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Science Advances Jan 2020Metabolic syndrome (MetS) is intricately linked to dysregulation of gut microbiota and host metabolomes. Here, we first find that a purified citrus...
Metabolic syndrome (MetS) is intricately linked to dysregulation of gut microbiota and host metabolomes. Here, we first find that a purified citrus polymethoxyflavone-rich extract (PMFE) potently ameliorates high-fat diet (HFD)-induced MetS, alleviates gut dysbiosis, and regulates branched-chain amino acid (BCAA) metabolism using 16 rDNA amplicon sequencing and metabolomic profiling. The metabolic protective effects of PMFE are gut microbiota dependent, as demonstrated by antibiotic treatment and fecal microbiome transplantation (FMT). The modulation of gut microbiota altered BCAA levels in the host serum and feces, which were significantly associated with metabolic features and actively responsive to therapeutic interventions with PMFE. Notably, PMFE greatly enriched the commensal bacterium , and gavage with reduced BCAA concentrations and alleviated MetS in HFD mice. PMFE may be used as a prebiotic agent to attenuate MetS, and target-specific microbial species may have unique therapeutic promise for metabolic diseases.
Topics: Amino Acids; Animals; Citrus; Dysbiosis; Feces; Flavones; Gastrointestinal Microbiome; Humans; Insulin Resistance; Metabolic Syndrome; Metabolome; Mice; Obesity; Prebiotics
PubMed: 31922003
DOI: 10.1126/sciadv.aax6208 -
Cell Jul 2022Plant fibers in byproduct streams produced by non-harsh food processing methods represent biorepositories of diverse, naturally occurring, and physiologically active...
Plant fibers in byproduct streams produced by non-harsh food processing methods represent biorepositories of diverse, naturally occurring, and physiologically active biomolecules. To demonstrate one approach for their characterization, mass spectrometry of intestinal contents from gnotobiotic mice, plus in vitro studies, revealed liberation of N-methylserotonin from orange fibers by human gut microbiota members including Bacteroides ovatus. Functional genomic analyses of B. ovatus strains grown under permissive and non-permissive N-methylserotonin "mining" conditions revealed polysaccharide utilization loci that target pectins whose expression correlate with strain-specific liberation of this compound. N-methylserotonin, orally administered to germ-free mice, reduced adiposity, altered liver glycogenesis, shortened gut transit time, and changed expression of genes that regulate circadian rhythm in the liver and colon. In human studies, dose-dependent, orange-fiber-specific fecal accumulation of N-methylserotonin positively correlated with levels of microbiome genes encoding enzymes that digest pectic glycans. Identifying this type of microbial mining activity has potential therapeutic implications.
Topics: Animals; Citrus sinensis; Dietary Fiber; Gastrointestinal Microbiome; Germ-Free Life; Humans; Mice; Pectins; Polysaccharides; Serotonin
PubMed: 35764090
DOI: 10.1016/j.cell.2022.06.004 -
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 -
Nutrients Dec 2022Fecal microbiota transplantation (FMT) is a promising therapeutic modality for the treatment and prevention of metabolic disease. We previously conducted a double-blind,... (Randomized Controlled Trial)
Randomized Controlled Trial
Fecal microbiota transplantation (FMT) is a promising therapeutic modality for the treatment and prevention of metabolic disease. We previously conducted a double-blind, randomized, placebo-controlled pilot trial of FMT in obese metabolically healthy patients in which we found that FMT enhanced gut bacterial bile acid metabolism and delayed the development of impaired glucose tolerance relative to the placebo control group. Therefore, we conducted a secondary analysis of fecal samples collected from these patients to assess the potential gut microbial species contributing to the effect of FMT to improve metabolic health and increase gut bacterial bile acid metabolism. Fecal samples collected at baseline and after 4 weeks of FMT or placebo treatment underwent shotgun metagenomic analysis. Ultra-high-performance liquid chromatography-mass spectrometry was used to profile fecal bile acids. FMT-enriched bacteria that have been implicated in gut bile acid metabolism included and . To identify candidate bacteria involved in gut microbial bile acid metabolism, we assessed correlations between bacterial species abundance and bile acid profile, with a focus on bile acid products of gut bacterial metabolism. and were positively correlated with unconjugated bile acids. , , and were positively correlated with secondary bile acids. Together, these data identify several candidate bacteria that may contribute to the metabolic benefits of FMT and gut bacterial bile acid metabolism that requires further functional validation.
Topics: Humans; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Feces; Bacteria; Bile Acids and Salts
PubMed: 36558359
DOI: 10.3390/nu14245200 -
The American Journal of Pathology Apr 2021The intestinal microbiota influences the development and function of the mucosal immune system. However, the exact mechanisms by which commensal microbes modulate...
