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Journal of Food and Drug Analysis Jul 2019Studies on the role of gut commensal bacteria in health development have rapidly attracted much more attention beyond the classical pathogens over the last decade. Many... (Review)
Review
Studies on the role of gut commensal bacteria in health development have rapidly attracted much more attention beyond the classical pathogens over the last decade. Many important reports have highlighted the changes in the gut microbiota (dysbiosis) are closely related to development of intra- and extra-intestinal, chronic inflammation related diseases such as colitis, obesity/metabolic syndromes, diabetes mellitus, liver diseases, cardiovascular diseases and also cancer and neurodegenerative diseases. To circumvent these difficulties, the strategy of modulating the structure of the gut microbiota has been under intensive study and shed more light on amelioration of these inflammation related diseases. While traditional probiotics generally show marginal ameliorative effects, emerging next generation probiotics start to reveal as new preventive and therapeutic tools. Recent studies have unraveled many potential next generation probiotics (NGP). These include Prevotella copri and Christensenella minuta that control insulin resistance, Parabacteroides goldsteinii, Akkermansia muciniphila and Bacteroides thetaiotaomicron that reverse obesity and insulin resistance, Faecalibacterium prausnitzii that protects mice against intestinal diseases, and Bacteroides fragilis that reduces inflammation and shows anticancer effect. New agents will soon be revealed for targeted therapy on specific inflammation related diseases. The important roles of next generation probiotics and gut microbiota normobiosis on the maintenance of intestinal integrity and homeostasis are emphasized.
Topics: Animals; Cardiovascular Diseases; Colitis; Diabetes Mellitus; Gastrointestinal Microbiome; Humans; Inflammation; Liver Diseases; Metabolic Syndrome; Neoplasms; Neurodegenerative Diseases; Obesity; Probiotics
PubMed: 31324278
DOI: 10.1016/j.jfda.2018.12.011 -
Science (New York, N.Y.) Nov 2015Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides...
Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.
Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Bacterial Agents; Antibodies, Monoclonal; Bacteroides; CTLA-4 Antigen; Dysbiosis; Fecal Microbiota Transplantation; Female; Gastrointestinal Microbiome; Germ-Free Life; Humans; Immunologic Memory; Immunotherapy; Intestines; Ipilimumab; Male; Melanoma; Mice; Mice, Inbred C57BL; Middle Aged; Skin Neoplasms; T-Lymphocytes
PubMed: 26541610
DOI: 10.1126/science.aad1329 -
Cell Sep 2022The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation...
The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for intestinal GVHD, but mechanisms are not well understood. In this study, we found that treatment with meropenem, a commonly used carbapenem, aggravates colonic GVHD in mice via the expansion of Bacteroides thetaiotaomicron (BT). BT has a broad ability to degrade dietary polysaccharides and host mucin glycans. BT in meropenem-treated allogeneic mice demonstrated upregulated expression of enzymes involved in the degradation of mucin glycans. These mice also had thinning of the colonic mucus layer and decreased levels of xylose in colonic luminal contents. Interestingly, oral xylose supplementation significantly prevented thinning of the colonic mucus layer in meropenem-treated mice. Specific nutritional supplementation strategies, including xylose supplementation, may combat antibiotic-mediated microbiome injury to reduce the risk for intestinal GVHD in allo-HSCT patients.
Topics: Animals; Anti-Bacterial Agents; Bacteroides; Carbapenems; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Meropenem; Mice; Mucins; Mucus; Polysaccharides; Xylose
PubMed: 36179667
DOI: 10.1016/j.cell.2022.09.007 -
Cell Host & Microbe Jun 2022Microbially-derived gut metabolites are important contributors to host phenotypes, many of which may link microbiome composition to metabolic disease. However,...
Microbially-derived gut metabolites are important contributors to host phenotypes, many of which may link microbiome composition to metabolic disease. However, relatively few metabolites with known bioactivity have been traced from specific microbes to host tissues. Here, we use a labeling strategy to characterize and trace bacterial sphingolipids from the gut symbiont Bacteroides thetaiotaomicron to mouse colons and livers. We find that bacterial sphingolipid synthesis rescues excess lipid accumulation in a mouse model of hepatic steatosis and observe the transit of a previously uncharacterized bacterial sphingolipid to the liver. The addition of this sphingolipid to hepatocytes improves respiration in response to fatty-acid overload, suggesting that sphingolipid transfer to the liver could potentially contribute to microbiota-mediated liver function. This work establishes a role for bacterial sphingolipids in modulating hepatic phenotypes and defines a workflow that permits the characterization of other microbial metabolites with undefined functions in host health.
Topics: Animals; Bacteroides thetaiotaomicron; Gastrointestinal Microbiome; Liver; Mice; Microbiota; Sphingolipids
PubMed: 35623356
DOI: 10.1016/j.chom.2022.05.002 -
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 -
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 -
Gastroenterology Sep 2020Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects gastrointestinal tissues, little is known about the roles of gut commensal microbes in...
BACKGROUND & AIMS
Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects gastrointestinal tissues, little is known about the roles of gut commensal microbes in susceptibility to and severity of infection. We investigated changes in fecal microbiomes of patients with SARS-CoV-2 infection during hospitalization and associations with severity and fecal shedding of virus.
