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Nature Communications Oct 2023Hypertriglyceridemic pancreatitis (HTGP) is featured by higher incidence of complications and poor clinical outcomes. Gut microbiota dysbiosis is associated with...
Hypertriglyceridemic pancreatitis (HTGP) is featured by higher incidence of complications and poor clinical outcomes. Gut microbiota dysbiosis is associated with pancreatic injury in HTGP and the mechanism remains unclear. Here, we observe lower diversity of gut microbiota and absence of beneficial bacteria in HTGP patients. In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from HTGP patients recruits neutrophils and increases neutrophil extracellular traps (NETs) formation that exacerbates pancreatic injury and systemic inflammation. We find that decreased abundance of Bacteroides uniformis in gut microbiota impairs taurine production and increases IL-17 release in colon that triggers NETs formation. Moreover, Bacteroides uniformis or taurine inhibits the activation of NF-κB and IL-17 signaling pathways in neutrophils which harness NETs and alleviate pancreatic injury. Our findings establish roles of endogenous Bacteroides uniformis-derived metabolic and inflammatory products on suppressing NETs release, which provides potential insights of ameliorating HTGP through gut microbiota modulation.
Topics: Mice; Animals; Humans; Extracellular Traps; Interleukin-17; Gastrointestinal Microbiome; Pancreatitis; Taurine
PubMed: 37794047
DOI: 10.1038/s41467-023-41950-y -
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 -
International Journal of Molecular... Apr 2023Obesity and obesity-associated disorders pose a major public health issue worldwide. Apart from conventional weight loss drugs, next-generation probiotics (NGPs) seem to... (Review)
Review
Obesity and obesity-associated disorders pose a major public health issue worldwide. Apart from conventional weight loss drugs, next-generation probiotics (NGPs) seem to be very promising as potential preventive and therapeutic agents against obesity. Candidate NGPs such as , , and have shown promise in preclinical models of obesity and obesity-associated disorders. Proposed mechanisms include the modulation of gut flora and amelioration of intestinal dysbiosis, improvement of intestinal barrier function, reduction in chronic low-grade inflammation and modulation of gut peptide secretion. and have already been administered in overweight/obese patients with encouraging results. However, safety issues and strict regulations should be constantly implemented and updated. In this review, we aim to explore (1) current knowledge regarding NGPs; (2) their utility in obesity and obesity-associated disorders; (3) their safety profile; and (4) their therapeutic potential in individuals with overweight/obesity. More large-scale, multicentric and longitudinal studies are mandatory to explore their preventive and therapeutic potential against obesity and its related disorders.
Topics: Humans; Overweight; Obesity; Probiotics; Gastrointestinal Microbiome; Inflammation
PubMed: 37047729
DOI: 10.3390/ijms24076755 -
Annals of the Rheumatic Diseases Aug 2022Rheumatoid arthritis (RA) is a progressive disease including four stages, where gut microbiome is associated with pathogenesis. We aimed to investigate stage-specific...
OBJECTIVE
Rheumatoid arthritis (RA) is a progressive disease including four stages, where gut microbiome is associated with pathogenesis. We aimed to investigate stage-specific roles of microbial dysbiosis and metabolic disorders in RA.
METHODS
We investigated stage-based profiles of faecal metagenome and plasma metabolome of 76 individuals with RA grouped into four stages (stages I-IV) according to 2010 RA classification criteria, 19 individuals with osteroarthritis and 27 healthy individuals. To verify bacterial invasion of joint synovial fluid, 16S rRNA gene sequencing, bacterial isolation and scanning electron microscopy were conducted on another validation cohort of 271 patients from four RA stages.
RESULTS
First, depletion of and weakened glycosaminoglycan metabolism (p<0.001), continuously hurting articular cartilage across four stages. Second, elevation of enhanced arginine succinyltransferase pathway in the stage II and stage III (p<0.001), which was correlated with the increase of the rheumatoid factor (p=1.35×10) and could induce bone loss. Third, abnormally high levels of methoxyacetic acid (p=1.28×10) and cysteine-S-sulfate (p=4.66×10) inhibited osteoblasts in the stage II and enhanced osteoclasts in the stage III, respectively, promoting bone erosion. Fourth, continuous increase of gut permeability may induce gut microbial invasion of the joint synovial fluid in the stage IV.