The intestinal microbiota influences the development and function of the mucosal immune system. However, the exact mechanisms by which commensal microbes modulate immunity is not clear. We previously demonstrated that commensal Bacteroides ovatus ATCC 8384 reduces mucosal inflammation. Herein, we aimed to identify immunomodulatory pathways employed by B. ovatus. In germ-free mice, mono-association with B. ovatus shifted the CD11b/CD11c and CD103/CD11c dendritic cell populations. Because indole compounds are known to modulate dendritic cells, B. ovatus cell-free supernatant was screened for tryptophan metabolites by liquid chromatography-tandem mass spectrometry and larger quantities of indole-3-acetic acid were detected. Analysis of cecal and fecal samples from germ-free and B. ovatus mono-associated mice confirmed that B. ovatus could elevate indole-3-acetic acid concentrations in vivo. Indole metabolites have previously been shown to stimulate immune cells to secrete the reparative cytokine IL-22. Addition of B. ovatus cell-free supernatant to immature bone marrow-derived dendritic cells stimulated IL-22 secretion. The ability of IL-22 to drive repair in the intestinal epithelium was confirmed using a physiologically relevant human intestinal enteroid model. Finally, B. ovatus shifted the immune cell populations in trinitrobenzene sulfonic acid-treated mice and up-regulated colonic IL-22 expression, effects that correlated with decreased inflammation. Our data suggest that B. ovatus-produced indole-3-acetic acid promotes IL-22 production by immune cells, yielding beneficial effects on colitis.
Topics: Animals; Bacteroides; Colitis; Colon; Cytokines; Dextran Sulfate; Humans; Inflammation; Interleukins; Intestinal Mucosa; Intestines; Mice; Trinitrobenzenesulfonic Acid; Interleukin-22
PubMed: 33516788
DOI: 10.1016/j.ajpath.2021.01.009 -
Gut Microbes 2022Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous psychiatric disorder that can have three phenotypical presentations: inattentive (I-ADHD),...
Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous psychiatric disorder that can have three phenotypical presentations: inattentive (I-ADHD), hyperactive-impulsive (HI-ADHD), and combined (C-ADHD). Environmental factors correlated with the gut microbiota community have been implicated in the development of ADHD. However, whether different ADHD symptomatic presentations are associated with distinct microbiota compositions and whether patients could benefit from the correction of aberrant bacterial colonization are still largely unclear. We carried out metagenomic shotgun analysis with 207 human fecal samples to characterize the gut microbial profiles of patients with ADHD grouped according to their phenotypical presentation. Then, we transplanted the candidate low-abundance bacteria identified in patient subgroups into ADHD rats and evaluated ADHD-associated behaviors and neuronal activation in these rats. Patients with C-ADHD had a different gut microbial composition from that of healthy controls (HCs) ( = .02), but not from that of I-ADHD patients. Eight species became progressively attenuated or enriched when comparing the compositions of HCs to those of I-ADHD and C-ADHD; in particular, the abundance of was depleted in patients with C-ADHD. In turn, supplementation ameliorated spatial working memory deficits and reversed θ electroencephalogram rhythm alterations in ADHD rats. In addition, induced enhanced neuronal activation in the hippocampal CA1 subregion. These findings indicate that gut microbial characteristics that are unique to patients with C-ADHD may be masked when considering a more heterogeneous group of patients. We link the gut microbiota to brain function in an ADHD animal model, suggesting the relevance of testing a potential bacteria-based intervention for some aspects of ADHD.
Topics: Animals; Attention Deficit Disorder with Hyperactivity; Bacteroides; Cognition; Cognitive Dysfunction; Gastrointestinal Microbiome; Humans; Rats
PubMed: 36128620
DOI: 10.1080/19490976.2022.2125747 -
Cellular & Molecular Immunology Jul 2022Type 2 diabetes (T2D) is highly associated with obesity. However, the factors that drive the transition from excessive weight gain to glucose metabolism disruption are...
