Gut Microbiome and Inflammation: A Study of Diabetic Inflammasome-Knockout Mice

Aims. Diabetes is a proinflammatory state, evidenced by increased pattern recognition receptors and the inflammasome (NOD-like receptor family pyrin domain (NLRP)) complex. Recent reports have elucidated the role of the gut microbiome in diabetes, but there is limited data on the gut microbiome in NLRP-KO mice and its effect on diabetes-induced inflammation. Methods. Gut microbiome composition and biomarkers of inflammation (IL-18, serum amyloid A) were assessed in streptozotocin- (STZ-) induced diabetic mice on a NLRP3-knockout (KO) background versus wild-type diabetic mice. Results. SAA and IL-18 levels were significantly elevated in diabetic mice (STZ) compared to control (WT) mice, and there was a significant attenuation of inflammation in diabetic NLRP3-KO mice (NLRP3-KO STZ) compared to control mice (p<0.005). Principal coordinate analysis clearly separated controls, STZ, and NLRP3-KO STZ mice. Among the different phyla, there was a significant increase in the Firmicutes : Bacteroidetes ratio in the diabetic group compared to controls. When compared to the WT STZ group, the NLRP3-KO STZ group showed a significant decrease in the Firmicutes : Bacteroidetes ratio. Together, these findings indicate that interaction of the intestinal microbes with the innate immune system is a crucial factor that could modify diabetes and complications.

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Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/1806344 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Yang Zhang ◽

Weifang Liu ◽

Yanqi Zhong ◽

Qi Li ◽

Mengying Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Nlrp3 Inflammasome ◽

Low Dose ◽

Therapeutic Potential ◽

Metabolic Phenotypes ◽

Pyrin Domain ◽

Underlying Mechanisms ◽

And Oxidative Stress ◽

Receptor Family

NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

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The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process

Cells ◽

10.3390/cells9061552 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1552

Author(s):

Maria Sebastian-Valverde ◽

Giulio M. Pasinetti

Keyword(s):

Nlrp3 Inflammasome ◽

Low Grade ◽

Cellular Mechanisms ◽

Pyrin Domain ◽

Human Lifespan ◽

Age Related ◽

Inflammatory State ◽

Chronic Activation ◽

Receptor Family

As a consequence of the considerable increase in the human lifespan over the last century, we are experiencing the appearance and impact of new age-related diseases. The causal relationships between aging and an enhanced susceptibility of suffering from a broad spectrum of diseases need to be better understood. However, one specific shared feature seems to be of capital relevance for most of these conditions: the low-grade chronic inflammatory state inherently associated with aging, i.e., inflammaging. Here, we review the molecular and cellular mechanisms that link aging and inflammaging, focusing on the role of the innate immunity and more concretely on the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, as well as how the chronic activation of this inflammasome has a detrimental effect on different age-related disorders.

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Role of Adenosine Kinase In Sphingosine-1-Phosphate Receptor 1-Induced Mechano-Hypersensitivities

10.21203/rs.3.rs-852148/v1 ◽

2021 ◽

Author(s):

Filomena Lauro ◽

Luigino Antonio Giancotti ◽

Grant Kolar ◽

Caron Harada ◽

Taylor A Harmon ◽

...

Keyword(s):

Spinal Cord ◽

Adenosine Kinase ◽

Receptor Subtype ◽

Beneficial Effects ◽

Pyrin Domain ◽

Sphingosine 1 Phosphate ◽

Expression Activity ◽

Receptor Family ◽

Adenosine Signaling

Abstract Emerging evidence implicates the sphingosine-1-phosphate (S1P) receptor subtype 1 (S1PR1) in the development of neuropathic pain. Continued investigation of the signaling pathways downstream of S1PR1 are needed to support development of S1PR1 antagonists. In rodents, intrathecal (i.th.) injection of SEW2871, a selective S1PR1 agonist, activates the nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, increases interleukin-1β (IL-1β) and causes behavioral hypersensitivity. I.th. injection of a IL-1β receptor antagonist blocks SEW2871-induced hypersensitivity, suggesting that IL-1β contributes to S1PR1’s actions. Interestingly, previous studies have suggested that IL-1β increases the expression/activity of adenosine kinase (ADK), a key regulator of adenosine signaling at its receptors (ARs). Increased ADK expression reduces adenosine signaling whereas inhibiting ADK restores the action of adenosine. Here, we show that SEW287-induced behavioral hypersensitivity is associated with increased expression of ADK in astrocytes of the dorsal horn of the spinal cord (DH-SC). Moreover, the ADK inhibitor, ABT702, blocks SEW2871-induced hypersensitivity. These findings link ADK activation to S1PR1. If SEW2871-induced pain is mediated by IL-1β, which in turn activates ADK and leads to mechano-allodynia, then blocking ADK should attenuate IL-1β effects. In support of this idea, recombinant rat (rrIL-1β)-induced allodynia was blocked by at least 90% with ABT702, functionally linking ADK to IL-1β. Moreover, the selective A3AR antagonist, MRS1523, prevents the ability of ABT702 to block SEW2871 and IL-1β-induced allodynia, implicating A3AR signaling in the beneficial effects exerted by ABT702. Our findings provide novel mechanistic insight into how S1PR1 signaling in the spinal cord produces hypersensitivity through IL1-b and ADK activation.