CONCLUSIONS
Clinical microbial intervention should consider the RA stage, where microbial dysbiosis and metabolic disorders present distinct patterns and played stage-specific roles. Our work provides a new insight in understanding gut-joint axis from a perspective of stages, which opens up new avenues for RA prognosis and therapy.
PubMed: 35985811
DOI: 10.1136/ard-2022-222871 -
Gut Mar 2022Our goals were to evaluate the antitumour efficacy of GG (LGG) in combination with immune checkpoint blockade (ICB) immunotherapies on tumour growth and to investigate...
OBJECTIVE
Our goals were to evaluate the antitumour efficacy of GG (LGG) in combination with immune checkpoint blockade (ICB) immunotherapies on tumour growth and to investigate the underlying mechanisms.
DESIGN
We used murine models of colorectal cancer and melanoma to evaluate whether oral administration of LGG improves the efficacy of ICB therapies. We performed the whole genome shotgun metagenome sequencing of intestinal contents and RNA sequencing of dendritic cells (DCs). In a series of in vitro and in vivo experiments, we further defined the immunological and molecular mechanisms of LGG-mediated antitumour immunity.
RESULTS
We demonstrate that oral administration of live LGG augmented the antitumour activity of anti-programmed cell death 1 (PD-1) immunotherapy by increasing tumour-infiltrating DCs and T cells. Moreover, the combination treatment shifted the gut microbial community towards enrichment in and , that are known to increase DC activation and CD8tumour recruitment. Mechanistically, treatment with live LGG alone or in combination with anti-PD-1 antibody triggered type I interferon (IFN) production in DCs, enhancing the cross-priming of antitumour CD8 T cells. In DCs, cyclic GMP-AMP synthase (cGAS)/stimulator of IFN genes (STING) was required for IFN-β induction in response to LGG, as evidenced by the significant decrease in IFN-β levels in cGAS or STING-deficient DCs. LGG induces IFN-β production via the cGAS/STING/TANK binding kinase 1/interferon regulatory factor 7 axis in DCs.
CONCLUSION
Our findings have offered valuable insight into the molecular mechanisms of live LGG-mediated antitumour immunity and establish an empirical basis for developing oral administration of live LGG as a combination agent with ICB for cancer therapies.
Topics: Administration, Oral; Animals; Colorectal Neoplasms; Disease Models, Animal; Immune Checkpoint Inhibitors; Interferon Type I; Lacticaseibacillus rhamnosus; Melanoma; Mice; Probiotics
PubMed: 33685966
DOI: 10.1136/gutjnl-2020-323426 -
Gastroenterology Feb 2024Dietary fibers are mainly fermented by the gut microbiota, but their roles in colorectal cancer (CRC) are largely unclear. Here, we investigated the associations of...
BACKGROUND & AIMS
Dietary fibers are mainly fermented by the gut microbiota, but their roles in colorectal cancer (CRC) are largely unclear. Here, we investigated the associations of different fibers with colorectal tumorigenesis in mice.
METHODS
Apc mice and C57BL/6 mice with azoxymethane (AOM) injection were used as CRC mouse models. Mice were fed with mixed high-fiber diet (20% soluble fiber and 20% insoluble fiber), high-inulin diet, high-guar gum diet, high-cellulose diet, or diets with different inulin dose. Germ-free mice were used for validation. Fecal microbiota and metabolites were profiled by shotgun metagenomic sequencing and liquid chromatography-mass spectrometry, respectively.
RESULTS
Mixed high-fiber diet promoted colorectal tumorigenesis with increased tumor number and tumor load in AOM-treated and Apc mice. Antibiotics use abolished the pro-tumorigenic effect of mixed high-fiber diet, while transplanting stools from mice fed with mixed high-fiber diet accelerated tumor growth in AOM-treated germ-free mice. We therefore characterized the contribution of soluble and insoluble fiber in CRC separately. Our results revealed that soluble fiber inulin or guar gum, but not insoluble fiber cellulose, promoted colorectal tumorigenesis in AOM-treated and Apc mice. Soluble fiber induced gut dysbiosis with Bacteroides uniformis enrichment and Bifidobacterium pseudolongum depletion, accompanied by increased fecal butyrate and serum bile acids and decreased inosine. We also identified a positive correlation between inulin dosage and colorectal tumorigenesis. Moreover, transplanting stools from mice fed with high-inulin diet increased colonic cell proliferation and oncogene expressions in germ-free mice.
