Abstract 14: An Anti-inflammatory Proton Sensing-receptor Contributes To Cardiovascular Protection Of Gut Microbiota-derived Metabolites

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Liang Xie ◽  
Rikeish R Muralitharan ◽  
Evany Dinakis ◽  
Michael E Nakai ◽  
Hamdi Jama ◽  
...  
Keyword(s):  
T Cell ◽  
Gut Microbiota ◽  
Dietary Fibre ◽  
Dietary Intervention ◽  
Immune Cell ◽  
Ang Ii ◽  
Direct Role ◽  
Cardiovascular Protection ◽  
Anti Inflammatory ◽  
The Impact

High fibre (HF) diet protects against hypertension via the production of acidic metabolites, e.g. short-chain fatty acids, by the gut microbiota. While these metabolites have a direct role in blood pressure (BP) regulation, their acidic nature may activate proton-sensing receptors, which have anti-inflammatory functions. G-protein coupled receptor 65 (GPR65) is a proton-sensing receptor activated around pH 6.5 and is critical for gut homeostasis. We hypothesized that GPR65 is involved in the cardiovascular protection by dietary fibre. We first measured cecal pH of C57BL/6 (WT) mice after a 7-day dietary intervention with either HF or low fibre (LF) diets (n=6/group). HF diet lowered cecal pH to a level where GPR65 is highly activated, compared to the LF diet (6.5±0.1 vs 7.6±0.1, P<0.001). The impact of pH and GPR65 on T cell production of IFNγ, a pro-inflammatory cytokine, in vitro was measured by flow cytometry. Acidic pH inhibited the production of IFNγ by CD8+ T cells (pH 6.5 vs pH 7.5, P<0.001). Cells lacking GPR65 had higher IFNγ at both pH (P<0.001). To determine if GPR65 is involved in BP regulation by dietary fibre, WT and GPR65 knockout ( Gpr65 -/- ) mice were implanted with minipumps containing angiotensin II (Ang II, 0.5mg/kg/day, 28 days, n=8-9/group) and fed with HF diet. BP, cardiorenal function and immune cell infiltration were measured. Gpr65 -/- mice had higher BP compared to WT mice after 2 weeks (mean arterial pressure ± SEM; WT 79.8±2.4 vs Gpr65 -/- 95.8±1.6mmHg, P<0.001) and 4 weeks of Ang II infusion (WT 92.3±2.4 vs Gpr65 -/- 99.5±1.3, P=0.062). Gpr65 -/- mice developed cardiac (P=0.035) and renal (P=0.025) hypertrophy, and impaired renal natriuretic (P=0.054) and diuretic (P=0.056) function compared to WT mice. This was accompanied by higher macrophage (P=0.009) and γδ T cell (P=0.014) infiltration in the kidneys. In conclusion, our data suggest that pH-sensing by GPR65 contributes to the protection against hypertension by dietary fibre via inflammatory mechanisms. This is a novel mechanism that contributes to BP regulation via the gut microbiota.

Ellagitannins, Gallotannins and their Metabolites- The Contribution to the Anti-Inflammatory Effect of Food Products and Medicinal Plants

2019 ◽  
Vol 25 (37) ◽  
pp. 4946-4967 ◽  
Author(s):  
Anna K. Kiss ◽  
Jakub P. Piwowarski
Keyword(s):  
Immune Response ◽  
Gastrointestinal Tract ◽  
Gut Microbiota ◽  
Health Effects ◽  
Biological Effects ◽  
Food Products ◽  
Anti Inflammatory ◽  
The Impact

