scholarly journals The parasitic worm product ES-62 normalises the gut microbiota/bone marrow axis in inflammatory arthritis

2018 ◽  
Author(s):  
James Doonan ◽  
Anuradha Tarafdar ◽  
Miguel A. Pineda ◽  
Felicity E. Lumb ◽  
Jenny Crowe ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Subcutaneous Administration ◽  
Intestinal Barrier ◽  
Joint Disease ◽  
Human Immune System ◽  
Gastrointestinal Helminths ◽  
Parasitic Helminths ◽  
Inflammatory Conditions ◽  
Parasitic Worm ◽  
Acanthocheilonema Viteae

AbstractThe human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths. Reflecting this, the rapid eradication of pathogens appears to have resulted in reduced microbiome diversity and generation of chronically activated immune systems, presaging the recent rise of allergic, autoimmune and metabolic disorders. Certainly, gastrointestinal helminths can protect against gut and lung mucosa inflammatory conditions by modulating the microbiome and suppressing the chronic inflammation associated with dysbiosis. Here, we employ ES-62, an immunomodulator secreted by tissue-dwelling Acanthocheilonema viteae to show that modulation of the gut microbiome does not require live infection with gastrointestinal-based helminths nor is protection restricted to mucosal diseases. Specifically, subcutaneous administration of this defined parasitic worm product affords protection against joint disease in collagen-induced arthritis, a mouse model of rheumatoid arthritis, which is associated with normalisation of gut microbiota and prevention of loss of intestinal barrier integrity.

scholarly journals Suppression of inflammatory arthritis by the parasitic worm product ES-62 is associated with epigenetic changes in synovial fibroblasts

2021 ◽  
Vol 17 (11) ◽  
pp. e1010069
Author(s):  
Marlene Corbet ◽  
Miguel A. Pineda ◽  
Kun Yang ◽  
Anuradha Tarafdar ◽  
Sarah McGrath ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Joint Inflammation ◽  
Synovial Fibroblasts ◽  
Therapeutic Interventions ◽  
Joint Disease ◽  
Functional Responses ◽  
Inflammatory Microenvironment ◽  
Inflammatory Conditions ◽  
Parasitic Worm

ES-62 is the major secreted protein of the parasitic filarial nematode, Acanthocheilonema viteae. The molecule exists as a large tetramer (MW, ~240kD), which possesses immunomodulatory properties by virtue of multiple phosphorylcholine (PC) moieties attached to N-type glycans. By suppressing inflammatory immune responses, ES-62 can prevent disease development in certain mouse models of allergic and autoimmune conditions, including joint pathology in collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Such protection is associated with functional suppression of “pathogenic” hyper-responsive synovial fibroblasts (SFs), which exhibit an aggressive inflammatory and bone-damaging phenotype induced by their epigenetic rewiring in response to the inflammatory microenvironment of the arthritic joint. Critically, exposure to ES-62 in vivo induces a stably-imprinted CIA-SF phenotype that exhibits functional responses more typical of healthy, Naïve-SFs. Consistent with this, ES-62 “rewiring” of SFs away from the hyper-responsive phenotype is associated with suppression of ERK and STAT3 activation and miR-155 upregulation, signals widely associated with SF pathogenesis. Surprisingly however, DNA methylome analysis of Naïve-, CIA- and ES-62-CIA-SF cohorts reveals that rather than simply preventing pathogenic rewiring of SFs, ES-62 induces further changes in DNA methylation under the inflammatory conditions pertaining in the inflamed joint, including targeting genes associated with ciliogenesis, to programme a novel “resolving” CIA-SF phenotype. In addition to introducing a previously unsuspected aspect of ES-62’s mechanism of action, such unique behaviour signposts the potential for developing DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA. Pertinent to these translational aspects of ES-62-behavior, small molecule analogues (SMAs) based on ES-62’s active PC-moiety mimic the rewiring of SFs as well as the protection against joint disease in CIA afforded by the parasitic worm product.

scholarly journals Pathophysiological Roles of Mucosal-Associated Invariant T Cells in the Context of Gut Microbiota-Liver Axis

2021 ◽  
Vol 9 (2) ◽  
pp. 296
Author(s):  
Yoseph Asmelash Gebru ◽  
Mi Ran Choi ◽  
Ganesan Raja ◽  
Haripriya Gupta ◽  
Satya Priya Sharma ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Cell Activation ◽  
Intestinal Barrier ◽  
Antigen Presenting Cells ◽  
Cell Receptor ◽  
Immune Functions ◽  
Human Immune System ◽  
Mait Cells ◽  
Antigen Presenting ◽  
Microbial Biosynthesis

Mucosal-associated invariant T (MAIT) cells are a subset of T lymphocytes expressing a semi-invariant T-cell receptor (TCR) present as TCR Vα7.2-Jα33 in humans and TCR Vα19-Jα33 in mice. They are activated by ligands produced during microbial biosynthesis of riboflavin that is presented by major histocompatibility complex class I-related (MR1) molecules on antigen-presenting cells. MAIT cells also possess interleukin (IL)-12 and IL-18 receptors and can be activated by the respective cytokines released from microbially stimulated antigen-presenting cells. Therefore, MAIT cells can be involved in bacterial and viral defenses and are a significant part of the human immune system. They are particularly abundant in the liver, an organ serving as the second firewall of gut microbes next to the intestinal barrier. Therefore, the immune functions of MAIT cells are greatly impacted by changes in the gut-microbiota and play important roles in the gut-liver pathogenesis axis. In this review, we discuss the nature and mechanisms of MAIT cell activation and their dynamics during different types of liver pathogenesis conditions. We also share our perspectives on important aspects that should be explored further to reveal the exact roles that MAIT cells play in liver pathogenesis in the context of the gut microbiota.

