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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 -
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 -
Cell Apr 2024The gut microbiota has been found to play an important role in the progression of metabolic dysfunction-associated steatohepatitis (MASH), but the mechanisms have not...
The gut microbiota has been found to play an important role in the progression of metabolic dysfunction-associated steatohepatitis (MASH), but the mechanisms have not been established. Here, by developing a click-chemistry-based enrichment strategy, we identified several microbial-derived bile acids, including the previously uncharacterized 3-succinylated cholic acid (3-sucCA), which is negatively correlated with liver damage in patients with liver-tissue-biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). By screening human bacterial isolates, we identified Bacteroides uniformis strains as effective producers of 3-sucCA both in vitro and in vivo. By activity-based protein purification and identification, we identified an enzyme annotated as β-lactamase in B. uniformis responsible for 3-sucCA biosynthesis. Furthermore, we found that 3-sucCA is a lumen-restricted metabolite and alleviates MASH by promoting the growth of Akkermansia muciniphila. Together, our data offer new insights into the gut microbiota-liver axis that may be leveraged to augment the management of MASH.
PubMed: 38653239
DOI: 10.1016/j.cell.2024.03.034 -
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 -
Gut Microbes 2024Hepatic immunity is one of the driving forces for the development of nonalcoholic steatohepatitis (NASH), and targeting gut microbiota is believed to affect the hepatic...
Hepatic immunity is one of the driving forces for the development of nonalcoholic steatohepatitis (NASH), and targeting gut microbiota is believed to affect the hepatic immune constitution. Here, we aimed to investigate the hepatic immunological state in NASH, with a specific emphasis on natural killer (NK) cells. In addition, we aimed to identify the contributing species that target hepatic immunity to provide new directions and support the feasibility of immunotherapy for NASH. A possible NASH population was determined by combination of long-term severe fatty liver, metabolic disorders and increased serum CK18 to detect serum immune factors and gut microbiota. NASH was induced in mice fed a high-fat diet to verify the prophylactic effect of the functional species on the immunopathology and development of NASH. Hepatic immunologic state was examined, and the effector functions of NK cells were detected. Hepatic transcriptome, proteomic, and fecal metagenome were performed. We observed a statistical increase in serum IL-10 (p < 0.001) and non-statistical decrease in interferon-γ and IL-6 in NASH population, hinting at the possibility of immune tolerance. Fecal Bacteroides uniformis and Bifidobacterium bifidum were abundant in healthy population but depleted in NASH patients. In NASH mice, hepatic CD8+T cells, macrophages, and dendritic cells were increased (p < 0.01), and NK cells were inhibited, which were identified with decreased granzyme B (p < 0.05). Bacteroides uniformis and Bifidobacterium bifidum improved hepatic pathological and metabolic cues, increased hepatic NK cells and reduced macrophages (p < 0.05). Bacteroides uniformis also restored hepatic NK cell function, which was identified as increased CD107a (p < 0.05). Transcriptional and translational profiling revealed that the functional species might restore the function of hepatic NK cells through multiple pathways, such as reduction of inhibitory molecules in NK cells. Bacteroides uniformis and Bifidobacterium bifidum are novel prophylactics for NASH that restore the impaired function of hepatic NK cells.
Topics: Humans; Animals; Mice; Non-alcoholic Fatty Liver Disease; Diet, High-Fat; Bifidobacterium bifidum; Proteomics; Gastrointestinal Microbiome; Killer Cells, Natural; Immune Tolerance
PubMed: 38196273
DOI: 10.1080/19490976.2024.2302065 -
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 -
Signal Transduction and Targeted Therapy Sep 2023Whether the alternated microbiota in the gut contribute to the risk of allograft rejection (AR) and pulmonary infection (PI) in the setting of lung transplant recipients...
Whether the alternated microbiota in the gut contribute to the risk of allograft rejection (AR) and pulmonary infection (PI) in the setting of lung transplant recipients (LTRs) remains unexplored. A prospective multicenter cohort of LTRs was identified in the four lung transplant centers. Paired fecal and serum specimens were collected and divided into AR, PI, and event-free (EF) groups according to the diagnosis at sampling. Fecal samples were determined by metagenomic sequencing. And metabolites and cytokines were detected in the paired serum to analyze the potential effect of the altered microbiota community. In total, we analyzed 146 paired samples (AR = 25, PI = 43, and EF = 78). Notably, we found that the gut microbiome of AR followed a major depletion pattern with decreased 487 species and compositional diversity. Further multi-omics analysis showed depleted serum metabolites and increased inflammatory cytokines in AR and PI. Bacteroides uniformis, which declined in AR (2.4% vs 0.6%) and was negatively associated with serum IL-1β and IL-12, was identified as a driven specie in the network of gut microbiome of EF. Functionally, the EF specimens were abundant in probiotics related to mannose and cationic antimicrobial peptide metabolism. Furthermore, a support-vector machine classifier based on microbiome, metabolome, and clinical parameters highly predicted AR (AUPRC = 0.801) and PI (AUPRC = 0.855), whereby the microbiome dataset showed a particularly high diagnostic power. In conclusion, a disruptive gut microbiota showed a significant association with allograft rejection and infection and with systemic cytokines and metabolites in LTRs.