The popularity of food products and medicinal plant materials containing hydrolysable tannins (HT) is nowadays rapidly increasing. Among various health effects attributable to the products of plant origin rich in gallotannins and/or ellagitannins the most often underlined is the beneficial influence on diseases possessing inflammatory background. Results of clinical, interventional and animal in vivo studies clearly indicate the antiinflammatory potential of HT-containing products, as well as pure ellagitannins and gallotannins. In recent years a great emphasis has been put on the consideration of metabolism and bioavailability of natural products during examination of their biological effects. Conducted in vivo and in vitro studies of polyphenols metabolism put a new light on this issue and indicate the gut microbiota to play a crucial role in the health effects following their oral administration. The aim of the review is to summarize the knowledge about HT-containing products’ phytochemistry and their anti-inflammatory effects together with discussion of the data about observed biological activities with regards to the current concepts on the HTs’ bioavailability and metabolism. Orally administered HT-containing products due to the limited bioavailability of ellagitannins and gallotannins can influence immune response at the level of gastrointestinal tract as well as express modulating effects on the gut microbiota composition. However, due to the chemical changes being a result of their transit through gastrointestinal tract, comprising of hydrolysis and gut microbiota metabolism, the activity of produced metabolites has to be taken into consideration. Studies regarding biological effects of the HTs’ metabolites, in particular urolithins, indicate their strong and structure-dependent anti-inflammatory activities, being observed at the concentrations, which fit the range of their established bioavailability. The impact of HTs on inflammatory processes has been well established on various in vivo and in vitro models, while influence of microbiota metabolites on silencing the immune response gives a new perspective on understanding anti-inflammatory effects attributed to HT containing products, especially their postulated effectiveness in inflammatory bowel diseases (IBD) and cardiovascular diseases.

scholarly journals B cell, CD8+ T cell and gamma delta T cell infiltration alters alveolar immune cell homeostasis in HIV-infected Malawian adults

2018 ◽  
Vol 2 ◽  
pp. 105 ◽  
Author(s):  
Andrew Mwale ◽  
Annemarie Hummel ◽  
Leonard Mvaya ◽  
Raphael Kamng'ona ◽  
Elizabeth Chimbayo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Immune Cell ◽  
Cell Populations ◽  
Monocyte Subset ◽  
Gamma Delta ◽  
Cell Homeostasis ◽  
Tract Infections ◽  
The Impact

Background: HIV infection is associated with increased risk to lower respiratory tract infections (LRTI). However, the impact of HIV infection on immune cell populations in the lung is not well defined. We sought to comprehensively characterise the impact of HIV infection on immune cell populations in the lung. Methods: Twenty HIV-uninfected controls and 17 HIV-1 infected ART-naïve adults were recruited from Queen Elizabeth Central Hospital, Malawi. Immunophenotyping of lymphocyte and myeloid cell populations was done on bronchoalveolar lavage fluid and peripheral blood cells. Results: We found that the numbers of CD8 + T cells, B cells and gamma delta T cells were higher in BAL fluid of HIV-infected adults compared to HIV-uninfected controls (all p<0.05). In contrast, there was no difference in the numbers of alveolar CD4 + T cells in HIV-infected adults compared to HIV-uninfected controls (p=0.7065). Intermediate monocytes were the predominant monocyte subset in BAL fluid (HIV-, 63%; HIV+ 81%), while the numbers of classical monocytes was lower in HIV-infected individuals compared to HIV-uninfected adults (1 × 10 5 vs. 2.8 × 10 5 cells/100ml of BAL fluid, p=0.0001). The proportions of alveolar macrophages and myeloid dendritic cells was lower in HIV-infected adults compared to HIV-uninfected controls (all p<0.05). Conclusions: Chronic HIV infection is associated with broad alteration of immune cell populations in the lung, but does not lead to massive depletion of alveolar CD4 + T cells. Disruption of alveolar immune cell homeostasis likely explains in part the susceptibility for LRTIs in HIV-infected adults.

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Gut ◽  
2019 ◽  
Vol 69 (2) ◽  
pp. 283-294 ◽  
Author(s):  
Min-Soo Kim ◽  
Yoonhee Kim ◽  
Hyunjung Choi ◽  
Woojin Kim ◽  
Sumyung Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Neurofibrillary Tangles ◽  
Immune Cell ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Faecal Microbiota ◽  
Inflammatory Monocytes ◽  
The Impact

ObjectiveCerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.DesignUsing a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.ResultsComposition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.ConclusionThese results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

scholarly journals IMMU-46. EXAMINATION OF THE EFFECTS OF DEXAMETHASONE ON THE EFFICACY OF IMMUNOTHERAPY IN GLIOMA USING GENE-MEDIATED CYTOTOXIC IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi129-vi129
Author(s):  
Marilin Koch ◽  
Mykola Zdioruk ◽  
M Oskar Nowicki ◽  
Estuardo Aguilar ◽  
Laura Aguilar ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Symptomatic Treatment ◽  
Tumor Cell Death ◽  
The Impact

