gastrointestinal Tract; Gene Expression Profiling; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Whole Genome Sequencing; Young Adult; gamma-Aminobutyric Acid
PubMed: 30531975
DOI: 10.1038/s41564-018-0307-3 -
Cell Jun 2018The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut...
The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protection, including reductions in systemic gamma-glutamylated amino acids and elevated hippocampal GABA/glutamate levels. Bacterial cross-feeding decreases gamma-glutamyltranspeptidase activity, and inhibiting gamma-glutamylation promotes seizure protection in vivo. Overall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.
Topics: Animals; Anti-Bacterial Agents; Bacteroides; Diet, Ketogenic; Disease Models, Animal; Feces; Gastrointestinal Microbiome; Glutamic Acid; Hippocampus; Intestinal Mucosa; Kv1.1 Potassium Channel; Metabolome; Mice; Mice, Inbred C3H; Mice, Knockout; Principal Component Analysis; RNA, Ribosomal, 16S; Seizures; gamma-Aminobutyric Acid; gamma-Glutamyltransferase
PubMed: 29804833
DOI: 10.1016/j.cell.2018.04.027 -
Nature Jul 2021Gut microorganisms modulate host phenotypes and are associated with numerous health effects in humans, ranging from host responses to cancer immunotherapy to metabolic...
Gut microorganisms modulate host phenotypes and are associated with numerous health effects in humans, ranging from host responses to cancer immunotherapy to metabolic disease and obesity. However, difficulty in accurate and high-throughput functional analysis of human gut microorganisms has hindered efforts to define mechanistic connections between individual microbial strains and host phenotypes. One key way in which the gut microbiome influences host physiology is through the production of small molecules, yet progress in elucidating this chemical interplay has been hindered by limited tools calibrated to detect the products of anaerobic biochemistry in the gut. Here we construct a microbiome-focused, integrated mass-spectrometry pipeline to accelerate the identification of microbiota-dependent metabolites in diverse sample types. We report the metabolic profiles of 178 gut microorganism strains using our library of 833 metabolites. Using this metabolomics resource, we establish deviations in the relationships between phylogeny and metabolism, use machine learning to discover a previously undescribed type of metabolism in Bacteroides, and reveal candidate biochemical pathways using comparative genomics. Microbiota-dependent metabolites can be detected in diverse biological fluids from gnotobiotic and conventionally colonized mice and traced back to the corresponding metabolomic profiles of cultured bacteria. Collectively, our microbiome-focused metabolomics pipeline and interactive metabolomics profile explorer are a powerful tool for characterizing microorganisms and interactions between microorganisms and their host.
Topics: Animals; Bacteria; Bacteroides; Gastrointestinal Microbiome; Genes, Bacterial; Genomics; Host Microbial Interactions; Humans; Male; Metabolome; Metabolomics; Mice; Nitrogen; Phenotype; Phylogeny
PubMed: 34262212
DOI: 10.1038/s41586-021-03707-9 -
Bacteroides-Derived Sphingolipids Are Critical for Maintaining Intestinal Homeostasis and Symbiosis.Cell Host & Microbe May 2019Sphingolipids are structural membrane components and important eukaryotic signaling molecules. Sphingolipids regulate inflammation and immunity and were recently...
Sphingolipids are structural membrane components and important eukaryotic signaling molecules. Sphingolipids regulate inflammation and immunity and were recently identified as the most differentially abundant metabolite in stool from inflammatory bowel disease (IBD) patients. Commensal bacteria from the Bacteroidetes phylum also produce sphingolipids, but the impact of these metabolites on host pathways is largely uncharacterized. To determine whether bacterial sphingolipids modulate intestinal health, we colonized germ-free mice with a sphingolipid-deficient Bacteroides thetaiotaomicron strain. A lack of Bacteroides-derived sphingolipids resulted in intestinal inflammation and altered host ceramide pools in mice. Using lipidomic analysis, we described a sphingolipid biosynthesis pathway and revealed a variety of Bacteroides-derived sphingolipids including ceramide phosphoinositol and deoxy-sphingolipids. Annotating Bacteroides sphingolipids in an IBD metabolomic dataset revealed lower abundances in IBD and negative correlations with inflammation and host sphingolipid production. These data highlight the role of bacterial sphingolipids in maintaining homeostasis and symbiosis in the gut.