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Antimicrobial Effect of Zophobas morio Hemolymph against Bovine Mastitis Pathogens

Microorganisms ◽

10.3390/microorganisms8101488 ◽

2020 ◽

Vol 8 (10) ◽

pp. 1488

Author(s):

Mengze Du ◽

Xiaodan Liu ◽

Jiajia Xu ◽

Shuxian Li ◽

Shenghua Wang ◽

...

Keyword(s):

Mammary Epithelial Cells ◽

Bovine Mastitis ◽

Antimicrobial Effect ◽

Mammary Epithelial ◽

Bovine Mammary Epithelial Cells ◽

E Coli ◽

Pyrin Domain ◽

Staphylococcus Spp ◽

Receptor Family

Coliforms and Staphylococcus spp. infections are the leading causes of bovine mastitis. Despite extensive research and development in antibiotics, they have remained inadequately effective in treating bovine mastitis induced by multiple pathogen infection. In the present study, we showed the protective effect of Zophobas morio (Z. morio) hemolymph on bovine mammary epithelial cells against bacterial infection. Z. morio hemolymph directly kills both Gram-positive and Gram-negative bacteria through membrane permeation and prevents the adhesion of E. coli or the clinically isolated S. simulans strain to bovine mammary epithelial (MAC-T) cells. In addition, Z. morio hemolymph downregulates the expression of nucleotide-binding oligomerization domain (NOD)-like receptor family member pyrin domain-containing protein 3 (NLRP3), caspase-1, and NLRP6, as well as inhibits the secretion of interleukin-1β (IL-1β) and IL-18, which attenuates E. coli or S. simulans-induced pyroptosis. Overall, our results suggest the potential role of Z. morio hemolymph as a novel therapeutic candidate for bovine mastitis.

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Potential Role of Antioxidant and Anti-Inflammatory Therapies to Prevent Severe SARS-Cov-2 Complications

Antioxidants ◽

10.3390/antiox10020272 ◽

2021 ◽

Vol 10 (2) ◽

pp. 272

Author(s):

Anna M. Fratta Pasini ◽

Chiara Stranieri ◽

Luciano Cominacini ◽

Chiara Mozzini

Keyword(s):

Potential Role ◽

Viral Infections ◽

Host Cells ◽

Nuclear Factor ◽

Angiotensin Converting Enzyme 2 ◽

Pyrin Domain ◽

Nrf2 Activation ◽

Anti Inflammatory ◽

Receptor Family

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2). Here, we review the molecular pathogenesis of SARS-CoV-2 and its relationship with oxidative stress (OS) and inflammation. Furthermore, we analyze the potential role of antioxidant and anti-inflammatory therapies to prevent severe complications. OS has a potential key role in the COVID-19 pathogenesis by triggering the NOD-like receptor family pyrin domain containing 3 inflammasome and nuclear factor-kB (NF-kB). While exposure to many pro-oxidants usually induces nuclear factor erythroid 2 p45-related factor2 (NRF2) activation and upregulation of antioxidant related elements expression, respiratory viral infections often inhibit NRF2 and/or activate NF-kB pathways, resulting in inflammation and oxidative injury. Hence, the use of radical scavengers like N-acetylcysteine and vitamin C, as well as of steroids and inflammasome inhibitors, has been proposed. The NRF2 pathway has been shown to be suppressed in severe SARS-CoV-2 patients. Pharmacological NRF2 inducers have been reported to inhibit SARS-CoV-2 replication, the inflammatory response, and transmembrane protease serine 2 activation, which for the entry of SARS-CoV-2 into the host cells through the angiotensin converting enzyme 2 receptor. Thus, NRF2 activation may represent a potential path out of the woods in COVID-19 pandemic.