Abstract RATIONALE Dexamethasone is frequently used in symptomatic treatment of glioma patients, although it is known to cause immune suppression. Checkpoint inhibitor immunotherapies have not yet been successful in glioma treatments. Gene-mediated cytotoxic immunotherapy (GMCI) is an immunotherapeutic approach that uses aglatimagene besadenovec with an anti-herpetic prodrug to induce immunogenic tumor cell death and immune cell attraction to the tumor site with potent CD8 T cell activation. GMCI is currently in clinical trials for solid tumors including glioblastoma, where it showed encouraging survival results in a Phase 2 study that did not limit the use of dexamethasone. However, the effects of dexamethasone on its efficacy have not been explored. METHODS We investigated the effects of dexamethasone on GMCI in vitro using cytotoxicity and T-cell-killing assays in glioblastoma cell lines. The impact of dexamethasone in vivo was assessed in an orthotopic syngeneic murine glioblastoma model. RESULTS Cyotoxicity assays showed that Dexamethasone has a slight impact on GMCI in vitro. In contrast, we observed a highly significant effect in T-cell-functional assays in which killing was greatly impaired. Immune cell response assays revealed a reduced T-cell proliferation after co-culture with supernatant from dexamethasone or combination treated glioblastoma cells in contrast to GMCI alone. In a murine model, the combination of GMCI and dexamethasone resulted in a significant reduction in median symptom-free survival (29d) in comparison to GMCI alone (39.5d) (P = 0.0184). CONCLUSION Our data suggest that high doses of dexamethasone may negatively impact the efficacy of immunotherapy for glioma, which may be a consequence of impaired T cell function. These results support the idea that there is a need in identifying possible alternatives to dexamethasone to maximize the effectiveness of immunostimulatory therapies such as GMCI.

Calpastatin overexpression impairs postinfarct scar healing in mice by compromising reparative immune cell recruitment and activation

2015 ◽  
Vol 309 (11) ◽  
pp. H1883-H1893 ◽  
Author(s):  
Feng Wan ◽  
Emmanuel Letavernier ◽  
Claude Jourdan Le Saux ◽  
Amal Houssaini ◽  
Shariq Abid ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Left Ventricular ◽  
M2 Macrophage ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cell Recruitment ◽  
The Impact ◽  
Scar Healing ◽  
Calpain System

The activation of the calpain system is involved in the repair process following myocardial infarction (MI). However, the impact of the inhibition of calpain by calpastatin, its natural inhibitor, on scar healing and left ventricular (LV) remodeling is elusive. Male mice ubiquitously overexpressing calpastatin (TG) and wild-type (WT) controls were subjected to an anterior coronary artery ligation. Mortality at 6 wk was higher in TG mice (24% in WT vs. 44% in TG, P < 0.05) driven by a significantly higher incidence of cardiac rupture during the first week post-MI, despite comparable infarct size and LV dysfunction and dilatation. Calpain activation post-MI was blunted in TG myocardium. In TG mice, inflammatory cell infiltration and activation were reduced in the infarct zone (IZ), particularly affecting M2 macrophages and CD4+ T cells, which are crucial for scar healing. To elucidate the role of calpastatin overexpression in macrophages, we stimulated peritoneal macrophages obtained from TG and WT mice in vitro with IL-4, yielding an abrogated M2 polarization in TG but not in WT cells. Lymphopenic Rag1−/− mice receiving TG splenocytes before MI demonstrated decreased T-cell recruitment and M2 macrophage activation in the IZ day 5 after MI compared with those receiving WT splenocytes. Calpastatin overexpression prevented the activation of the calpain system after MI. It also impaired scar healing, promoted LV rupture, and increased mortality. Defective scar formation was associated with blunted CD4+ T-cell and M2-macrophage recruitment.

scholarly journals Checkpoint protein expression in the tumor microenvironment defines the outcome of classical Hodgkin lymphoma patients

2021 ◽  
Author(s):  
Kristiina Karihtala ◽  
Suvi-Katri Leivonen ◽  
Marja-Liisa Karjalainen-Lindsberg ◽  
Fong Chun Chan ◽  
Christian Steidl ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Immune Cell ◽  
Immune Escape ◽  
Multivariable Analysis ◽  
Classical Hodgkin Lymphoma ◽  
Checkpoint Protein ◽  
The Impact

