Antiviral effect of vitamin A on norovirus infection via modulation of the gut microbiome.
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ABSTRACT:
SUBMITTER: Lee H
PROVIDER: S-EPMC4867650 | biostudies-other | 2016
REPOSITORIES: biostudies-other
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Project description:Human norovirus is the primary cause of non-bacterial gastroenteritis globally and is the second leading cause of diarrheal deaths in children in developing countries. However, effective therapeutics which prevent or clear norovirus infection are not yet available due to a lack of understanding regarding norovirus pathogenesis. Evidence shows that noroviruses can bind to the surface of commensal bacteria, and the presence of these bacteria alters both acute and persistent murine norovirus infection through the modulation of host immune responses. Interestingly, norovirus-bacterial interactions also affect the bacteria by inducing bacterial stress responses and increasing the production of bacterial extracellular vesicles. Given the established ability of these vesicles to easily cross the intestinal barriers, enter the lamina propria, and modulate host responses, we hypothesized that bacterial extracellular vesicles influence murine norovirus infection through modulation of the antiviral immune response. In this study, we show that murine norovirus can attach to purified bacterial vesicles, facilitating co-inoculation of target cells with both virus and vesicle. Furthermore, we have found that when murine noroviruses and vesicles are used to co-inoculate macrophages, viral infection is reduced compared to virus infection alone. Specifically, co-inoculation with bacterial vesicles results in higher production and release of pro-inflammatory cytokines in response to viral infection. Ultimately, given that murine norovirus infection increases bacterial vesicle production in vivo, these data indicate that bacterial vesicles may serve as a mechanism by which murine norovirus infection is ultimately controlled and limited to a short-term disease.
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Project description:Norovirus infections are a significant health and economic burden globally, accounting for hundreds of millions of cases of acute gastroenteritis every year. In the absence of an approved norovirus vaccine, there is an urgent need to develop antivirals to treat chronic infections and provide prophylactic therapy to limit viral spread during epidemics and pandemics. Toll-like receptor (TLR) agonists have been explored widely for their antiviral potential, and several are progressing through clinical trials for the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and as adjuvants for norovirus viruslike particle (VLP) vaccines. However, norovirus therapies in development are largely direct-acting antivirals (DAAs) with fewer compounds that target the host. Our aim was to assess the antiviral potential of TLR7 agonist immunomodulators on norovirus infection using the murine norovirus (MNV) and human Norwalk replicon models. TLR7 agonists R-848, Gardiquimod, GS-9620, R-837, and loxoribine were screened using a plaque reduction assay, and each displayed inhibition of MNV replication (50% effective concentrations [EC50s], 23.5 nM, 134.4 nM, 0.59 ?M, 1.5 ?M, and 79.4 ?M, respectively). RNA sequencing of TLR7-stimulated cells revealed a predominant upregulation of innate immune response genes and interferon (IFN)-stimulated genes (ISGs) that are known to drive an antiviral state. Furthermore, the combination of R-848 and the nucleoside analogue (NA) 2'C-methylcytidine elicited a synergistic antiviral effect against MNV, demonstrating that combinational therapy of host modulators and DAAs might be used to reduce drug cytotoxicity. In summary, we have identified that TLR7 agonists display potent inhibition of norovirus replication and are a therapeutic option to combat norovirus infections.
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Project description:Norovirus infection is a leading cause of acute gastroenteritis worldwide and can also cause harmful chronic infections in individuals with weakened immune systems. The role of the gut microbiota in the interactions between the host and noroviruses has been extensively studied. While most past studies were conducted in vitro or focused on murine noroviruses, recent research has expanded to human noroviruses using in vivo or ex vivo human intestinal enteroids culture studies. The gut microbiota has been observed to have both promoting and inhibiting effects on human noroviruses. Understanding the interaction between noroviruses and the gut microbiota or probiotics is crucial for studying the pathogenesis of norovirus infection and its potential implications, including probiotics and vaccines for infection control. Recently, several clinical trials of probiotics and norovirus vaccines have also been published. Therefore, in this review, we discuss the current understanding and recent updates on the interactions between noroviruses and gut microbiota, including the impact of norovirus on the microbiota profile, pro-viral and antiviral effects of microbiota on norovirus infection, the use of probiotics for treating norovirus infections, and human norovirus vaccine development.