Topics: Animals; Bacteroides thetaiotaomicron; Germ-Free Life; Homeostasis; Host Microbial Interactions; Inflammatory Bowel Diseases; Intestines; Mice; Sphingolipids; Symbiosis
PubMed: 31071294
DOI: 10.1016/j.chom.2019.04.002 -
Nature Jun 2019Individuals vary widely in their responses to medicinal drugs, which can be dangerous and expensive owing to treatment delays and adverse effects. Although increasing...
Individuals vary widely in their responses to medicinal drugs, which can be dangerous and expensive owing to treatment delays and adverse effects. Although increasing evidence implicates the gut microbiome in this variability, the molecular mechanisms involved remain largely unknown. Here we show, by measuring the ability of 76 human gut bacteria from diverse clades to metabolize 271 orally administered drugs, that many drugs are chemically modified by microorganisms. We combined high-throughput genetic analyses with mass spectrometry to systematically identify microbial gene products that metabolize drugs. These microbiome-encoded enzymes can directly and substantially affect intestinal and systemic drug metabolism in mice, and can explain the drug-metabolizing activities of human gut bacteria and communities on the basis of their genomic contents. These causal links between the gene content and metabolic activities of the microbiota connect interpersonal variability in microbiomes to interpersonal differences in drug metabolism, which has implications for medical therapy and drug development across multiple disease indications.
Topics: Animals; Bacteria; Bacteroides thetaiotaomicron; Diltiazem; Female; Gastrointestinal Microbiome; Genome, Bacterial; Germ-Free Life; Humans; Male; Mice; Pharmaceutical Preparations; Substrate Specificity
PubMed: 31158845
DOI: 10.1038/s41586-019-1291-3 -
Nature Microbiology Feb 2022Ulcerative colitis (UC) is driven by disruptions in host-microbiota homoeostasis, but current treatments exclusively target host inflammatory pathways. To understand how...
Ulcerative colitis (UC) is driven by disruptions in host-microbiota homoeostasis, but current treatments exclusively target host inflammatory pathways. To understand how host-microbiota interactions become disrupted in UC, we collected and analysed six faecal- or serum-based omic datasets (metaproteomic, metabolomic, metagenomic, metapeptidomic and amplicon sequencing profiles of faecal samples and proteomic profiles of serum samples) from 40 UC patients at a single inflammatory bowel disease centre, as well as various clinical, endoscopic and histologic measures of disease activity. A validation cohort of 210 samples (73 UC, 117 Crohn's disease, 20 healthy controls) was collected and analysed separately and independently. Data integration across both cohorts showed that a subset of the clinically active UC patients had an overabundance of proteases that originated from the bacterium Bacteroides vulgatus. To test whether B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases found in patients and bacterial cultures. Use of a broad-spectrum protease inhibitor improved B. vulgatus-induced barrier dysfunction in vitro, and prevented colitis in B. vulgatus monocolonized, IL10-deficient mice. Furthermore, transplantation of faeces from UC patients with a high abundance of B. vulgatus proteases into germfree mice induced colitis dependent on protease activity. These results, stemming from a multi-omics approach, improve understanding of functional microbiota alterations that drive UC and provide a resource for identifying other pathways that could be inhibited as a strategy to treat this disease.
Topics: Adult; Animals; Bacterial Proteins; Bacteroides; Cohort Studies; Colitis, Ulcerative; Feces; Female; Gastrointestinal Microbiome; Humans; Longitudinal Studies; Male; Metagenome; Metagenomics; Mice; Middle Aged; Peptide Hydrolases; Proteomics; Severity of Illness Index
PubMed: 35087228
DOI: 10.1038/s41564-021-01050-3 -
Cell Host & Microbe Oct 2019The human gut contains a vast array of viruses, mostly bacteriophages. The majority remain uncharacterized, and their roles in shaping the gut microbiome and in...