The Gut Microbiota of Rats under Experimental Osteoarthritis and Administration of Chondroitin Sulfate and Probiotic

2020 ◽  
Vol 82 (6) ◽  
pp. 64-73
Author(s):  
O.H. Korotkyi ◽  
◽  
T.V. Luhovska ◽  
T.M. Serhiychuk ◽  
K.O. Dvorshchenko ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Chondroitin Sulfate ◽  
Joint Inflammation ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Quantitative Composition ◽  
Combined Administration ◽  
Osteoarthritis Progression ◽  
Experimental Osteoarthritis ◽  
Gut Microbiota Composition

Osteoarthritis is a most widespread chronic degenerative joint disease that causes pain, cartilage deformation, and joint inflammation. Adverse alterations of intestinal microbiota like dysbiosis may lead to metabolic syndrome and inflammation, two important components of osteoarthritis progression. Aim. In this study we investigated the effect of chondroitin sulfate and probiotics on the gut microbiome in monoiodoacetate-induced osteoarthritis model in rats. Methods. The species and quantitative composition of feces were determined using diagnostic media with selective properties. Further identification of isolated microorganisms was carried out according to morphological, tinctorial, physiological and metabolic parameters. The results are presented in the form of lg CFU/g. Results. Induction of osteoarthritis caused significant increasing the number of opportunistic enterobacteria and lactose-negative Escherichia coli against the decreasing of lacto- and bifidobacteria that may indicate a dysbiotic condition. Coadministration of chondroitin sulfate and probiotic bacteria has led to improvement the quantitative composition of the gut microbiota in experimental animals, the numerous of Bifidobacterium, Lactobacillus were increasing against decreasing the quantitative composition of opportunistic microorganisms. Conclusions. Monoiodoacetate-induced osteoarthritis caused dysbiosis of gut in rat. We observed beneficial effect of combined administration of chondroitin sulfate and probiotics on gut microbiota composition in rats with experimental osteoarthritis. Thus, adding of supplements like probiotics to standard treatment of osteoarthritis may have potentials to prevent and treat this disease.

scholarly journals Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiuli Lin ◽  
Yingying Liu ◽  
Lili Ma ◽  
Xiaomeng Ma ◽  
Liping Shen ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Gut Microbiota ◽  
Blood Brain Barrier ◽  
Intestinal Barrier ◽  
Brain Barrier ◽  
Autoimmune Encephalomyelitis ◽  
Gm Csf ◽  
Blood Brain ◽  
Gut Microbiota Dysbiosis ◽  
Experimental Autoimmune

Abstract Background Constipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Methods Constipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood–brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-β, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups. Results Compared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood–brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-β, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota. Conclusions Our results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

scholarly journals Insights into the Impact of Microbiota in the Treatment of NAFLD/NASH and Its Potential as a Biomarker for Prognosis and Diagnosis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 145
Author(s):  
Julio Plaza-Díaz ◽  
Patricio Solis-Urra ◽  
Jerónimo Aragón-Vela ◽  
Fernando Rodríguez-Rodríguez ◽  
Jorge Olivares-Arancibia ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Fecal Microbiota Transplantation ◽  
Liver Steatosis ◽  
Intestinal Barrier ◽  
Fecal Microbiota ◽  
Current Treatment ◽  
Immune Defense ◽  
Alcoholic Fatty Liver ◽  
The Impact

Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver illness associated with obesity and metabolic disorders, such as hypertension, dyslipidemia, or type 2 diabetes mellitus. A more severe type of NAFLD, non-alcoholic steatohepatitis (NASH), is considered an ongoing global health threat and dramatically increases the risks of cirrhosis, liver failure, and hepatocellular carcinoma. Several reports have demonstrated that liver steatosis is associated with the elevation of certain clinical and biochemical markers but with low predictive potential. In addition, current imaging methods are inaccurate and inadequate for quantification of liver steatosis and do not distinguish clearly between the microvesicular and the macrovesicular types. On the other hand, an unhealthy status usually presents an altered gut microbiota, associated with the loss of its functions. Indeed, NAFLD pathophysiology has been linked to lower microbial diversity and a weakened intestinal barrier, exposing the host to bacterial components and stimulating pathways of immune defense and inflammation via toll-like receptor signaling. Moreover, this activation of inflammation in hepatocytes induces progression from simple steatosis to NASH. In the present review, we aim to: (a) summarize studies on both human and animals addressed to determine the impact of alterations in gut microbiota in NASH; (b) evaluate the potential role of such alterations as biomarkers for prognosis and diagnosis of this disorder; and (c) discuss the involvement of microbiota in the current treatment for NAFLD/NASH (i.e., bariatric surgery, physical exercise and lifestyle, diet, probiotics and prebiotics, and fecal microbiota transplantation).