METHODS
We performed shotgun metagenomic sequencing analyses of fecal samples from 15 patients with Coronavirus Disease 2019 (COVID-19) in Hong Kong, from February 5 through March 17, 2020. Fecal samples were collected 2 or 3 times per week from time of hospitalization until discharge; disease was categorized as mild (no radiographic evidence of pneumonia), moderate (pneumonia was present), severe (respiratory rate ≥30/min, or oxygen saturation ≤93% when breathing ambient air), or critical (respiratory failure requiring mechanical ventilation, shock, or organ failure requiring intensive care). We compared microbiome data with those from 6 subjects with community-acquired pneumonia and 15 healthy individuals (controls). We assessed gut microbiome profiles in association with disease severity and changes in fecal shedding of SARS-CoV-2.
RESULTS
Patients with COVID-19 had significant alterations in fecal microbiomes compared with controls, characterized by enrichment of opportunistic pathogens and depletion of beneficial commensals, at time of hospitalization and at all timepoints during hospitalization. Depleted symbionts and gut dysbiosis persisted even after clearance of SARS-CoV-2 (determined from throat swabs) and resolution of respiratory symptoms. The baseline abundance of Coprobacillus, Clostridium ramosum, and Clostridium hathewayi correlated with COVID-19 severity; there was an inverse correlation between abundance of Faecalibacterium prausnitzii (an anti-inflammatory bacterium) and disease severity. Over the course of hospitalization, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides massiliensis, and Bacteroides ovatus, which downregulate expression of angiotensin-converting enzyme 2 (ACE2) in murine gut, correlated inversely with SARS-CoV-2 load in fecal samples from patients.
CONCLUSIONS
In a pilot study of 15 patients with COVID-19, we found persistent alterations in the fecal microbiome during the time of hospitalization, compared with controls. Fecal microbiota alterations were associated with fecal levels of SARS-CoV-2 and COVID-19 severity. Strategies to alter the intestinal microbiota might reduce disease severity.
Topics: Adult; Aged; Betacoronavirus; COVID-19; Coronavirus Infections; Dysbiosis; Feces; Female; Gastrointestinal Microbiome; Gastrointestinal Tract; Hong Kong; Hospitalization; Humans; Male; Middle Aged; Pandemics; Pilot Projects; Pneumonia, Viral; SARS-CoV-2
PubMed: 32442562
DOI: 10.1053/j.gastro.2020.05.048 -
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 -
Microbial Cell Factories Feb 2020The gut microbiota can significantly affect the function of the intestinal barrier. Some intestinal probiotics (such as Lactobacillus, Bifidobacteria, a few Escherichia... (Review)
Review
The gut microbiota can significantly affect the function of the intestinal barrier. Some intestinal probiotics (such as Lactobacillus, Bifidobacteria, a few Escherichia coli strains, and a new generation of probiotics including Bacteroides thetaiotaomicron and Akkermansia muciniphila) can maintain intestinal epithelial homeostasis and promote health. This review first summarizes probiotics' regulation of the intestinal epithelium via their surface compounds. Surface layer proteins, flagella, pili and capsular polysaccharides constitute microbial-associated molecular patterns and specifically bind to pattern recognition receptors, which can regulate signaling pathways to produce cytokines or inhibit apoptosis, thereby attenuating inflammation and enhancing the function of the gut epithelium. The review also explains the effects of metabolites (such as secreted proteins, organic acids, indole, extracellular vesicles and bacteriocins) of probiotics on host receptors and the mechanisms by which these metabolites regulate gut epithelial barrier function. Previous reviews summarized the role of the surface macromolecules or metabolites of gut microbes (including both probiotics and pathogens) in human health. However, these reviews were mostly focused on the interactions between these substances and the intestinal mucosal immune system. In the current review, we only focused on probiotics and discussed the molecular interaction between these bacteria and the gut epithelial barrier.
Topics: Animals; Bacteria; Cell Line; Gastrointestinal Microbiome; Homeostasis; Host Microbial Interactions; Humans; Intestinal Mucosa; Mice; Probiotics
PubMed: 32024520
DOI: 10.1186/s12934-020-1289-4 -
Science (New York, N.Y.) Mar 2023Therapeutic manipulation of the gut microbiota holds great potential for human health. The mechanisms bacteria use to colonize the gut therefore present valuable targets...
Therapeutic manipulation of the gut microbiota holds great potential for human health. The mechanisms bacteria use to colonize the gut therefore present valuable targets for clinical intervention. We now report that bacteria use phase separation to enhance fitness in the mammalian gut. We establish that the intrinsically disordered region (IDR) of the broadly and highly conserved transcription termination factor Rho is necessary and sufficient for phase separation in vivo and in vitro in the human commensal . Phase separation increases transcription termination by Rho in an IDR-dependent manner. Moreover, the IDR is critical for gene regulation in the gut. Our findings expose phase separation as vital for host-commensal bacteria interactions and relevant for novel clinical applications.
Topics: Animals; Humans; Bacteroides thetaiotaomicron; Gastrointestinal Microbiome; Intrinsically Disordered Proteins; Bacterial Proteins; RNA Helicases; Genetic Fitness; Rho Factor; Transcription Termination, Genetic; Protein Domains; Mice; Germ-Free Life; Mice, Inbred C57BL; Male; Female
PubMed: 36927025
DOI: 10.1126/science.abn7229