Type 2 diabetes (T2D) is highly associated with obesity. However, the factors that drive the transition from excessive weight gain to glucose metabolism disruption are still uncertain and seem to revolve around systemic immune disorder. Mucosal-associated invariant T (MAIT) cells, which are innate-like T cells that recognize bacterial metabolites, have been reported to be altered in obese people and to lead to metabolic dysfunction during obesity. By studying the immunophenotypes of blood MAIT cells from a cross-sectional cohort of obese participants with/without T2D, we found an elevation in CD27-negative (CD27) MAIT cells producing a high level of IL-17 under T2D obese conditions, which could be positively correlated with impaired glucose metabolism in obese people. We further explored microbial translocation caused by gut barrier dysfunction in obese people as a triggering factor of MAIT cell abnormalities. Specifically, accumulation of the bacterial strain Bacteroides ovatus in the peripheral blood drove IL-17-producing CD27 MAIT cell expansion and could be associated with T2D risk in obese individuals. Overall, these results suggest that an aberrant gut microbiota-immune axis in obese people may drive or exacerbate T2D. Importantly, CD27 MAIT cell subsets and Bacteroides ovatus could represent targets for novel interventional strategies. Our findings extend current knowledge regarding the clinical relevance of body mass index (BMI)-associated variation in circulating MAIT cells to reveal the role of these cells in obesity-related T2D progression and the underlying cellular mechanisms.
Topics: Bacteroides; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucose; Humans; Interleukin-17; Mucosal-Associated Invariant T Cells; Obesity; Tumor Necrosis Factor Receptor Superfamily, Member 7
PubMed: 35545662
DOI: 10.1038/s41423-022-00871-4 -
Research Square Jan 2023Acute gastrointestinal intestinal GVHD (aGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation, and the intestinal microbiota is known...
Acute gastrointestinal intestinal GVHD (aGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation, and the intestinal microbiota is known to impact on its severity. However, an association between treatment response of aGI-GVHD and the intestinal microbiota has not been well-studied. In a cohort of patients with aGI-GVHD (n=37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and loss of from the microbiome. In a mouse model of carbapenem-aggravated GVHD, introducing reduced severity of GVHD and improved survival. reduced degradation of colonic mucus by another intestinal commensal, , via its ability to metabolize dietary polysaccharides into monosaccharides, which then inhibit mucus degradation by and reduce GVHD-related mortality.
PubMed: 36778495
DOI: 10.21203/rs.3.rs-2460097/v1 -
IScience May 2022Gut microbes can synthesize multiple neuro-active metabolites. We profiled neuro-active compounds produced by the gut commensal and by LC-MS/MS. We found that...
Gut microbes can synthesize multiple neuro-active metabolites. We profiled neuro-active compounds produced by the gut commensal and by LC-MS/MS. We found that generates acetic acid, propionic acid, isobutyric acid, and isovaleric acid. , consumed tryptophan and glutamate and synthesized the neuro-active compounds glutamine and GABA. Consistent with our LC-MS/MS-based data, we observed elevated levels of acetic acid, propionic acid, isobutyric acid, and isovaleric acid in the intestines of mono-associated mice compared with germ-free controls. mono-association also increased the concentrations of intestinal GABA and decreased the concentrations of tryptophan and glutamine compared with germ-free controls. Computational network analysis revealed unique links between SCFAs, neuro-active compounds, and colonization status. These results highlight connections between microbial colonization and intestinal neurotransmitter concentrations, suggesting that selectively influences the presence of intestinal neurotransmitters.
PubMed: 35494230
DOI: 10.1016/j.isci.2022.104158 -
Nature Communications Oct 2023Malaria is caused by Plasmodium species and remains a significant cause of morbidity and mortality globally. Gut bacteria can influence the severity of malaria, but the... (Meta-Analysis)
Meta-Analysis
Malaria is caused by Plasmodium species and remains a significant cause of morbidity and mortality globally. Gut bacteria can influence the severity of malaria, but the contribution of specific bacteria to the risk of severe malaria is unknown. Here, multiomics approaches demonstrate that specific species of Bacteroides are causally linked to the risk of severe malaria. Plasmodium yoelii hyperparasitemia-resistant mice gavaged with murine-isolated Bacteroides fragilis develop P. yoelii hyperparasitemia. Moreover, Bacteroides are significantly more abundant in Ugandan children with severe malarial anemia than with asymptomatic P. falciparum infection. Human isolates of Bacteroides caccae, Bacteroides uniformis, and Bacteroides ovatus were able to cause susceptibility to severe malaria in mice. While monocolonization of germ-free mice with Bacteroides alone is insufficient to cause susceptibility to hyperparasitemia, meta-analysis across multiple studies support a main role for Bacteroides in susceptibility to severe malaria. Approaches that target gut Bacteroides present an opportunity to prevent severe malaria and associated deaths.
Topics: Child; Humans; Animals; Mice; Microbial Consortia; Malaria; Bacteroides; Bacteroides fragilis; Anemia; Plasmodium yoelii
PubMed: 37833304
DOI: 10.1038/s41467-023-42235-0