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Project description:Neonatal rotavirus infections are predominantly asymptomatic. While an association with gastrointestinal symptoms has been described in some settings, factors influencing differences in clinical presentation are not well understood. Using multidisciplinary approaches, we show that a complex interplay between human milk oligosaccharides (HMOs), milk microbiome, and infant gut microbiome impacts neonatal rotavirus infections. Validating in vitro studies where HMOs are not decoy receptors for neonatal strain G10P[11], population studies show significantly higher levels of Lacto-N-tetraose (LNT), 2'-fucosyllactose (2'FL), and 6'-siallylactose (6'SL) in milk from mothers of rotavirus-positive neonates with gastrointestinal symptoms. Further, these HMOs correlate with abundance of Enterobacter/Klebsiella in maternal milk and infant stool. Specific HMOs also improve the infectivity of a neonatal strain-derived rotavirus vaccine. This study provides molecular and translational insight into host factors influencing neonatal rotavirus infections and identifies maternal components that could promote the performance of live, attenuated rotavirus vaccines.
| S-EPMC6258677 | biostudies-other
Project description:Norovirus infections take a heavy toll on worldwide public health. While progress has been made toward understanding host responses to infection, the role of the gut microbiome in determining infection outcome is unknown. Moreover, data are lacking on the nature and duration of the microbiome response to norovirus infection, which has important implications for diagnostics and host recovery. Here, we characterized the gut microbiomes of subjects enrolled in a norovirus challenge study. We analyzed microbiome features of asymptomatic and symptomatic individuals at the genome (population) and gene levels and assessed their response over time in symptomatic individuals. We show that the preinfection microbiomes of subjects with asymptomatic infections were enriched in Bacteroidetes and depleted in Clostridia relative to the microbiomes of symptomatic subjects. These compositional differences were accompanied by differences in genes involved in the metabolism of glycans and sphingolipids that may aid in host resilience to infection. We further show that microbiomes shifted in composition following infection and that recovery times were variable among human hosts. In particular, Firmicutes increased immediately following the challenge, while Bacteroidetes and Proteobacteria decreased over the same time. Genes enriched in the microbiomes of symptomatic subjects, including the adenylyltransferase glgC, were linked to glycan metabolism and cell-cell signaling, suggesting as-yet unknown roles for these processes in determining infection outcome. These results provide important context for understanding the gut microbiome role in host susceptibility to symptomatic norovirus infection and long-term health outcomes.IMPORTANCE The role of the human gut microbiome in determining whether an individual infected with norovirus will be symptomatic is poorly understood. This study provides important data on microbes that distinguish asymptomatic from symptomatic microbiomes and links these features to infection responses in a human challenge study. The results have implications for understanding resistance to and treatment of norovirus infections.
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Project description:Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious side effects such as addiction, immunosuppression and gastrointestinal symptoms limit long term use. In the current study using a chronic morphine-murine model a longitudinal approach was undertaken to investigate the role of morphine modulation of gut microbiome as a mechanism contributing to the negative consequences associated with opioids use. The results revealed a significant shift in the gut microbiome and metabolome within 24 hours following morphine treatment when compared to placebo. Morphine induced gut microbial dysbiosis exhibited distinct characteristic signatures profiles including significant increase in communities associated with pathogenic function, decrease in communities associated with stress tolerance. Collectively, these results reveal opioids-induced distinct alteration of gut microbiome, may contribute to opioids-induced pathogenesis. Therapeutics directed at these targets may prolong the efficacy long term opioid use with fewer side effects.
2018-04-16 | E-MTAB-5550 | biostudies-arrayexpress
Project description:Domestic yaks (Bos grunniens) are indigenous to the Tibetan Plateau and display a high diarrhea rate due to poor habitat and husbandry conditions. Lactobacillus has been shown to exert beneficial effects as antimicrobial, growth promotion, and gut microbiota in humans and/or murine models, but the relevant data regarding Lactobacillus isolated from yaks was unavailable. Therefore, this study aimed to investigate the effects of Lactobacillus from yaks on the intestinal microbial community in a mouse model and determine whether Lactobacillus supplementation contributed in alleviating diarrhea by modulating gut microbiota. A total of 12 ileac samples from four groups were collected for 16S rRNA gene amplicon sequencing of V3-V4 region. Results revealed that although Lactobacillus supplementation did not change the diversity of gut microbiota in mice, the proportion of some intestinal microbiota significantly changed. Specifically, the proportion of Lactobacillus and Sphingomonas in the Lactobacillus treated-group (L-group) were increased as compared to control group (C-group), whereas Pantoea, Cutibacterium, Glutamicibacter, Turicibacter, Globicatella, Microbacterium, Facklamia, unidentified_Corynebacteriaceae, Brachybacterium, and Staphylococcus were significantly decreased in the L-group. In contrast, Escherichia coli (E. coli) infection significantly decreased the proportion of beneficial bacteria such as Globicatella, Acinetobacter, Aerococcus, and Comamonas, while loads of pathogenic bacteria significantly increased including Roseburia and Megasphaera. Interestingly, Lactobacillus administration could ameliorate the microbial community structure of E. coli-induced diarrheal mice by reducing the relative abundance of pathogenic bacteria such as Paenibacillus, Aerococcus, Comamonas, Acinetobacter, Corynebacterium, Facklamia, and Globicatella. Results in this study revealed that Lactobacillus supplementation not only improved the gut microbiota but also alleviated diarrhea in mice, which may be mediated by modulating the composition and function of gut microbiota. Moreover, this study is expected to provide a new theoretical basis for the establishment of a preventive and treatment system for diarrhea in yaks.