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The Potential Role of Lithium as an Antiviral Agent against SARS-CoV-2 via Membrane Depolarization: Review and Hypothesis

Scientia Pharmaceutica ◽

10.3390/scipharm89010011 ◽

2021 ◽

Vol 89 (1) ◽

pp. 11

Author(s):

Abdallah Barjas Qaswal ◽

Aiman Suleiman ◽

Hasan Guzu ◽

Taima’a Harb ◽

Bashir Atiyat

Keyword(s):

Cell Death ◽

Immune System ◽

Antiviral Agent ◽

Membrane Depolarization ◽

The Body ◽

Pyrin Domain ◽

The Face ◽

Preclinical And Clinical Studies ◽

Receptor Family

Studies on potential treatments of Coronavirus Disease 2019 (COVID-19) are important to improve the global situation in the face of the pandemic. This review proposes lithium as a potential drug to treat COVID-19. Our hypothesis states that lithium can suppress NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome activity, inhibit cell death, and exhibit immunomodulation via membrane depolarization. Our hypothesis was formulated after finding consistent correlations between these actions and membrane depolarization induced by lithium. Eventually, lithium could serve to mitigate the NLRP3-mediated cytokine storm, which is allegedly reported to be the inciting event of a series of retrogressive events associated with mortality from COVID-19. It could also inhibit cell death and modulate the immune system to attenuate its release, clear the virus from the body, and interrupt the cycle of immune-system dysregulation. Therefore, these effects are presumed to improve the morbidity and mortality of COVID-19 patients. As the numbers of COVID-19 cases and deaths continue to rise exponentially without a clear consensus on potential therapeutic agents, urgent conduction of preclinical and clinical studies to prove the efficacy and safety of lithium is reasonable.

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The Role of the Interplay Between Autophagy and NLRP3 Inflammasome in Metabolic Disorders

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.634118 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shuangyu Lv ◽

Honggang Wang ◽

Xiaotian Li

Keyword(s):

Nlrp3 Inflammasome ◽

Metabolic Disorders ◽

Interleukin 1 ◽

Basic Research ◽

Interleukin 1 Beta ◽

Cell Composition ◽

Pyrin Domain ◽

Receptor Family ◽

Oligomerization Domain

Autophagy is an important and conserved cellular pathway in which cells transmit cytoplasmic contents to lysosomes for degradation. It plays an important role in maintaining the balance of cell composition synthesis, decomposition and reuse, and participates in a variety of physiological and pathological processes. The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome can induce the maturation and secretion of Interleukin-1 beta (IL-1β) and IL-18 by activating caspase-1. It is involved in many diseases. In recent years, the interplay between autophagy and NLRP3 inflammasome has been reported to contribute to many diseases including metabolic disorders related diseases. In this review, we summarized the recent studies on the interplay between autophagy and NLRP3 inflammasome in metabolic disorders to provide ideas for the relevant basic research in the future.

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Examining the Effects of an Anti-Salmonella Bacteriophage Preparation, BAFASAL®, on Ex-Vivo Human Gut Microbiome Composition and Function Using a Multi-Omics Approach

Viruses ◽

10.3390/v13091734 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1734

Author(s):

Janice Mayne ◽

Xu Zhang ◽

James Butcher ◽

Krystal Walker ◽

Zhibin Ning ◽

...

Keyword(s):

Food Chain ◽

Gut Microbiome ◽

Food Industry ◽

Ex Vivo ◽

Human Gut ◽

Microbiome Composition ◽

Human Gut Microbiome ◽

And Function ◽

The Impact

Salmonella infections (salmonellosis) pose serious health risks to humans, usually via food-chain contamination. This foodborne pathogen causes major food losses and human illnesses, with significant economic impacts. Overuse of antibiotics in the food industry has led to multidrug-resistant strains of bacteria, and governments are now restricting their use, leading the food industry to search for alternatives to secure food chains. Bacteriophages, viruses that infect and kill bacteria, are currently being investigated and used as replacement treatments and prophylactics due to their specificity and efficacy. They are generally regarded as safe alternatives to antibiotics, as they are natural components of the ecosystem. However, when specifically used in the industry, they can also make their way into humans through our food chain or exposure, as is the case for antibiotics. In particular, agricultural workers could be repeatedly exposed to bacteriophages supplemented to animal feeds. To our knowledge, no studies have investigated the effects of such exposure to bacteriophages on the human gut microbiome. In this study, we used a novel in-vitro assay called RapidAIM to investigate the effect of a bacteriophage mixture, BAFASAL®, used in poultry farming on five individual human gut microbiomes. Multi-omics analyses, including 16S rRNA gene sequencing and metaproteomic, revealed that ex-vivo human gut microbiota composition and function were unaffected by BAFASAL® treatment, providing an additional measure for its safety. Due to the critical role of the gut microbiome in human health and the known role of bacteriophages in regulation of microbiome composition and function, we suggest assaying the impact of bacteriophage-cocktails on the human gut microbiome as a part of their safety assessment.

