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Science (New York, N.Y.) Apr 2024A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater...
A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of , which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.
Topics: Animals; Female; Humans; Male; Mice; Bacteroides fragilis; Gastrointestinal Microbiome; Immune Checkpoint Inhibitors; Immunotherapy; Intestinal Mucosa; Mice, Inbred C57BL; Neoplasms; Vitamin D; Diet; Cell Line, Tumor; Calcifediol; Vitamin D-Binding Protein
PubMed: 38662827
DOI: 10.1126/science.adh7954 -
Inflammatory Bowel Diseases Jul 2023One of the prospective sequelae of periodontal disease (PD), chronic inflammation of the oral mucosa, is the development of inflammatory gastrointestinal (GI) disorders... (Review)
Review
One of the prospective sequelae of periodontal disease (PD), chronic inflammation of the oral mucosa, is the development of inflammatory gastrointestinal (GI) disorders due to the amplification and expansion of the oral pathobionts. In addition, chronic inflammatory diseases related to the GI tract, which include inflammatory bowel disease (IBD), can lead to malignancy susceptibility in the colon of both animals and humans. Recent studies suggest that dysbiosis of the oral microbiota can alter the microbial composition in relative abundance or diversity of the distal gut, leading to the progression of digestive carcinogenesis. The link between PD and specific GI disorders is also closely associated with the migration and colonization of periodontal pathogens and the subsequent microbe-reactive T cell induction within the intestines. In this review, an in-depth examination of this relationship and the accessibility of different mouse models of IBD and PD may shed light on the current dogma. As such, oral microbiota dysbiosis involving specific bacteria, including Fusobacterium nucleatum and Porphyromonas gingivalis, can ultimately lead to gut malignancies. Further understanding the precise mechanism(s) of the oral-gut microbial axis in PD, IBD, and colorectal cancer pathogenesis will be pivotal in diagnosis, prognosis, and future treatment.
Topics: Animals; Mice; Humans; Dysbiosis; Prospective Studies; Periodontal Diseases; Gastrointestinal Diseases; Inflammatory Bowel Diseases; Porphyromonas gingivalis
PubMed: 36527679
DOI: 10.1093/ibd/izac241 -
Journal of Advanced Research Dec 2023Porphyromonas gingivalis (PG)-infected periodontitis is in close connection with the development of Alzheimer's disease (AD). PG-derived extracellular vesicles (pEVs)...
INTRODUCTION
Porphyromonas gingivalis (PG)-infected periodontitis is in close connection with the development of Alzheimer's disease (AD). PG-derived extracellular vesicles (pEVs) contain inflammation-inducing virulence factors, including gingipains (GPs) and lipopolysaccharide (LPS).
OBJECTIVES
To understand how PG could cause cognitive decline, we investigated the effects of PG and pEVs on the etiology of periodontitis and cognitive impairment in mice.
METHODS
Cognitive behaviors were measured in the Y-maze and novel object recognition tasks. Biomarkers were measured using ELISA, qPCR, immunofluorescence assay, and pyrosequencing.
RESULTS
pEVs contained neurotoxic GPs and inflammation-inducible fimbria protein and LPS. Gingivally exposed, but not orally gavaged, PG or pEVs caused periodontitis and induced memory impairment-like behaviors. Gingival exposure to PG or pEVs increased TNF-α expression in the periodontal and hippocampus tissues. They also increased hippocampal GPIba1, LPSIba1, and NF-κBIba1 cell numbers. Gingivally exposed PG or pEVs decreased BDNF, claudin-5, and N-methyl-D-aspartate receptor expression and BDNFNeuN cell number. Gingivally exposed fluorescein-5-isothiocyanate-labeled pEVs (F-pEVs) were detected in the trigeminal ganglia and hippocampus. However, right trigeminal neurectomy inhibited the translocation of gingivally injected F-EVs into the right trigeminal ganglia. Gingivally exposed PG or pEVs increased blood LPS and TNF-α levels. Furthermore, they caused colitis and gut dysbiosis.
CONCLUSION
Gingivally infected PG, particularly pEVs, may cause cognitive decline with periodontitis. PG products pEVs and LPS may be translocated into the brain through the trigeminal nerve and periodontal blood pathways, respectively, resulting in the cognitive decline, which may cause colitis and gut dysbiosis. Therefore, pEVs may be a remarkable risk factor for dementia.
Topics: Mice; Animals; Porphyromonas gingivalis; Lipopolysaccharides; Dysbiosis; Tumor Necrosis Factor-alpha; Brain-Derived Neurotrophic Factor; Periodontitis; Inflammation; Trigeminal Nerve; Colitis; Cognitive Dysfunction
PubMed: 36796586
DOI: 10.1016/j.jare.2023.02.006 -
Precision Clinical Medicine Jun 2023Observational studies have indicated a potential link between gut microbiota and sarcopenia. However, the underlying mechanisms and a causal relationship have not been...
