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BioRxiv : the Preprint Server For... May 2024While many studies have examined the bacterial taxa associated with dental caries, the most common chronic infectious disease globally, little is known about the...
While many studies have examined the bacterial taxa associated with dental caries, the most common chronic infectious disease globally, little is known about the caries-associated virome. In this study, the salivary viromes of 21 children with severe caries (>2 dentin lesions) and 23 children with healthy dentition were examined. 2,485 viral metagenome-assembled genomes (vMAGs) were identified, binned, and quantified from the metagenomic assemblies. These vMAGs were mostly phage, and represented 1,547 unique species-level vOTUs, 247 of which appear to be novel. The metagenomes were also queried for all 3,835 unique species-level vOTUs of DNA viruses with a human host on NCBI Virus, however all but were at very low abundance in the saliva. The oral viromes of the children with caries exhibited significantly different beta diversity compared to the oral virome of the children with healthy dentition; several vOTUs predicted to infect and were strongly correlated with health, and two vOTUs predicted to infect Saccharibacteria and respectively, were correlated with caries. Co-occurrence analysis indicated that phage typically co-occurred with both their predicted hosts and with bacteria that were themselves associated with the same disease status. Overall, this study provided the sequences of 53 complete or nearly complete novel oral phages and illustrated the significance of the oral virome in the context of dental caries, which has been largely overlooked. This work represents an important step towards the identification and study of phage therapy candidates which treat or prevent caries pathogenesis.
PubMed: 38826395
DOI: 10.1101/2024.05.22.595360 -
Frontiers in Medicine 2024Psoriasis is a chronic inflammatory skin disease. EDP1815 is an oral, gut-restricted preparation of non-live , the first of a new immunomodulatory therapeutic class...
BACKGROUND
Psoriasis is a chronic inflammatory skin disease. EDP1815 is an oral, gut-restricted preparation of non-live , the first of a new immunomodulatory therapeutic class targeting the small intestine to generate systemic anti-inflammatory responses.
OBJECTIVE
To evaluate safety and efficacy of EDP1815 in mild-to-moderate psoriasis in a proof-of-concept study.
METHODS
A phase 2, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study with a 16-week treatment period and up to 24 weeks of follow-up. Participants were randomized to receive 1, 4, or 10 capsules daily.
RESULTS
EDP1815 was well tolerated with comparable rates of treatment-emergent adverse events to placebo, and no drug-related serious adverse events. Clinically meaningful responses to EDP1815, defined as at least 50% reduction in Psoriasis Area and Severity Index (PASI-50) at week 16, were observed in all 3 cohorts, statistically significant in the 1-capsule (29.7%; = 0.048) and 4-capsule (31.9%; = 0.022) groups, compared with placebo (12.1%). Among EDP1815-treated PASI-50 responders at week 16, 60% (18/30) maintained or improved off-treatment responses at week 40.
LIMITATIONS
Continued off-treatment improvement past 16 weeks shows potential for greater therapeutic benefit that was not assessed.
CONCLUSION
EDP1815 was well-tolerated with a placebo-like safety profile, and had meaningful efficacy outcomes in psoriasis, validating this novel immunomodulatory approach.
CLINICAL TRIAL REGISTRATION
https://www.clinicaltrials.gov/search?term=NCT04603027, identifier NCT04603027.
PubMed: 38813388
DOI: 10.3389/fmed.2024.1292406 -
Brain Sciences Jul 2023Vascular dementia is a type of dementia from brain damage caused by cerebrovascular lesions and vascular risk factors. is a species of , belonging to the category of...
Vascular dementia is a type of dementia from brain damage caused by cerebrovascular lesions and vascular risk factors. is a species of , belonging to the category of obligate anaerobe. The purpose of our work was to study the protection of on cognitive function in rats subjected to vascular dementia (VaD) and investigate underlying molecular mechanisms. The rats were randomly divided into three groups: control group, 2VO group and 2VO + group. The VaD rats (the 2VO group and 2VO + group) were generated by bilateral common carotid artery occlusion (2VO). Rats in the 2VO+ group were administered with twice daily. In comparison with the rats in the 2VO group, rats in the 2VO + group presented an enhanced cognitive ability, increased synapse-associated protein expression, a downregulation of proinflammatory factors and an upregulation of neurotrophic factors. The relevant mechanism of the protective effect of may be associated with the inhibition of glial cell-associated inflammation by regulating phosphorylation of CaMKII. In conclusion, attenuates neurological impairments via regulating synapse-associated protein expression and the liberation of inflammatory elements in vascular dementia rats. The findings above might benefit the development of transplantation as a promising treatment of VaD.
