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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 -
Brain, Behavior, and Immunity May 2022Gut microbiome disturbances have been widely implicated in major depressive disorder (MDD), although the identity of causal microbial species and the underlying...
Gut microbiome disturbances have been widely implicated in major depressive disorder (MDD), although the identity of causal microbial species and the underlying mechanisms are yet to be fully elucidated. Here we show that Bacteroides species enriched in the gut microbiome from MDD patients differentially impact the susceptibility to depressive behaviors. Transplantation of fecal microbiome from MDD patients into antibiotic-treated mice induced anxiety and despair-like behavior and impaired hippocampal neurogenesis. Colonization of Bacteroides fragilis, Bacteroides uniformis, and, to a lesser extent, Bacteroides caccae, but not Bacteroides ovatus, recapitulated the negative effects of MDD microbiome on behavior and neurogenesis. The varying impacts of Bacteroides species were partially explained by differential alternations of tryptophan pathway metabolites and neurotransmitters along the gut-brain axis. Notably, an intensified depletion of cerebral serotonin concurred with the enhanced susceptibility to depression. Together, these findings identify select Bacteroidetes species that contribute to depression susceptibility in mice by metabolic regulation along the gut-brain axis.
Topics: Animals; Bacteroides; Brain; Depression; Depressive Disorder, Major; Gastrointestinal Microbiome; Humans; Mice
PubMed: 35143877
DOI: 10.1016/j.bbi.2022.02.007 -
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 -
NPJ Biofilms and Microbiomes Jul 2023Vitamin B12 (VB12) deficiency, which may lead to hematologic and neurologic symptoms, has been associated with metformin use, but the underlying mechanism is unclear....
Vitamin B12 (VB12) deficiency, which may lead to hematologic and neurologic symptoms, has been associated with metformin use, but the underlying mechanism is unclear. Here we report the B. ovatus as an effective VB12 catcher which was enriched in the type 2 diabetes patients suffered from VB12 deficiency after 3 to 6 months of metformin treatment. Colonization of B. ovatus increased the plasma levels of methylmalonic acid and homocysteine in high-fat diet (HFD)-fed mice treated with metformin, and compromised the efficacy of metformin against the HFD-induced metabolic disorders. Mechanistically, metformin increased the intracellular accumulation of VB12 in B. ovatus via btuB upregulation and promoted ATP production for energy-dependent translocation of VB12 transporters at the inner membrane, leading to an enhanced colonization of B. ovatus to compete for VB12 with hosts and subsequently an aggravated VB12 deficiency in the host. Our findings illustrate a previously unappreciated mechanism of metformin leads to host VB12 deficiency by acting directly on gut bacteria to increase their VB12 uptake and consumption, and suggest that inter-host-microbe competition for nutrients may broadly impact human health and drug safety.
Topics: Humans; Animals; Mice; Vitamin B 12; Diabetes Mellitus, Type 2; Metformin; Vitamin B 12 Deficiency; Homocysteine
PubMed: 37488134
DOI: 10.1038/s41522-023-00419-y -
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 -
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 -
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 -
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 -
Gut Microbes 2019: Bacteriotherapy aimed at addressing dysbiosis may be therapeutic for Inflammatory Bowel Diseases (IBDs). We sought to determine if defined -based bacteriotherapy could... (Comparative Study)
Comparative Study
: Bacteriotherapy aimed at addressing dysbiosis may be therapeutic for Inflammatory Bowel Diseases (IBDs). We sought to determine if defined -based bacteriotherapy could be an effective and consistent alternative to fecal microbiota transplantation (FMT) in a murine model of IBD. : We induced experimental colitis in 8- 12-week-old C57BL/6 mice using 2-3% dextran sodium sulfate. Mice were simultaneously treated by oral gavage with a triple- cocktail, individual strains, FMT using stool from healthy donor mice, or their own stool as a control. Survival, weight loss and markers of inflammation (histology, serum amyloid A, cytokine production) were correlated to gene profiling of fecal and mucosal microbiomes. : Triple- combination therapy was more protective against weight loss and mortality than traditional FMT therapy. ATCC8483 was more effective than any individual strain, or a combination of strains, in preventing weight loss, decreasing histological damage, dampening inflammatory response, and stimulating epithelial recovery. Irrespective of the treatment group, overall abundance associated with treatment success and decreased cytokine production while the presence of correlated with treatment failure. However, the therapeutic benefit associated with high abundance was negated in the presence of . : monotherapy was more consistent and effective than traditional FMT at ameliorating colitis and stimulating epithelial recovery in a murine model of IBD. Given the tolerability of ATCC 8483 in an active, on-going human study, this therapy may be repurposed for the management of IBD in a clinically expedient timeline.
Topics: Animals; Bacteria; Bacteroides; Colitis; Dextran Sulfate; Disease Models, Animal; Fecal Microbiota Transplantation; Feces; Gastrointestinal Tract; Inflammation; Male; Mice, Inbred C57BL; RNA, Ribosomal, 16S; Survival Analysis; Treatment Outcome
PubMed: 30663928
DOI: 10.1080/19490976.2018.1560753