scholarly journals The Influence of Gut Microbiota on the Cardiovascular System Under Conditions of Obesity and Chronic Stress

2021 ◽  
Vol 23 (5) ◽  
Author(s):  
Piotr Dubinski ◽  
Katarzyna Czarzasta ◽  
Agnieszka Cudnoch-Jedrzejewska
Keyword(s):  
Gut Microbiota ◽  
Cardiovascular System ◽  
Chronic Stress ◽  
Human Body ◽  
High Fat Diet ◽  
Intestinal Barrier ◽  
Microbial Composition ◽  
Enhanced Absorption ◽  
Bacterial Accumulation ◽  
Metabolic Endotoxemia

Abstract Purpose of Review Based on the available data, it can be assumed that microbiota is an integral part of the human body. The most heavily colonized area of the human body is the gut, with bacterial accumulation ranging from 101–103 cells/g in the upper intestine to 1011–1012 cells/g in the colon. However, colonization of the gut is not the same throughout, as it was shown that there are differences between the composition of the microbiota in the intestine lumen and in the proximity of the mucus layer. Recent Findings Gut microbiota gradient can be differentially regulated by factors such as obesity and chronic stress. In particular, a high fat diet influences the gut microbial composition. It was also found that chronic stress may cause the development of obesity and thus change the organization of the intestinal barrier. Recent research has shown the significant effect of intestinal microflora on cardiovascular function. Enhanced absorption of bacterial fragments, such as lipopolysaccharide (LPS), promotes the onset of “metabolic endotoxemia,” which could activate toll-like receptors, which mediates an inflammatory response and in severe cases could cause cardiovascular diseases. It is presumed that the intestinal microbiota, and especially its metabolites (LPS and trimethylamine N-oxide (TMAO)), may play an important role in the pathogenesis of arterial hypertension, atherosclerosis, and heart failure. Summary This review focuses on how gut microbiota can change the morphological and functional activity of the cardiovascular system in the course of obesity and in conditions of chronic stress.

Perturbation of gut microbiota plays an important role in micro/nanoplastics-induced gut barrier dysfunction

Nanoscale ◽  
2021 ◽  
Author(s):  
Jiyan Qiao ◽  
Rui Chen ◽  
Mengjie Wang ◽  
Ru Bai ◽  
Xuejing Cui ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Intestinal Barrier ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Bacterial Composition

Exposure to micro/nanoplastics (M/NPLs) deteriorates the intestinal barrier by disturbing the bacterial composition in the gut.

scholarly journals Mediterranean Diet to Prevent the Development of Colon Diseases: A Meta-Analysis of Gut Microbiota Studies

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2234
Author(s):  
Oscar Illescas ◽  
Miriam Rodríguez-Sosa ◽  
Manuela Gariboldi
Keyword(s):  
Gut Microbiota ◽  
Mediterranean Diet ◽  
Meta Analysis ◽  
Intestinal Barrier ◽  
Preventive Measure ◽  
Bowel Diseases ◽  
Preventive Method ◽  
Inflammatory Bowel ◽  
Colon Diseases ◽  
Cancer And Inflammation

Gut microbiota dysbiosis is a common feature in colorectal cancer (CRC) and inflammatory bowel diseases (IBD). Adoption of the Mediterranean diet (MD) has been proposed as a therapeutic approach for the prevention of multiple diseases, and one of its mechanisms of action is the modulation of the microbiota. We aimed to determine whether MD can be used as a preventive measure against cancer and inflammation-related diseases of the gut, based on its capacity to modulate the local microbiota. A joint meta-analysis of publicly available 16S data derived from subjects following MD or other diets and from patients with CRC, IBD, or other gut-related diseases was conducted. We observed that the microbiota associated with MD was enriched in bacteria that promote an anti-inflammatory environment but low in taxa with pro-inflammatory properties capable of altering intestinal barrier functions. We found an opposite trend in patients with intestinal diseases, including cancer. Some of these differences were maintained even when MD was compared to healthy controls without a defined diet. Our findings highlight the unique effects of MD on the gut microbiota and suggest that integrating MD principles into a person’s lifestyle may serve as a preventive method against cancer and other gut-related diseases.

scholarly journals The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 959 ◽  
Author(s):  
Jefferson Antônio Leite ◽  
Gabriela Pessenda ◽  
Isabel C. Guerra-Gomes ◽  
Alynne Karen Mendonça de Santana ◽  
Camila André Pereira ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Bacterial Translocation ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Dna Sensor ◽  
Proinflammatory Response

Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2−/−) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2−/− mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2−/− mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing β cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.

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