PubMed: 37626492
DOI: 10.3390/brainsci13081136 -
BioRxiv : the Preprint Server For... Jul 2023The microbiome is a complex micro-ecosystem that provides the host with pathogen defense, food metabolism, and other vital processes. Alterations of the microbiome...
The microbiome is a complex micro-ecosystem that provides the host with pathogen defense, food metabolism, and other vital processes. Alterations of the microbiome (dysbiosis) have been linked with a number of diseases such as cancers, multiple sclerosis (MS), Alzheimer's disease, etc. Generally, differential abundance testing between the healthy and patient groups is performed to identify important bacteria (enriched or depleted in one group). However, simply providing a singular species of bacteria to an individual lacking that species for health improvement has not been as successful as fecal matter transplant (FMT) therapy. Interestingly, FMT therapy transfers the entire gut microbiome of a healthy (or mixture of) individual to an individual with a disease. FMTs do, however, have limited success, possibly due to concerns that not all bacteria in the community may be responsible for the healthy phenotype. Therefore, it is important to identify the of microorganisms linked to the health as well as the disease state of the host. Here we applied topic modeling, a natural language processing tool, to assess latent interactions occurring among microbes; thus, providing a representation of the of bacteria relevant to healthy vs. disease state. Specifically, we utilized our previously published data that studied the gut microbiome of patients with relapsing-remitting MS (RRMS), a neurodegenerative autoimmune disease that has been linked to a variety of factors, including a dysbiotic gut microbiome. With topic modeling we identified communities of bacteria associated with RRMS, including genera previously discovered, but also other taxa that would have been overlooked simply with differential abundance testing. Our work shows that topic modeling can be a useful tool for analyzing the microbiome in dysbiosis and that it could be considered along with the commonly utilized differential abundance tests to better understand the role of the gut microbiome in health and disease.
PubMed: 37546903
DOI: 10.1101/2023.07.21.549984 -
Microorganisms Apr 2023(1) Background: The human gut microbiome may regulate sleep through the gut-brain axis. However, the sleep-promoting effects of gut microbiota remain unclear. (2)...
(1) Background: The human gut microbiome may regulate sleep through the gut-brain axis. However, the sleep-promoting effects of gut microbiota remain unclear. (2) Methods: We obtained sleep-wake profiles from 25 rats receiving ( group), 5 rats receiving ( group), 4 rats not receiving bacteria (No administration group), and 8 rats receiving extracellular vesicles (EV) (EV group) during the baseline, administration, and withdrawal periods. (3) Results: The group showed increased total sleep, rapid eye movement (REM) sleep, and non-rapid eye movement (NREM) sleep time during the administration and withdrawal periods; on the last day of administration, we found significant increases of 52 min for total sleep ( < 0.01), 13 min for REM sleep ( < 0.05), and 39 min for NREM sleep ( < 0.01) over the baseline. EV administration also increased NREM sleep time on Day 3 of administration ( = 0.05). We observed a linear trend in the dose-response relationship for total sleep and NREM sleep in the group. However, neither the no-administration group nor the group showed significant findings. (4) Conclusions: Oral administration of probiotic may improve sleep and could be a potential sleep aid. Further rigorous evaluations for the safety and efficacy of supplementation are warranted.
PubMed: 37317125
DOI: 10.3390/microorganisms11051151 -
Frontiers in Medicine 2023EDP1815 is a non-colonizing pharmaceutical preparation of a single stain of isolated from the duodenum of a human donor. We report here preclinical and clinical studies...
INTRODUCTION
EDP1815 is a non-colonizing pharmaceutical preparation of a single stain of isolated from the duodenum of a human donor. We report here preclinical and clinical studies showing that the action of EDP1815, an orally delivered and gut restricted single strain of commensal bacteria can regulate inflammatory responses throughout the body.
METHODS
Supported by evidence for anti-inflammatory activity in three preclinical mouse models of Th1-, TH2-, and Th17-mediated inflammation, EDP1815 was tested clinically in three Phase 1b studies in patients with psoriasis, patients with atopic dermatitis, and healthy volunteers in a KLH skin challenge model.