The human gut contains a vast array of viruses, mostly bacteriophages. The majority remain uncharacterized, and their roles in shaping the gut microbiome and in impacting on human health remain poorly understood. We performed longitudinal metagenomic analysis of fecal viruses in healthy adults that reveal high temporal stability, individual specificity, and correlation with the bacterial microbiome. Using a database-independent approach that uses most of the sequencing data, we uncovered the existence of a stable, numerically predominant individual-specific persistent personal virome. Clustering of viral genomes and de novo taxonomic annotation identified several groups of crAss-like and Microviridae bacteriophages as the most stable colonizers of the human gut. CRISPR-based host prediction highlighted connections between these stable viral communities and highly predominant gut bacterial taxa such as Bacteroides, Prevotella, and Faecalibacterium. This study provides insights into the structure of the human gut virome and serves as an important baseline for hypothesis-driven research.
Topics: Bacteroides; Faecalibacterium; Gastrointestinal Microbiome; Humans; Longitudinal Studies; Metagenome; Microviridae; Prevotella; Viral Load
PubMed: 31600503
DOI: 10.1016/j.chom.2019.09.009 -
Science Advances Jan 2023Although gut microbiota has been linked to exercise, whether alterations in the abundance of specific bacteria improve exercise performance remains ambiguous. In a... (Randomized Controlled Trial)
Randomized Controlled Trial
Although gut microbiota has been linked to exercise, whether alterations in the abundance of specific bacteria improve exercise performance remains ambiguous. In a cross-sectional study involving 25 male long-distance runners, we found a correlation between abundance in feces and the 3000-m race time. In addition, we administered flaxseed lignan or α-cyclodextrin as a test tablet to healthy, active males who regularly exercised in a randomized, double-blind, placebo-controlled study to increase in the gut (UMIN000033748). The results indicated that α-cyclodextrin supplementation improved human endurance exercise performance. Moreover, administration in mice increased swimming time to exhaustion, cecal short-chain fatty acid concentrations, and the gene expression of enzymes associated with gluconeogenesis in the liver while decreasing hepatic glycogen content. These findings indicate that enhances endurance exercise performance, which may be mediated by facilitating hepatic endogenous glucose production.
Topics: Humans; Mice; Male; Animals; Cross-Sectional Studies; alpha-Cyclodextrins; Bacteroides; Gastrointestinal Microbiome
PubMed: 36696509
DOI: 10.1126/sciadv.add2120 -
The Journal of Pediatrics Dec 2018To determine the association between diet during pregnancy and infancy, including breastfeeding vs formula feeding, solid food introduction, and the infant intestinal... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To determine the association between diet during pregnancy and infancy, including breastfeeding vs formula feeding, solid food introduction, and the infant intestinal microbiome.
STUDY DESIGN
Infants participating in the Vitamin D Antenatal Asthma Reduction Trial were included in this study (n = 323). Maternal and infant diets were assessed by questionnaire. Infant stool samples were collected at age 3-6 months. Stool sequencing was performed using the Roche 454 platform. Analyses were stratified by race/ethnicity.
RESULTS
Breastfeeding, compared with formula feeding, was independently associated with infant intestinal microbial diversity. Breastfeeding also had the most consistent associations with individual taxa that have been previously linked to early-life diet and health outcomes (eg, Bifidobacterium). Maternal diet during pregnancy and solid food introduction were less associated with the infant gut microbiome than breastfeeding status. We found evidence of a possible interaction between breastfeeding and child race/ethnicity on microbial composition.
CONCLUSIONS
Breastfeeding vs formula feeding is the dietary factor that is most consistently independently associated with the infant intestinal microbiome. The relationship between breastfeeding status and intestinal microbiome composition varies by child race/ethnicity. Future studies will need to investigate factors, including genomic factors, which may influence the response of the microbiome to diet.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT00920621.
Topics: Bacteroides; Bifidobacterium; Breast Feeding; Clostridium; Diet; Feces; Female; Gastrointestinal Microbiome; Humans; Infant; Infant Formula; Male; Pregnancy; RNA, Ribosomal, 16S; Race Factors; Sequence Analysis, RNA; Surveys and Questionnaires
PubMed: 30173873
DOI: 10.1016/j.jpeds.2018.07.066