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Project description:Interventions: Group 1: A probiotic product OMNi-BiOTiC from the company Allergosan containing a mix of 10 probiotic bacterial strains will be administered orally in lyophilized form. Administration will be applied once daily with one dose equivalent to 5 * 109 colony forming units (cfu), in the morning over a period of 6 months.
Screening-phase will take up to two weeks and will be followed by a treatment period of 24 weeks. In Total 4 visits will be performed: Screening visit between -14 to -1 days before baseline. Treatment duration with probiotic product will be 24 weeks starting at the baseline visit. A study visit will be performed at week 8. End of treatment visit (EOT) takes place at week 24.
At each visit, physical examination takes place and vital signs, questionnaires (quality of life and dietary) as well as adverse events will be documented. At screening visit, study visit and EOT visit serum and whole blood as well as stool samples are collected for further analyses.
Primary outcome(s): Demonstrate a persistent modification of the intestinal microbiome in the feces (stool) of the participants following Bacteria administration as measured by metagenomics analysis by Shotgun Sequencing. Analyses are performed at the beginning of the study, after 8 weeks and at the end of the study after 24 weeks.
Study Design: Allocation: N/A: single arm study; Masking: Open (masking not used); Control: uncontrolled; Assignment: single; Study design purpose: other
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Project description:Non-lethal doses of ionizing radiation (IR) delivered to humans because of terrorist events, nuclear accidents or radiotherapy can result in carcinogenesis. Means of protecting against carcinogenesis are lacking. We questioned the role of the gut microbiome in IR-induced carcinogenesis. The gut microbiome was modulated by administering broad spectrum antibiotics (Ab) in the drinking water. Mice were given Ab 3 weeks before and 3 weeks after 3 Gy total body irradiation (TBI) or for 6 weeks one month after TBI. Three weeks of Ab treatment resulted in a 98% reduction in total 16S rRNA counts for 4 out of 6 of the phylum groups detected. However, 3 more weeks of Ab treatment (6 weeks total) saw an expansion in the phylum groups Proteobacteria and Actinobacteria. The Ab treatment altered the bacteria diversity in the gut, and shortened the lifespan when Ab were administered before and after TBI. Mortality studies indicated that the adverse Ab lifespan effects were due to a decrease in the time in which solid tumors started to appear and not to any changes in hematopoietic or benign tumors. In contrast, when Ab were administered one month after TBI, lifespan was unchanged compared to the control TBI group. Use of broad-spectrum antibiotics to simulate the germ-free condition did not afford an advantage on carcinogenesis or lifespan.
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Project description:Studies suggest that inducing gut microbiota changes may alter both muscle physiology and cognitive behaviour. Gut microbiota may play a role in both anabolic resistance of older muscle, and cognition. In this placebo controlled double blinded randomised controlled trial of 36 twin pairs (72 individuals), aged ≥60, each twin pair are block randomised to receive either placebo or prebiotic daily for 12 weeks. Resistance exercise and branched chain amino acid (BCAA) supplementation is prescribed to all participants. Outcomes are physical function and cognition. The trial is carried out remotely using video visits, online questionnaires and cognitive testing, and posting of equipment and biological samples. The prebiotic supplement is well tolerated and results in a changed gut microbiome [e.g., increased relative Bifidobacterium abundance]. There is no significant difference between prebiotic and placebo for the primary outcome of chair rise time (β = 0.579; 95% CI -1.080-2.239 p = 0.494). The prebiotic improves cognition (factor score versus placebo (β = -0.482; 95% CI,-0.813, -0.141; p = 0.014)). Our results demonstrate that cheap and readily available gut microbiome interventions may improve cognition in our ageing population. We illustrate the feasibility of remotely delivered trials for older people, which could reduce under-representation of older people in clinical trials. ClinicalTrials.gov registration: NCT04309292.
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