Emerging evidence indicates a major impact for the tumor microenvironment (TME) and immune escape in the pathogenesis and clinical course of classical Hodgkin lymphoma (cHL). We used gene expression profiling (n=88), CIBERSORT, and multiplex immunohistochemistry (n=131) to characterize the immunoprofile of cHL TME, and correlated the findings with survival. Gene expression analysis divided tumors into subgroups with T cell-inflamed and non-inflamed TME. Several macrophage-related genes were upregulated in samples with the non-T cell-inflamed TME, and based on the immune cell proportions, the samples clustered according to the content of T cells and macrophages. A cluster with high proportions of checkpoint protein (PD-1, PD-L1, IDO-1, LAG-3, and TIM-3) positive immune cells translated to unfavorable overall survival (OS) (5-year OS 76% vs. 96%, P=0.010), and remained as an independent prognostic factor for OS in multivariable analysis (HR 4.34, 95% CI 1.05-17.91, P=0.043). cHLs with high proportions of checkpoint proteins overexpressed genes coding for cytolytic factors, proposing paradoxically that they were immunologically active. This checkpoint molecule gene signature translated to inferior survival in a validation cohort of 290 diagnostic cHL samples (P&lt;0.001) and in an expansion cohort of 84 cHL relapse samples (P=0.048). Our findings demonstrate the impact of T cell- and macrophage-mediated checkpoint system on the survival of patients with cHL.

scholarly journals Effect of Sequentially Fed High Protein, Hydrolysed Protein, and High Fibre Diets on The Faecal Microbiota of Healthy Dogs: A Cross-Over Study

2020 ◽  
Author(s):  
Lina Maria Martinez-Lopez ◽  
Amy Pepper ◽  
Rachel Pilla ◽  
Andrew Woodward ◽  
Jan Suchodolski ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Dietary Intervention ◽  
High Protein ◽  
Commercial Diet ◽  
High Fibre ◽  
Healthy Dogs ◽  
The Individual ◽  
Faecal Microbiome ◽  
The Impact ◽  
Protein Diets

Abstract Background Dietary content and environmental factors can shape the gut microbiota, and consequently, the way the gut microbiota metabolises fats, carbohydrates and proteins, affecting overall health of the host. We evaluated the impact of 3 diets (high protein, high fibre and hypoallergenic [hydrolysed protein]) diets on the gut microbiota of healthy dogs in a cross-over sequential study. Results We showed that diet can have a large effect on the gut microbiome in dogs, regardless of the order of feeding. High-protein (all meat) diets were characterised by an increase in bacteria belonging to the Fusobacteria and Bacteroidetes phyla, whereas a high-fibre commercial diet correlated with increases in Firmicutes and Actinobacteria phyla. However, the individual dog’s baseline microbiota had the most impact on the magnitude and nature of the changes in response to dietary intervention. Conclusion Our results suggest that the dog faecal microbiome is driven by protein and fibre composition, and targeted modification of these patterns could be useful in the modulation of the gut microbiota in different diseases.

scholarly journals Dietary Intervention Impacts Immune Cell Functions and Dynamics by Inducing Metabolic Rewiring

2021 ◽  
Vol 11 ◽  
Author(s):  
Takuma Okawa ◽  
Motoyoshi Nagai ◽  
Koji Hase
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Dietary Intervention ◽  
Immune Cell ◽  
Aerobic Glycolysis ◽  
Acid Oxidation ◽  
Intermittent Fasting ◽  
Cell Trafficking ◽  
Cell Functions

Accumulating evidence has shown that nutrient metabolism is closely associated with the differentiation and functions of various immune cells. Cellular metabolism, including aerobic glycolysis, fatty acid oxidation, and oxidative phosphorylation, plays a key role in germinal center (GC) reaction, B-cell trafficking, and T-cell-fate decision. Furthermore, a quiescent metabolic status consolidates T-cell-dependent immunological memory. Therefore, dietary interventions such as calorie restriction, time-restricted feeding, and fasting potentially manipulate immune cell functions. For instance, intermittent fasting prevents the development of experimental autoimmune encephalomyelitis. Meanwhile, the fasting response diminishes the lymphocyte pool in gut-associated lymphoid tissue to minimize energy expenditure, leading to the attenuation of Immunoglobulin A (IgA) response. The nutritional status also influences the dynamics of several immune cell subsets. Here, we describe the current understanding of the significance of immunometabolism in the differentiation and functionality of lymphocytes and macrophages. The underlying molecular mechanisms also are discussed. These experimental observations could offer new therapeutic strategies for immunological disorders like autoimmunity.