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A Bibliometric Analysis of Pyroptosis From 2001 to 2021

Frontiers in Immunology ◽

10.3389/fimmu.2021.731933 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dan Ma ◽

Bin Yang ◽

Baoyi Guan ◽

Luxia Song ◽

Qiyu Liu ◽

...

Keyword(s):

Cell Death ◽

Bibliometric Analysis ◽

Future Research ◽

Pyrin Domain ◽

The Future ◽

The Usa ◽

The Relationship ◽

Related Pathway ◽

Receptor Family

BackgroundPyroptosis is a new programmed cell death discovered in recent years. Pyroptosis plays an important role in various diseases. Nevertheless, there are few bibliometric analysis systematically studies this field. We aimed to visualize the research hotspots and trends of pyroptosis using a bibliometric analysis to help understand the future development of basic and clinical research.MethodsThe articles and reviews regarding pyroptosis were culled from Web of Science Core Collection. Countries, institutions, authors, references and keywords in this field were visually analyzed by using CtieSpace and VOSviewer software.ResultsA total of 2845 articles and reviews were included. The number of articles regarding pyroptosis significantly increased yearly. These publications mainly come from 70 countries led by China and the USA and 418 institutions. We identified 605 authors, among which Thirumaladevi Kanneganti had the most significant number of articles, and Shi JJ was co-cited most often. Frontiers in immunology was the journal with the most studies, and Nature was the most commonly cited journal. After analysis, the most common keywords are nod like receptor family pyrin domain containing 3 inflammasome, apoptosis, cell death, gasdermin D, mechanism, caspase-1, and others are current and developing areas of study.ConclusionResearch on the pyroptosis is flourishing. Cooperation and exchanges between countries and institutions must be strengthened in the future. The related pathway mechanism of pyroptosis, the relationship between pyroptosis and other types of programmed cell deaths as well as the role of pyroptosis in various diseases have been the focus of current research and developmental trends in the future research.

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Composition of the Gut Microbiome Influences Production of Sulforaphane-Nitrile and Iberin-Nitrile from Glucosinolates in Broccoli Sprouts

Nutrients ◽

10.3390/nu13093013 ◽

2021 ◽

Vol 13 (9) ◽

pp. 3013

Author(s):

John A. Bouranis ◽

Laura M. Beaver ◽

Jaewoo Choi ◽

Carmen P. Wong ◽

Duo Jiang ◽

...

Keyword(s):

Gut Microbiome ◽

Ex Vivo ◽

Human Subjects ◽

Individual Variability ◽

16S Sequencing ◽

Microbiome Composition ◽

Broccoli Sprouts ◽

Broccoli Sprout

Isothiocyanates, such as sulforaphane and iberin, derived from glucosinolates (GLS) in cruciferous vegetables, are known to prevent and suppress cancer development. GLS can also be converted by bacteria to biologically inert nitriles, such as sulforaphane-nitrile (SFN-NIT) and iberin-nitrile (IBN-NIT), but the role of the gut microbiome in this process is relatively undescribed and SFN-NIT excretion in humans is unknown. An ex vivo fecal incubation model with in vitro digested broccoli sprouts and 16S sequencing was utilized to explore the role of the gut microbiome in SFN- and IBN-NIT production. SFN-NIT excretion was measured among human subjects following broccoli sprout consumption. The fecal culture model showed high inter-individual variability in nitrile production and identified two sub-populations of microbial communities among the fecal cultures, which coincided with a differing abundance of nitriles. The Clostridiaceae family was associated with high levels, while individuals with a low abundance of nitriles were more enriched with taxa from the Enterobacteriaceae family. High levels of inter-individual variation in urine SFN-NIT levels were also observed, with peak excretion of SFN-NIT at 24 h post broccoli sprout consumption. These results suggest that nitrile production from broccoli, as opposed to isothiocyanates, could be influenced by gut microbiome composition, potentially lowering efficacy of cruciferous vegetable interventions.

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