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Frontiers in Microbiology 2023Recent observational and small-sample case-control studies have shown a relationship between gut microbiota composition and prostatic cancer (PCa). Nevertheless, the...
AIM
Recent observational and small-sample case-control studies have shown a relationship between gut microbiota composition and prostatic cancer (PCa). Nevertheless, the causal association between gut microbiota and PCa is still unclear. Herein, we used the Mendelian randomization (MR) method to explore the potential causal relationship between gut microbiota and PCa.
METHODS
In this two-sample MR study, data were extracted from the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis conducted by the MiBioGen consortium ( = 14,306) and the Dutch Microbiome Project ( = 8,208). Summary statistics for PCa were obtained from the FinnGen consortium release data ( = 95,213). Inverse variance weighted (IVW), MR-Egger, strength test (F), and MR-PRESSO were used to examine the potential causal association between gut microbiota and PCa. Cochran's Q statistics were used to quantify the heterogeneity of instrumental variables.
RESULTS
IVW estimates suggested that the relative abundance of (odds ratio [OR] = 0.7926, 95% confidence interval [CI]: 0.6655-0.9440) and (OR = 0.9023, 95% CI: 0.8262-0.9853) were negatively associated with the odds of PCa, while that of (OR = 1.1629, 95% CI: 1.0110-1.3376) was positively associated with the odds of PCa. In addition, we explored these relationships among patients without other cancers and similarly found that the relative abundance of , and were linked to PCa (all < 0.05).
CONCLUSION
Gut microbiota potentially influenced the occurrence of PCa. Our findings may provide some new ideas for researching the methods of PCa prevention. In addition, further studies are needed to explore the causal association and specific underlying mechanisms between gut microbiota and PCa.
PubMed: 38029073
DOI: 10.3389/fmicb.2023.1250369 -
Frontiers in Immunology 2023It has been demonstrated that gut microbes are closely associated with the pathogenesis of lymphoma, but the gut microbe landscape and its association with immune cells...
BACKGROUND/PURPOSE
It has been demonstrated that gut microbes are closely associated with the pathogenesis of lymphoma, but the gut microbe landscape and its association with immune cells in diffuse large B-cell lymphoma (DLBCL) remain largely unknown. In this study, we explored the associations between gut microbiota, clinical features and peripheral blood immune cell subtypes in DLBCL.
METHOD
A total of 87 newly diagnosed DLBCL adults were enrolled in this study. The peripheral blood samples were collected from all patients and then submitted to immune cell subtyping using full-spectral flow cytometry. Metagenomic sequencing was applied to assess the microbiota landscape of 69 of 87 newly diagnosed DLBCL patients. The microbiotas and peripheral blood immune cell subsets with significant differences between different National Comprehensive Center Network-International Prognostic Indexes (NCCN-IPIs) (low-risk, low-intermediate-risk, intermediate-high-risk, high-risk) groups were screened.
RESULTS
A total of 10 bacterial phyla, 31 orders and 455 bacteria species were identified in 69 patients with newly diagnosed DLBCL. The abundances of 6 bacteria, including sp., sp., , , and were significantly different between the low-risk, low-intermediate-risk, intermediate-high-risk and high-risk groups, among which and were markedly accumulated in the high-risk group. The different bacteria species were mostly enriched in the Pyridoxal 5'-phosphate biosynthesis I pathway. In addition, we found that 2 of the 6 bacteria showed close associations with the different immune cell subtypes which were also identified from different NCCN-IPIs. In detail, the abundance of was negatively correlated with Treg cells, CD38+ nonrescue exhausted T cells, nature killer 3 cells and CD38+CD8+ effector memory T cells, while the abundance of was negatively correlated with HLA-DR+ NK cells, CD4+ Treg cells, HLA-DR+ NKT cells and HLA-DR+CD94+CD159c+ NKT cells.
CONCLUSION
This study first reveals the gut microbiota landscape of patients with newly diagnosed DLBCL and highlights the association between the gut microbiota and immunity, which may provide a new idea for the prognosis assessment and treatment of DLBCL.
Topics: Adult; Humans; Metagenome; Lymphoma, Large B-Cell, Diffuse; HLA-DR Antigens
PubMed: 37234150
DOI: 10.3389/fimmu.2023.1146861 -
The Journal of Biological Chemistry Mar 2020Recent work exploring protein sequence space has revealed a new glycoside hydrolase (GH) family (GH164) of putative mannosidases. GH164 genes are present in several...