BACKGROUND
Observational studies have indicated a potential link between gut microbiota and sarcopenia. However, the underlying mechanisms and a causal relationship have not been established. Thus, the objective of this study is to examine the possible causal association between gut microbiota and sarcopenia-related traits, including low hand-grip strength and appendicular lean mass (ALM), to shed light on the gut-muscle axis.
METHODS
To investigate the potential impact of gut microbiota on low hand-grip strength and ALM, we utilized a two-sample Mendelian randomization (MR) approach. Summary statistics were obtained from genome-wide association studies of gut microbiota, low hand-grip strength, and ALM. The primary MR analysis employed the random-effects inverse-variance weighted (IVW) method. To assess the robustness, we conducted sensitivity analyses using the MR pleiotropy residual sum and outlier (MR-PRESSO) test to detect and correct for horizontal pleiotropy, as well as the MR-Egger intercept test and leave-one-out analysis.
RESULTS
, and were positively associated with the risk of low hand-grip strength (-values < 0.05). were negatively associated with low hand-grip strength (-values < 0.05). Eight bacterial taxa (, and were associated with a higher risk of ALM (-values < 0.05). group was negatively associated with ALM (-values < 0.05).
CONCLUSION
We found several gut microbiota components causally associated with sarcopenia-related traits. Our findings provided insights into novel strategies for the prevention and treatment of sarcopenia through the regulation of the gut microbiota, contributing to a better understanding of the gut-muscle axis.
PubMed: 37324750
DOI: 10.1093/pcmedi/pbad010 -
Cell Host & Microbe Jul 2023The human gut microbiome composition is generally in a stable dynamic equilibrium, but it can deteriorate into dysbiotic states detrimental to host health. To...
The human gut microbiome composition is generally in a stable dynamic equilibrium, but it can deteriorate into dysbiotic states detrimental to host health. To disentangle the inherent complexity and capture the ecological spectrum of microbiome variability, we used 5,230 gut metagenomes to characterize signatures of bacteria commonly co-occurring, termed enterosignatures (ESs). We find five generalizable ESs dominated by either Bacteroides, Firmicutes, Prevotella, Bifidobacterium, or Escherichia. This model confirms key ecological characteristics known from previous enterotype concepts, while enabling the detection of gradual shifts in community structures. Temporal analysis implies that the Bacteroides-associated ES is "core" in the resilience of westernized gut microbiomes, while combinations with other ESs often complement the functional spectrum. The model reliably detects atypical gut microbiomes correlated with adverse host health conditions and/or the presence of pathobionts. ESs provide an interpretable and generic model that enables an intuitive characterization of gut microbiome composition in health and disease.
Topics: Humans; Gastrointestinal Microbiome; Microbiota; Bacteria; Metagenome; Firmicutes; Bacteroides; Feces
PubMed: 37339626
DOI: 10.1016/j.chom.2023.05.024 -
Gut Microbes Dec 2023is an abundant member of the human gastrointestinal microbiome, whose relative abundance has curiously been associated with positive and negative impacts on diseases,... (Review)
Review
is an abundant member of the human gastrointestinal microbiome, whose relative abundance has curiously been associated with positive and negative impacts on diseases, such as Parkinson's disease and rheumatoid arthritis. Yet, the verdict is still out on the definitive role of in human health, and on the effect of different diets on its relative abundance in the gut microbiome. The puzzling discrepancies among studies have only recently been attributed to the diversity of its strains, which substantially differ in their encoded metabolic patterns from the commonly used reference strain. However, such strain differences cannot be resolved by common 16S rRNA amplicon profiling methods. Here, we scrutinize , its versatile metabolic potential, and the hypotheses behind the conflicting observations on its association with diet and human health. We also provide suggestions for designing studies and bioinformatics pipelines to better research .
Topics: Humans; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Prevotella; Computational Biology
PubMed: 37655441
DOI: 10.1080/19490976.2023.2249152 -
Proceedings of the National Academy of... Jul 2023Extracellular vesicles are produced in all three domains of life, and their biogenesis has common ancient origins in eukaryotes and archaea. Although bacterial vesicles...
