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Nature Jan 2014Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and... (Clinical Trial)
Clinical Trial
Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and reproducibly the human gut microbiome responds to short-term macronutrient change. Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles.
Topics: Adult; Bacteria; Bacteroides; Bile Acids and Salts; Bilophila; Carnivory; Diet; Diet, Vegetarian; Dietary Fats; Feces; Female; Fermentation; Food Microbiology; Gastrointestinal Tract; Gene Expression Regulation, Bacterial; Herbivory; Humans; Inflammatory Bowel Diseases; Male; Metagenome; Microbiota; Time Factors; Young Adult
PubMed: 24336217
DOI: 10.1038/nature12820 -
Science (New York, N.Y.) Oct 2011Diet strongly affects human health, partly by modulating gut microbiome composition. We used diet inventories and 16S rDNA sequencing to characterize fecal samples from... (Randomized Controlled Trial)
Randomized Controlled Trial
Diet strongly affects human health, partly by modulating gut microbiome composition. We used diet inventories and 16S rDNA sequencing to characterize fecal samples from 98 individuals. Fecal communities clustered into enterotypes distinguished primarily by levels of Bacteroides and Prevotella. Enterotypes were strongly associated with long-term diets, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella). A controlled-feeding study of 10 subjects showed that microbiome composition changed detectably within 24 hours of initiating a high-fat/low-fiber or low-fat/high-fiber diet, but that enterotype identity remained stable during the 10-day study. Thus, alternative enterotype states are associated with long-term diet.
Topics: Adolescent; Adult; Bacteria; Bacteroides; Child; Child, Preschool; Cross-Sectional Studies; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Fiber; Feces; Gastrointestinal Tract; Humans; Metagenome; Middle Aged; Prevotella; Ruminococcus; Time Factors; Young Adult
PubMed: 21885731
DOI: 10.1126/science.1208344 -
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 -
Gut Sep 2020High-fat diet (HFD)-induced metabolic disorders can lead to impaired sperm production. We aim to investigate if HFD-induced gut microbiota dysbiosis can functionally...
OBJECTIVE
High-fat diet (HFD)-induced metabolic disorders can lead to impaired sperm production. We aim to investigate if HFD-induced gut microbiota dysbiosis can functionally influence spermatogenesis and sperm motility.
DESIGN
Faecal microbes derived from the HFD-fed or normal diet (ND)-fed male mice were transplanted to the mice maintained on ND. The gut microbes, sperm count and motility were analysed. Human faecal/semen/blood samples were collected to assess microbiota, sperm quality and endotoxin.
RESULTS
Transplantation of the HFD gut microbes into the ND-maintained (HFD-FMT) mice resulted in a significant decrease in spermatogenesis and sperm motility, whereas similar transplantation with the microbes from the ND-fed mice failed to do so. Analysis of the microbiota showed a profound increase in genus and , both of which likely contributed to the metabolic endotoxaemia in the HFD-FMT mice. Interestingly, the gut microbes from clinical subjects revealed a strong negative correlation between the abundance of and sperm motility, and a positive correlation between blood endotoxin and abundance. Transplantation with HFD microbes also led to intestinal infiltration of T cells and macrophages as well as a significant increase of pro-inflammatory cytokines in the epididymis, suggesting that epididymal inflammation have likely contributed to the impairment of sperm motility. RNA-sequencing revealed significant reduction in the expression of those genes involved in gamete meiosis and testicular mitochondrial functions in the HFD-FMT mice.
CONCLUSION
We revealed an intimate linkage between HFD-induced microbiota dysbiosis and defect in spermatogenesis with elevated endotoxin, dysregulation of testicular gene expression and localised epididymal inflammation as the potential causes.
TRIAL REGISTRATION NUMBER
NCT03634644.
Topics: Animals; Bacteroides; Correlation of Data; Cytokines; Diet, High-Fat; Dysbiosis; Endotoxemia; Epididymis; Feces; Gastrointestinal Microbiome; Humans; Macrophages; Male; Mice; Prevotella; Sperm Motility; Spermatogenesis; T-Lymphocytes
PubMed: 31900292
DOI: 10.1136/gutjnl-2019-319127 -
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 Jun 2018Tryptamine, a tryptophan-derived monoamine similar to 5-hydroxytryptamine (5-HT), is produced by gut bacteria and is abundant in human and rodent feces. However, the...
Tryptamine, a tryptophan-derived monoamine similar to 5-hydroxytryptamine (5-HT), is produced by gut bacteria and is abundant in human and rodent feces. However, the physiologic effect of tryptamine in the gastrointestinal (GI) tract remains unknown. Here, we show that the biological effects of tryptamine are mediated through the 5-HT receptor (5-HTR), a G-protein-coupled receptor (GPCR) uniquely expressed in the colonic epithelium. Tryptamine increases both ionic flux across the colonic epithelium and fluid secretion in colonoids from germ-free (GF) and humanized (ex-GF colonized with human stool) mice, consistent with increased intestinal secretion. The secretory effect of tryptamine is dependent on 5-HTR activation and is blocked by 5-HTR antagonist and absent in 5-HTR mice. GF mice colonized by Bacteroides thetaiotaomicron engineered to produce tryptamine exhibit accelerated GI transit. Our study demonstrates an aspect of host physiology under control of a bacterial metabolite that can be exploited as a therapeutic modality. VIDEO ABSTRACT.
Topics: Animals; Bacteroides thetaiotaomicron; Colon; Epithelium; Feces; Gastrointestinal Microbiome; Humans; Intestinal Secretions; Mice; Mice, 129 Strain; Mice, Knockout; Primary Cell Culture; Receptors, Serotonin, 5-HT4; Sex Factors; Specific Pathogen-Free Organisms; Tryptamines
PubMed: 29902441
DOI: 10.1016/j.chom.2018.05.004 -
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 -
Nature Nov 2021Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease. Despite this...
Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease. Despite this well-known collateral damage, the activity spectrum of different antibiotic classes on gut bacteria remains poorly characterized. Here we characterize further 144 antibiotics from a previous screen of more than 1,000 drugs on 38 representative human gut microbiome species. Antibiotic classes exhibited distinct inhibition spectra, including generation dependence for quinolones and phylogeny independence for β-lactams. Macrolides and tetracyclines, both prototypic bacteriostatic protein synthesis inhibitors, inhibited nearly all commensals tested but also killed several species. Killed bacteria were more readily eliminated from in vitro communities than those inhibited. This species-specific killing activity challenges the long-standing distinction between bactericidal and bacteriostatic antibiotic classes and provides a possible explanation for the strong effect of macrolides on animal and human gut microbiomes. To mitigate this collateral damage of macrolides and tetracyclines, we screened for drugs that specifically antagonized the antibiotic activity against abundant Bacteroides species but not against relevant pathogens. Such antidotes selectively protected Bacteroides species from erythromycin treatment in human-stool-derived communities and gnotobiotic mice. These findings illluminate the activity spectra of antibiotics in commensal bacteria and suggest strategies to circumvent their adverse effects on the gut microbiota.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacteria, Anaerobic; Bacteroides; Clostridioides difficile; Dicumarol; Erythromycin; Feces; Female; Gastrointestinal Microbiome; Germ-Free Life; Humans; Macrolides; Male; Mice; Microbiota; Symbiosis; Tetracyclines
PubMed: 34646011
DOI: 10.1038/s41586-021-03986-2 -
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