CONCLUSION
High-dose soluble but not insoluble fiber potentiates colorectal tumorigenesis in a dose-dependent manner by dysregulating gut microbiota and metabolites in mice.
Topics: Mice; Animals; Gastrointestinal Microbiome; Inulin; Mice, Inbred C57BL; Carcinogenesis; Dietary Fiber; Cellulose; Azoxymethane; Colorectal Neoplasms
PubMed: 37858797
DOI: 10.1053/j.gastro.2023.10.012 -
NPJ Biofilms and Microbiomes Aug 2023Inflammatory bowel disease (IBD) is associated with gut dysbiosis and can lead to colitis-associated malignancies. Bacteroides uniformis (Bu) regulates animal intestinal...
Inflammatory bowel disease (IBD) is associated with gut dysbiosis and can lead to colitis-associated malignancies. Bacteroides uniformis (Bu) regulates animal intestinal homeostasis; however, the mechanism by which it alleviates colitis in mice remains unknown. We investigated the effects of B. uniformis JCM5828 and its metabolites on female C57BL/6J mice with dextran sulfate sodium salt (DSS) induced colitis. Treatment with Bu considerably alleviated colitis progression and restored the mechanical and immune barrier protein expression. Additionally, Bu increased the abundance of the symbiotic bacteria Bifidobacterium and Lactobacillus vaginalis while decreasing that of pathogenic Escherichia-Shigella, and modulated intestinal bile acid metabolism. Bu largely regulated the expression of key regulatory proteins of the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways in colonic tissues and the differentiation of TH17 cells. However, Bu could not directly inhibit TH17 cell differentiation in vitro; it modulated the process in the lamina propria by participating in bile acid metabolism and regulating key metabolites (alpha-muricholic, hyodeoxycholic, and isolithocholic acid), thereby modulating the intestinal immune response. Our findings suggest that Bu or bile acid supplements are potential therapies for colitis and other diseases associated with intestinal barrier dysfunction.
Topics: Female; Mice; Animals; Th17 Cells; Bile Acids and Salts; Gastrointestinal Microbiome; Mice, Inbred C57BL; Colitis; Microbiota; Cell Differentiation; Dextran Sulfate
PubMed: 37580334
DOI: 10.1038/s41522-023-00420-5 -
Cell Surface Xyloglucan Recognition and Hydrolysis by the Human Gut Commensal Bacteroides uniformis.Applied and Environmental Microbiology Jan 2022Xyloglucan (XyG) is a ubiquitous plant cell wall hemicellulose that is targeted by a range of syntenic, microheterogeneous xyloglucan utilization loci (XyGUL) in... (Review)
Review
Xyloglucan (XyG) is a ubiquitous plant cell wall hemicellulose that is targeted by a range of syntenic, microheterogeneous xyloglucan utilization loci (XyGUL) in species of the human gut microbiota (HGM), including Bacteroides ovatus and B. uniformis. Comprehensive biochemical and biophysical analyses have identified key differences in the protein complements of each locus that confer differential access to structurally diverse XyG side chain variants. A second, nonsyntenic XyGUL was previously identified in B. uniformis, although its function in XyG utilization compared to its syntenic counterpart was unclear. Here, complementary enzymatic product profiles and bacterial growth curves showcase the notable preference of XyGUL2 surface glycan-binding proteins (SGBPs) to bind full-length XyG, as well as a range of oligosaccharides produced by the glycoside hydrolase family 5 (GH5_4) -xyloglucanase from this locus. We use isothermal titration calorimetry (ITC) to characterize this binding capacity and pinpoint the specific contributions of each protein to nutrient capture. The high-resolution structure of XyGUL2 SGBP-B reveals remarkable putative binding site conservation with the canonical XyG-binding XyGUL SGBP-B, supporting similar roles for these proteins in glycan capture. Together, these data underpin the central role of complementary XyGUL function in B. uniformis and broaden our systems-based and mechanistic understanding of XyG utilization in the HGM. The omnipresence of xyloglucans in the human diet has led to the evolution of heterogeneous gene clusters in several species in the HGM, each specially tuned to respond to the structural variations of these complex plant cell wall polysaccharides. Our research illuminates the complementary roles of syntenic and nonsyntenic XyGUL in B. uniformis in conferring growth on a variety of XyG-derived substrates, providing evidence of glycan-binding protein microadaptation within a single species. These data serve as a comprehensive overview of the binding capacities of the SGBPs from a nonsyntenic B. uniformis XyGUL and will inform future studies on the roles of complementary loci in glycan targeting by key HGM species.