The effects of carbohydrate structure on the composition and functionality of the human gut microbiota

2020 ◽  
Author(s):  
L Payling ◽  
K Fraser ◽  
SM Loveday ◽  
Ian Sims ◽  
N Roy ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Human Health ◽  
Food Processing ◽  
Dietary Fibre ◽  
Keystone Species ◽  
Hierarchical Structures ◽  
Microbial Composition ◽  
Food Structure ◽  
Interacting Networks ◽  
The Impact

© 2020 Elsevier Ltd Background: Human health depends on a population of microorganisms that inhabit the gut and contribute to homeostasis of the host, including nutrition, immunity and metabolism. Many of the organisms are interactive and mutually dependent, where the end-products for one organism become the fuel for another through substrate and metabolic cross-feeding. To optimise the gut microbiota using diet, the composition and functionality of the gut microbiota, including these interacting networks, must be understood. Microbial composition and functionality is affected by the structure of the energy input, which is primarily dietary fibre for the gut microbiota. The structure of dietary fibre has been reviewed by carbohydrate chemists, but knowledge of how dietary fibre structure affects the gut microbiota is limited. Scope and approach: The hierarchical structures of dietary fibre are reviewed, encompassing macrostructure, mesostructure and molecular structure, and how they are affected by food processing and digestion. These factors are considered in relation to their affects on microbial composition and functionality, to provide insight on the interactions between diet, the microbiota, and human health. Key findings and conclusions: Food processing and digestion affect food structure, primarily through the removal of some soluble fractions and increased solubilisation of insoluble fractions. The provision of insoluble carbohydrates to the colon appears important for the sustenance of ‘keystone’ species that play a crucial role in stabilising the gut community. Further work is needed at the microbial strain level to understand the impact of increasing fibre solubility. This should be done in studies using well-characterised carbohydrates that consider the impact of food processing and digestion.

Abstract MP37: Epigenetic Changes Following Maternal Gut Microbiota Improvement With Dietary Fibre Lead To Cardio-protection In The Offspring

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Hamdi Jama ◽  
Malathi I Dona ◽  
Evany Dinakis ◽  
Michael E Nakai ◽  
Madeleine Paterson ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Dietary Fibre ◽  
Maternal Diet ◽  
Regulatory Region ◽  
Left Ventricular ◽  
Epigenetic Changes ◽  
Ang Ii ◽  
Microbial Composition ◽  
Fibre Intake ◽  
High Fibre

Dietary fibre is fermented by the gut microbiota and protects against the development of cardiovascular disease (CVD) through the production of gut microbial metabolites. We hypothesised dietary fibre intake during pregnancy may prevent the development of CVD in the offspring via in utero epigenetic mechanisms. To investigate this, we fed C57BL/6J female mice diets high or low in resistant starches (‘high-fibre’ and ‘low-fibre’, respectively) during gestation. At 6-weeks of age, we performed single-cell RNA-sequencing in the offspring (n=8/group) or they were challenged with saline (sham) or angiotensin II (Ang II, 0.25mg/kg/day, n=18-23/group). Maternal diet resulted in a distinct gut microbial composition ( P =0.001). This was still evident in the adult offspring, with high-fibre offspring having a different gut microbial colonisation ( P =0.001), irrespective of sham/Ang II treatment. Maternal fibre intake significantly changed the cardiac cellular and molecular landscape and promoted differential gene signatures in the offspring. This included upregulation of genes associated with extracellular matrix production in the offspring from low-fibre mothers. When challenged with Ang II, low-fibre offspring developed increased cardiac hypertrophy ( P =0.034) and fibrosis ( P =0.01) compared to high-fibre offspring. This was accompanied with decreased ejection fraction ( P =0.001) and increased left ventricular posterior wall thickness ( P= 0.017). These changes were independent of blood pressure. High-fibre offspring had decreased expression of natriuretic peptides ( Nppa , P =0.03, Nppb , P =0.002) compared to low-fibre offspring. Chromatin-immunoprecipitation assay revealed decrease in H3-acetylation at the cis-regulatory region of Nppa gene in Ang II-treated high-fibre offspring (P=0.002), suggesting that maternal fibre intake influences the epigenetic changes of the Nppa gene in the offspring’s heart. Together, these data reveal maternal high-fibre intake leads to foetal epigenetic reprogramming, likely through maternal to foetal transfer of gut microbial-derived metabolites.

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