Recent work exploring protein sequence space has revealed a new glycoside hydrolase (GH) family (GH164) of putative mannosidases. GH164 genes are present in several commensal bacteria, implicating these genes in the degradation of dietary glycans. However, little is known about the structure, mechanism of action, and substrate specificity of these enzymes. Herein we report the biochemical characterization and crystal structures of the founding member of this family (164) from the human gut symbiont Previous reports of this enzyme indicated that it has α-mannosidase activity, however, we conclusively show that it cleaves only β-mannose linkages. Using NMR spectroscopy, detailed enzyme kinetics of WT and mutant 164, and multiangle light scattering we found that it is a trimeric retaining β-mannosidase, that is susceptible to several known mannosidase inhibitors. X-ray crystallography revealed the structure of 164, the first known structure of a GH164, at 1.91 Å resolution. 164 is composed of three domains: a (β/α) barrel, a trimerization domain, and a β-sandwich domain, representing a previously unobserved structural-fold for β-mannosidases. Structures of 164 at 1.80-2.55 Å resolution in complex with the inhibitors noeuromycin, mannoimidazole, or 2,4-dinitrophenol 2-deoxy-2-fluoro-mannoside reveal the residues essential for specificity and catalysis including the catalytic nucleophile (Glu-297) and acid/base residue (Glu-160). These findings further our knowledge of the mechanisms commensal microbes use for nutrient acquisition.
Topics: Amino Acid Sequence; Bacteroides; Catalysis; Catalytic Domain; Crystallography, X-Ray; Glycoside Hydrolases; Humans; Kinetics; Models, Molecular; Protein Conformation; Structure-Activity Relationship; Substrate Specificity; beta-Mannosidase
PubMed: 31871050
DOI: 10.1074/jbc.RA119.011591 -
Journal of Immunology Research 2021As a transitional state between normal aging and Alzheimer's disease (AD), mild cognitive impairment (MCI) is characterized by a worse cognitive decline than that of... (Observational Study)
Observational Study
BACKGROUND
As a transitional state between normal aging and Alzheimer's disease (AD), mild cognitive impairment (MCI) is characterized by a worse cognitive decline than that of natural aging. The association between AD and gut microbiota has been reported in a number of studies; however, microbial research regarding MCI remains limited.
METHODS
This study examined 48 participants, of whom 22 were MCI cases and 26 were normal control cases. Fecal samples were collected for 16S ribosomal RNA (rRNA) quantitative arrays and bioinformatics analysis.
RESULTS
A principal coordinates analysis (PCoA) and nonmetric multidimensional scaling (NMDS) both demonstrated that the microbial composition of participants with MCI deviated from that of healthy control participants. Multiple bacterial species were significantly increased (e.g., ) or decreased (e.g., ) in samples from the MCI group.
CONCLUSION
The composition of gut microbiota differed between normal control and MCI cases. This is the first study to identify a signature series of species in the gut microbiota of individuals with MCI. The results provide a new direction for the future development of an early diagnosis and probiotic regimen.
Topics: Aged; Aging; Case-Control Studies; Cognitive Dysfunction; Dysbiosis; Feces; Female; Gastrointestinal Microbiome; Healthy Volunteers; Humans; Male; Middle Aged; Probiotics
PubMed: 34869782
DOI: 10.1155/2021/5578958 -
European Urology Aug 2020The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and...
BACKGROUND
The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC.
OBJECTIVE
To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients.
DESIGN, SETTING, AND PARTICIPANTS
We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients' therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors.
RESULTS AND LIMITATIONS
Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae).
CONCLUSIONS
The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers.
PATIENT SUMMARY
We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy.
Topics: Animals; Carcinoma, Renal Cell; Drug Resistance, Neoplasm; Feces; Gastrointestinal Microbiome; Humans; Immune Checkpoint Inhibitors; Kidney Neoplasms; Mice; Nivolumab; Predictive Value of Tests; Prospective Studies
PubMed: 32376136
DOI: 10.1016/j.eururo.2020.04.044 -
MBio Aug 2022The reactions of α-d-phosphohexomutases (αPHM) are ubiquitous, key to primary metabolism, and essential for several processes in all domains of life. The functionality...
The reactions of α-d-phosphohexomutases (αPHM) are ubiquitous, key to primary metabolism, and essential for several processes in all domains of life. The functionality of these enzymes relies on an initial phosphorylation step which requires the presence of α-d-glucose-1,6-bisphosphate (Glc-1,6-BP). While well investigated in vertebrates, the origin of this activator compound in bacteria is unknown. Here we show that the Slr1334 protein from the unicellular cyanobacterium sp. PCC 6803 is a Glc-1,6-BP-synthase. Biochemical analysis revealed that Slr1334 efficiently converts fructose-1,6-bisphosphate (Frc-1,6-BP) and α-d-glucose-1-phosphate/α-d-glucose-6-phosphate into Glc-1,6-BP and also catalyzes the reverse reaction. As inferred from phylogenetic analysis, the product belongs to a primordial subfamily of αPHMs that is present especially in deeply branching bacteria and also includes human commensals and pathogens. Remarkably, the homologue of Slr1334 in the human gut bacterium Bacteroides salyersiae catalyzes the same reaction, suggesting a conserved and essential role for the members of this αPHM subfamily. Glc-1,6-BP is known as an essential activator of phosphoglucomutase (PGM) and other members of the αPHM superfamily, making it a central regulator in glycogen metabolism, glycolysis, amino sugar formation as well as bacterial cell wall and capsule formation. Despite this essential role in carbon metabolism, its origin in prokaryotes has so far remained elusive. In this study we identify a member of a specific αPHM subfamily as the first bacterial Glc-1,6-BP synthase, forming free Glc-1,6-BP by using Frc-1,6-BP as phosphoryl-donor. PGMs of this subfamily are widely distributed among prokaryotes including human commensals and pathogens. By showing that a distinct subfamily member can also form Glc-1,6-BP, we provide evidence that Glc-1,6-BP synthase activity is a general feature of this group.