RESULTS
Preclinically, EDP1815 was efficacious in all three mouse models of inflammation, showing reduction in skin inflammation as well as related tissue cytokines. In the Phase 1b studies, EDP1815 was found to be well tolerated by participants, with a safety profile comparable to placebo, including no severe or consistent side-effects reported, and no evidence of immunosuppression with no opportunistic infection occurring in these studies. In psoriasis patients, signs of clinical efficacy were seen after 4 weeks of treatment, which continued beyond the treatment period in the higher-dose cohort. In atopic dermatitis patients, improvements were seen throughout the key physician-and patient-reported outcomes. In a healthy-volunteer study of a KLH-induced skin inflammatory response, consistent anti-inflammatory effects were seen in two cohorts through imaging-based measures of skin inflammation.
DISCUSSION
This is the first report demonstrating clinical effects from targeting peripheral inflammation with a non-colonizing gut-restricted single strain of commensal bacteria, providing proof of concept for a new class of medicines. These clinical effects occur without systemic exposure of EDP1815 or modification of the resident gut microbiota, and with placebo-like safety and tolerability. The breadth of these clinical effects of EDP1815, combined with its excellent safety and tolerability profile and oral administration, suggests the potential for a new type of effective, safe, oral, and accessible anti-inflammatory medicine to treat the wide range of diseases driven by inflammation.: EudraCT # 2018-002807-32; EudraCT # 2018-002807-32; NL8676; https://clinicaltrials.gov/ct2/show/NCT03733353; http://www.trialregister.nl.
PubMed: 37215725
DOI: 10.3389/fmed.2023.1070433 -
Environmental Toxicology and... Jun 2023The widespread use of glyphosate, a broad-spectrum herbicide, has resulted in significant human exposure, and recent studies have challenged the notion that glyphosate...
The widespread use of glyphosate, a broad-spectrum herbicide, has resulted in significant human exposure, and recent studies have challenged the notion that glyphosate is safe for humans. Although the link between disease states and glyphosate exposure is increasingly appreciated, the mechanistic links between glyphosate and its toxic effects on human health are poorly understood. Recent studies have suggested that glyphosate may cause toxicity through modulation of the gut microbiome, but evidence for glyphosate-induced gut dysbiosis and its effect on host physiology at doses approximating the U.S. Acceptable Daily Intake (ADI = 1.75 mg/kg body weight) is limited. Here, utilizing shotgun metagenomic sequencing of fecal samples from C57BL/6 J mice, we show that glyphosate exposure at doses approximating the U.S. ADI significantly impacts gut microbiota composition. These gut microbial alterations were associated with effects on gut homeostasis characterized by increased proinflammatory CD4IL17A T cells and Lipocalin-2, a known marker of intestinal inflammation.
Topics: Mice; Humans; Animals; Gastrointestinal Microbiome; Mice, Inbred C57BL; Herbicides; Homeostasis; Glyphosate
PubMed: 37196884
DOI: 10.1016/j.etap.2023.104149 -
The Preventive Effects of Probiotic on the Bone Loss of Mice with Ovariectomy-Mediated Osteoporosis.Microorganisms Apr 2023It has been demonstrated that the disturbance of gut microbiota (GM) is closely related to the reduction of bone mass and incidence of osteoporosis (OP). The aim of this...
It has been demonstrated that the disturbance of gut microbiota (GM) is closely related to the reduction of bone mass and incidence of osteoporosis (OP). The aim of this study is to investigate whether the supplementation of (Ph) can prevent the bone loss in mice with ovariectomy (OVX)-mediated OP, and further explore relevant mechanisms. Regular (once a day for 8 consecutive weeks) and quantitative (200 µL/d) perfusion of Ph (the bacteria that orally gavaged) was conducted starting from 1 week after the construction of mice models. Bone mass and bone microstructure were detected by Micro-computed tomography (Micro-CT). Expressions of intestinal permeability, pro-inflammatory cytokines, and osteogenic and osteoclastic activities of mice were analyzed by histological staining and immunohistochemistry (IHC). 16S rRNA high throughput sequencing technique was applied to analyze the alterations of composition, abundance, and diversity of collected feces. Regular and quantitative perfusion of Ph mitigated the bone loss in mice with OVX-mediated OP. Compared with OVX + PBS group, perfusion of Ph repressed osteoclastogenesis and promoted osteogenesis, reduced release of pro-inflammatory cytokine cytokines (interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α)), and reversed expressions of tight junction proteins (zonula occludens protein 1 (ZO-1) and Occludin). Besides, the perfusion of Ph improved the composition, abundance, and diversity of GM. Collectively, this study revealed that regular and quantitative perfusion of Ph can improve the bone loss in mice with OVX-mediated OP by repairing intestinal mucosal barrier damage, optimizing intestinal permeability, inhibiting release of pro-osteoclastogenic cytokines, and improving disturbance of GM.