Topics: Bacteroides; Gastrointestinal Tract; Glucans; Humans; Hydrolysis; Xylans
PubMed: 34731054
DOI: 10.1128/AEM.01566-21 -
Nature Communications Mar 2022Autism spectrum disorder (ASD), a group of neurodevelopmental disorders characterized by social communication deficits and stereotyped behaviors, may be associated with...
Autism spectrum disorder (ASD), a group of neurodevelopmental disorders characterized by social communication deficits and stereotyped behaviors, may be associated with changes to the gut microbiota. However, how gut commensal bacteria modulate brain function in ASD remains unclear. Here, we used chromodomain helicase DNA-binding protein 8 (CHD8) haploinsufficient mice as a model of ASD to elucidate the pathways through which the host and gut microbiota interact with each other. We found that increased levels of amino acid transporters in the intestines of the mouse model of ASD contribute to the high level of serum glutamine and the increased excitation/inhibition (E/I) ratio in the brain. In addition, elevated α-defensin levels in the haploinsufficient mice resulted in dysregulation of the gut microbiota characterized by a reduced abundance of Bacteroides. Furthermore, supplementation with Bacteroides uniformis improved the ASD-like behaviors and restored the E/I ratio in the brain by decreasing intestinal amino acid transport and the serum glutamine levels. Our study demonstrates associations between changes in the gut microbiota and amino acid transporters, and ASD-like behavioral and electrophysiology phenotypes, in a mouse model.
Topics: Amino Acid Transport Systems; Animals; Autism Spectrum Disorder; Disease Models, Animal; Gastrointestinal Microbiome; Glutamine; Mice; Microbiota
PubMed: 35241668
DOI: 10.1038/s41467-022-28746-2 -
Gut Microbes 2021Gut microbiota represents a therapeutic target for obesity. We hypothesize that CECT 7771 combined with wheat bran extract (WBE), its preferred carbon source, may exert...
Gut microbiota represents a therapeutic target for obesity. We hypothesize that CECT 7771 combined with wheat bran extract (WBE), its preferred carbon source, may exert superior anti-obesity effects. We performed a 17-week intervention in diet-induced obese mice receiving either , WBE, or their combination to identify interactions and independent actions on metabolism and immunity. combined with WBE was the most effective intervention, curbing weight gain and adiposity, while exerting more modest effects separately. The combination restored insulin-dependent metabolic routes in fat and liver, although the bacterium was the primary driver for improving whole-body glucose disposal. Moreover, -combined with WBE caused the highest increases in butyrate and restored the proportion of induced intraepithelial lymphocytes and type-3 innate lymphoid cells in the intestinal epithelium. Thus, strengthening the first line of immune defense against unhealthy diets and associated dysbiosis in the intestine. This intervention also attenuated the altered IL22 signaling and liver inflammation. Our study shows opportunities for employing , combined with WBE, to aid in the treatment of obesity.
Topics: Adipose Tissue; Animals; Bacteroides; Cecum; Diet, High-Fat; Dietary Fiber; Epididymis; Fatty Acids; Gastrointestinal Microbiome; Inflammation; Insulin; Interleukins; Intestinal Mucosa; Liver; Lymphocytes; Male; Mice; Obesity; Signal Transduction; Thermogenesis; Weight Gain; Interleukin-22
PubMed: 33499721
DOI: 10.1080/19490976.2020.1865706