Extracellular vesicles are produced in all three domains of life, and their biogenesis has common ancient origins in eukaryotes and archaea. Although bacterial vesicles were discovered several decades ago and multiple roles have been attributed to them, no mechanism has been established for vesicles biogenesis in bacteria. For this reason, there is a significant level of skepticism about the biological relevance of bacterial vesicles. (), a prominent member of the human intestinal microbiota, produces significant amounts of outer membrane vesicles (OMVs) which have been proposed to play key physiological roles. Here, we employed a dual marker system, consisting of outer membrane- and OMV-specific markers fused to fluorescent proteins to visualize OMV biogenesis by time-lapse microscopy. Furthermore, we performed comparative proteomic analyses to show that, in , the OMV cargo is adapted for the optimal utilization of different polysaccharides. We also show that a negatively charged N-terminal motif acts as a signal for protein sorting into OMVs irrespective of the nutrient availability. Our results demonstrate that OMV production is the result of a highly regulated process in .
Topics: Humans; Proteomics; Extracellular Vesicles; Bacteroides thetaiotaomicron; Diet; Polysaccharides; Bacterial Outer Membrane Proteins
PubMed: 37364113
DOI: 10.1073/pnas.2306314120 -
International Journal of Molecular... Aug 2023Atherosclerosis (AS) is an inflammatory vascular disease that constitutes a major underlying cause of cardiovascular diseases (CVD) and stroke. Infection is a... (Review)
Review
Atherosclerosis (AS) is an inflammatory vascular disease that constitutes a major underlying cause of cardiovascular diseases (CVD) and stroke. Infection is a contributing risk factor for AS. Epidemiological evidence has implicated individuals afflicted by periodontitis displaying an increased susceptibility to AS and CVD. This review concisely outlines several prevalent periodontal pathogens identified within atherosclerotic plaques, including , , and . We review the existing epidemiological evidence elucidating the association between these pathogens and AS-related diseases, and the diverse mechanisms for which these pathogens may engage in AS, such as endothelial barrier disruption, immune system activation, facilitation of monocyte adhesion and aggregation, and promotion of foam cell formation, all of which contribute to the progression and destabilization of atherosclerotic plaques. Notably, the intricate interplay among bacteria underscores the complex impact of periodontitis on AS. In conclusion, advancing our understanding of the relationship between periodontal pathogens and AS will undoubtedly offer invaluable insights and potential therapeutic avenues for the prevention and management of AS.
Topics: Humans; Plaque, Atherosclerotic; Atherosclerosis; Fusobacterium nucleatum; Cardiovascular Diseases; Porphyromonas gingivalis
PubMed: 37629042
DOI: 10.3390/ijms241612861 -
Nature Communications Feb 2024Periodontitis is closely related to inflammatory bowel disease (IBD). An excessive and non-self-limiting immune response to the dysbiotic microbiome characterizes the...
Periodontitis is closely related to inflammatory bowel disease (IBD). An excessive and non-self-limiting immune response to the dysbiotic microbiome characterizes the two. However, the underlying mechanisms that overlap still need to be clarified. We demonstrate that the critical periodontal pathogen Porphyromonas gingivalis (Pg) aggravates intestinal inflammation and Th17/Treg cell imbalance in a gut microbiota-dependent manner. Specifically, metagenomic and metabolomic analyses shows that oral administration of Pg increases levels of the Bacteroides phylum but decreases levels of the Firmicutes, Verrucomicrobia, and Actinobacteria phyla. Nevertheless, it suppresses the linoleic acid (LA) pathway in the gut microbiota, which was the target metabolite that determines the degree of inflammation and functions as an aryl hydrocarbon receptor (AHR) ligand to suppress Th17 differentiation while promoting Treg cell differentiation via the phosphorylation of Stat1 at Ser727. Therapeutically restoring LA levels in colitis mice challenged with Pg exerts anti-colitis effects by decreasing the Th17/Treg cell ratio in an AHR-dependent manner. Our study suggests that Pg aggravates colitis via a gut microbiota-LA metabolism-Th17/Treg cell balance axis, providing a potential therapeutically modifiable target for IBD patients with periodontitis.
Topics: Humans; Mice; Animals; T-Lymphocytes, Regulatory; Porphyromonas gingivalis; Gastrointestinal Microbiome; Linoleic Acid; Mice, Inbred C57BL; Colitis; Inflammatory Bowel Diseases; Periodontitis; Inflammation; Th17 Cells
PubMed: 38388542
DOI: 10.1038/s41467-024-45473-y -
Nature Communications Sep 2023Gut dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown...
Gut dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors' fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPβ transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPβ transgenic mice.
Topics: Mice; Animals; Bacteroides fragilis; Mice, Transgenic; Gastrointestinal Microbiome; Alzheimer Disease; Dinoprostone; Microglia; RNA, Ribosomal, 16S; Bacteroides; Bacterial Infections; Hydroxy Acids
PubMed: 37673907
DOI: 10.1038/s41467-023-41283-w