PubMed: 37110373
DOI: 10.3390/microorganisms11040950 -
BMC Complementary Medicine and Therapies Apr 2023Ethanol-induced gastric mucosal lesions (EGML) is one of the most common digestive disorders for which current therapies have limited outcomes in clinical practice....
BACKGROUND
Ethanol-induced gastric mucosal lesions (EGML) is one of the most common digestive disorders for which current therapies have limited outcomes in clinical practice. Prevotella histicola (P. histicola) has shown probiotic efficacy against arthritis, multiple sclerosis and oestrogen deficiency-induced depression in mice; however, its role in EGML remains unclear in spite of its extensive colonisation of the stomach. Ferroptosis, which is characterised by lipid peroxidation, may be involved in EGML. Herein, we aimed to investigate the effects and underlying mechanism of action of P. histicola on EGML in the ferroptosis-dependent pathway.
METHODS
P. histicola was intragastrically administered for a week, and deferoxamine (DFO), a ferroptosis inhibitor, was intraperitoneally injected prior to oral ethanol administration. The gastric mucosal lesions and ferroptosis were assessed via histopathological examinations, quantitative real-time PCR, Western blot, immunohistochemistry and immunofluorescence.
RESULTS
P. histicola was originally found to attenuate EGML by reducing histopathological changes and lipid reactive oxygen species (ROS) accumulation. The pro-ferroptotic genes of Transferrin Receptor (TFR1), Solute Carrier Family 39 Member 14 (SLC39A14), Haem Oxygenase-1 (HMOX-1), Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4), Cyclooxygenase 2 (COX-2) and mitochondrial Voltage-dependent Anion Channels (VDACs) were up-regulated; the anti-ferroptotic System Xc-/Glutathione Peroxidase 4 (GPX4) axis was inhibited after ethanol administration. However, the changes of histopathology and ferroptosis-related parameters induced by ethanol were reversed by DFO. Furthermore, P. histicola treatment significantly downregulated the expression of ACSL4, HMOX-1 and COX-2, as well as TFR1 and SLC39A14, on mRNA or the protein level, while activating the System Xc-/GPX4 axis.
CONCLUSIONS
We found that P. histicola reduces ferroptosis to attenuate EGML by inhibiting the ACSL4- and VDAC-dependent pro-ferroptotic pathways and activating the anti-ferroptotic System Xc-/GPX4 axis.
Topics: Animals; Mice; Cyclooxygenase 2; Ferroptosis; Administration, Oral; Ethanol; Cation Transport Proteins
PubMed: 37060026
DOI: 10.1186/s12906-023-03946-5 -
ImmunoHorizons Mar 2023Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS that is linked with both genetic and environmental factors. A Western-style diet rich in fat...
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS that is linked with both genetic and environmental factors. A Western-style diet rich in fat and simple sugars is hypothesized as a potential factor contributing to the increased incidence of inflammatory autoimmune diseases, such as MS, in developed countries. Although the adverse effects of a high-fat diet in MS have been studied extensively, the effect of a fructose-rich diet (FRD) on MS etiology is unknown. We hypothesized that an FRD will alter the gut microbiome, influence immune populations, and negatively impact disease in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To test this, we fed C57BL/6 mice either an FRD or normal feed for 4 or 12 wk and analyzed the effect of an FRD on gut microbiota, immune populations, and EAE. An FRD significantly influenced the gut microbiota, with reduced abundance of beneficial bacteria and enrichment of potentially proinflammatory bacteria. We also observed immune modulation in the gut and periphery. Of particular interest was a population of Helios-RORγt+Foxp3+CD4+ T cells that was enriched in the small intestine lamina propria of FRD-fed mice. However, despite gut microbiota and immune modulations, we observed only a subtle effect of an FRD on EAE severity. Overall, our data suggest that in C57Bl6/J mice, an FRD modulates the gut microbiota and immune system without significantly impacting myelin oligodendrocyte glycoprotein 35-55/CFA-induced EAE.
Topics: Mice; Animals; Multiple Sclerosis; Gastrointestinal Microbiome; Mice, Inbred C57BL; Encephalomyelitis, Autoimmune, Experimental; Diet; Immunomodulation
PubMed: 36939622
DOI: 10.4049/immunohorizons.2300008