Topics: Humans; Gastrointestinal Microbiome; Prospective Studies; Lung Transplantation; Cytokines; Allografts
PubMed: 37652953
DOI: 10.1038/s41392-023-01515-3 -
Scientific Reports Aug 2023Gut microbiota metabolites have been mechanistically linked to inflammatory pathway activation and atherosclerosis, which are major causes of vascular stiffness (VS)....
Gut microbiota metabolites have been mechanistically linked to inflammatory pathway activation and atherosclerosis, which are major causes of vascular stiffness (VS). Aiming to investigate if the gut microbiome might be involved in VS development, we performed a cross-sectional study (n = 3,087), nested within the population-based European Prospective Investigations into Cancer and Nutrition (EPIC) Potsdam. We investigated the correlation of the gut microbiota (alpha diversity and taxa abundance) with 3 vascular stiffness measures: carotid-femoral (PWV), aortic augmentation index (AIX) and ankle-brachial index (ABI). Shannon index was not significantly associated with VS but the number of observed Amplicon Sequence Variants (ASV) was positively associated with PWV and AIX. We found a total of 19 ASVs significantly associated with at least one VS measure in multivariable-adjusted models. One ASV (classified as Sutterella wadsworthensis) was associated with 2 VS measures, AIX (- 0.11 ± 0.04) and PWV (-0.14 ± 0.03). Other examples of ASVs associated with VS were Collinsella aerofaciens, previously reported to be affected by diet and Bacteroides uniformis, commercially available as probiotics. In conclusion, our study suggests a potential role of individual components of the gut microbiota in the aetiology of VS.
Topics: Humans; Gastrointestinal Microbiome; Cross-Sectional Studies; Prospective Studies; Vascular Stiffness; Cancer Vaccines
PubMed: 37587126
DOI: 10.1038/s41598-023-40178-6 -
International Journal of Molecular... Sep 2023Previous studies have demonstrated that the intestinal abundance of is significantly higher in healthy controls than that in patients with ulcerative colitis (UC)....
Previous studies have demonstrated that the intestinal abundance of is significantly higher in healthy controls than that in patients with ulcerative colitis (UC). However, what effect has on the development of UC has not been characterized. Here, we show for the first time that F18-22, an alginate-fermenting bacterium isolated from the healthy human colon, protects against dextran-sulfate-sodium (DSS)-induced UC in mice. Specifically, oral intake of F18-22 alleviated colon contraction, improved intestinal bleeding and attenuated mucosal damage in diseased mice. Additionally, F18-22 improved gut dysbiosis in UC mice by increasing the abundance of anti-inflammatory acetate-producing bacterium and decreasing the amount of pro-inflammatory pathogenetic bacteria spp. Moreover, F18-22 was well-tolerated in mice and showed no oral toxicity after repeated daily administration for 28 consecutive days. Taken together, our study illustrates that F18-22 is a safe and novel probiotic bacterium for the treatment of UC from the healthy human colon.
Topics: Humans; Animals; Mice; Colitis, Ulcerative; Colon; Bacteroides; Probiotics; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL; Colitis
PubMed: 37834117
DOI: 10.3390/ijms241914669 -
BMC Pediatrics Oct 2023Sepsis is a life-threatening multiple-organ injury caused by disordered host immune response to microbial infection. However, the correlation between gut microbiota...
Sepsis is a life-threatening multiple-organ injury caused by disordered host immune response to microbial infection. However, the correlation between gut microbiota dysbiosis and immune indicators remains unexplored. To address this gap in knowledge, we carried out 16 S rDNA sequencing, analyzed clinical fecal samples from children with sepsis (n = 30) and control children (n = 25), and obtained immune indicators, including T cell subtypes (CD3, CD3CD4, CD3CD8, and CD4/CD8), NK cells, cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ), and immunoglobulin indices (IgA, IgE, IgM and IgG). In addition, we analyzed the correlation between gut microbiota dysbiosis and immune indicators, and evaluated the clinical discriminatory power of discovered bacterial biomarkers. We found that children with sepsis exhibited gut bacterial dysbiosis and low alpha diversity. The Spearman's rank correlation coefficient suggested that Rhodococcus erythropolis had a significantly positive correlation with IFN-γ and CD3 T cells. Klebsiella pneumoniae and Streptococcus mitis were significantly correlated with NK cells. Bacteroides uniformis was significantly positively correlated with IgM and erythrocyte sedimentation rate, and Eubacterium eligens was significantly positively correlated with IL-4 and CD3CD8 T cells. The biomarkers discovered in this study had strong discriminatory power. These changes in the gut microbiome may be closely related to immunologic dysfunction and to the development or exacerbation of sepsis. However, a large sample size is required for verification.
Topics: Humans; Child; Gastrointestinal Microbiome; CD8-Positive T-Lymphocytes; Dysbiosis; Interleukin-4; Sepsis; Bacteria; Biomarkers; Immunoglobulin M
PubMed: 37845615
DOI: 10.1186/s12887-023-04349-8