Topics: Animals; Glucose; Glucose-6-Phosphate; Humans; Phosphoglucomutase; Phylogeny
PubMed: 35856562
DOI: 10.1128/mbio.01469-22 -
Microbiome Feb 2024Chondroitin sulfate (CS) has widely been used as a symptomatic slow-acting drug or a dietary supplement for the treatment and prevention of osteoarthritis. However, CS...
Chondroitin sulfate (CS) has widely been used as a symptomatic slow-acting drug or a dietary supplement for the treatment and prevention of osteoarthritis. However, CS could not be absorbed after oral intake due to its polyanionic nature and large molecular weight. Gut microbiota has recently been proposed to play a pivotal role in the metabolism of drugs and nutrients. Nonetheless, how CS is degraded by the human gut microbiota has not been fully characterized. In the present study, we demonstrated that each human gut microbiota was characterized with a unique capability for CS degradation. Degradation and fermentation of CS by the human gut microbiota produced significant amounts of unsaturated CS oligosaccharides (CSOSs) and short-chain fatty acids. To uncover which microbes were responsible for CS degradation, we isolated a total of 586 bacterial strains with a potential CS-degrading capability from 23 human fecal samples. Bacteroides salyersiae was a potent species for CS degradation in the human gut microbiota and produced the highest amount of CSOSs as compared to other well-recognized CS-degraders, including Bacteroides finegoldii, Bacteroides thetaiotaomicron, Bacteroides xylanisolvens, and Bacteroides ovatus. Genomic analysis suggested that B. salyersiae was armed with multiple carbohydrate-active enzymes that could potentially degrade CS into CSOSs. By using a spent medium assay, we further demonstrated that the unsaturated tetrasaccharide (udp4) produced by the primary degrader B. salyersiae could serve as a "public goods" molecule for the growth of Bacteroides stercoris, a secondary CS-degrader that was proficient at fermenting CSOSs but not CS. Taken together, our study provides insights into the metabolism of CS by the human gut microbiota, which has promising implications for the development of medical and nutritional therapies for osteoarthritis. Video Abstract.
Topics: Humans; Chondroitin Sulfates; Gastrointestinal Microbiome; Oligosaccharides; Osteoarthritis; Bacteroides
PubMed: 38419055
DOI: 10.1186/s40168-024-01768-2 -
Journal of Structural Biology: X 2021The termite causes extensive damage due to the high efficiency and broad specificity of the ligno- and hemicellulolytic enzyme systems produced by its symbionts. Thus,...
The termite causes extensive damage due to the high efficiency and broad specificity of the ligno- and hemicellulolytic enzyme systems produced by its symbionts. Thus, the gut microbiome is expected to constitute an excellent source of enzymes that can be used for the degradation and valorization of plant biomass. The symbiont bacterium strain TAV5 belongs to the phylum Verrucomicrobia and thrives in the hindgut of . The sequence of the gene with the locus tag opit5_10225 in the bacterium strain TAV5 genome has been classified as a member of glycoside hydrolase family 5 (GH5), and provisionally annotated as an --mannanase. We characterized biochemically and structurally the opit5_10225 gene product, and show that the enzyme, Man5, is an --1,4-mannosidase [EC 3.2.1.25] that is highly specific for -1,4-mannosidic bonds in mannooligosaccharides and ivory nut mannan. The structure of Man5 was phased using electron cryo-microscopy and further determined and refined at 2.2 Å resolution using X-ray crystallography. Man5 features a 200-kDa large homotrimer composed of three modular monomers. Despite insignificant sequence similarity, the structure of the monomer, and homotrimeric assembly are similar to that of the GH42-family -galactosidases and the GH164-family --1,4-mannosidase 164 from . To the best of our knowledge Man5 is the first structure of a glycoside hydrolase from a bacterial symbiont isolated from the digestive tract, as well as the first example of a GH5 glycoside hydrolase with a GH42 -galactosidase-type homotrimeric structure.
PubMed: 34195602
DOI: 10.1016/j.yjsbx.2021.100048