TLR4 Deficiency Affects the Microbiome and Reduces Intestinal Dysfunctions and Inflammation in Chronic Alcohol-Fed Mice

Chronic alcohol abuse causes an inflammatory response in the intestinal tract with damage to the integrity of the mucosa and epithelium, as well as dysbiosis in the gut microbiome. However, the role of gut bacteria in ethanol effects and how these microorganisms interact with the immune system are not well understood. The aim of the present study was to evaluate if TLR4 alters the ethanol-induced intestinal inflammatory response, and whether the response of this receptor affects the gut microbiota profile. We analyzed the 16S rRNA sequence of the fecal samples from wild-type (WT) and TLR4-knockout (TLR4-KO) mice with and without ethanol intake for 3 months. The results demonstrated that chronic ethanol consumption reduces microbiota diversity and causes dysbiosis in WT mice. Likewise, ethanol upregulates several inflammatory genes (IL-1β, iNOS, TNF-α) and miRNAs (miR-155-5p, miR-146a-5p) and alters structural and permeability genes (INTL1, CDH1, CFTR) in the colon of WT mice. Our results further demonstrated that TLR4-KO mice exhibit a different microbiota that can protect against the ethanol-induced activation of the immune system and colon integrity dysfunctions. In short, our results reveal that TLR4 is a key factor for determining the gut microbiota, which can participate in dysbiosis and the inflammatory response induced by alcohol consumption.

Download Full-text

Microbiota-Immune System Interactions in Human Neurological Disorders

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200726222138 ◽

2020 ◽

Vol 19 (7) ◽

pp. 509-526

Author(s):

Qin Huang ◽

Fang Yu ◽

Di Liao ◽

Jian Xia

Keyword(s):

Immune System ◽

Gut Microbiota ◽

Neurological Disorders ◽

Brain Function ◽

Neurological Diseases ◽

Host Immune System ◽

Gut Dysbiosis ◽

Characteristic Features ◽

Novel Therapeutic Strategies

: Recent studies implicate microbiota-brain communication as an essential factor for physiology and pathophysiology in brain function and neurodevelopment. One of the pivotal mechanisms about gut to brain communication is through the regulation and interaction of gut microbiota on the host immune system. In this review, we will discuss the role of microbiota-immune systeminteractions in human neurological disorders. The characteristic features in the development of neurological diseases include gut dysbiosis, the disturbed intestinal/Blood-Brain Barrier (BBB) permeability, the activated inflammatory response, and the changed microbial metabolites. Neurological disorders contribute to gut dysbiosis and some relevant metabolites in a top-down way. In turn, the activated immune system induced by the change of gut microbiota may deteriorate the development of neurological diseases through the disturbed gut/BBB barrier in a down-top way. Understanding the characterization and identification of microbiome-immune- brain signaling pathways will help us to yield novel therapeutic strategies by targeting the gut microbiome in neurological disease.

Download Full-text

Let-7a-5p regulates the inflammatory response in chronic rhinosinusitis with nasal polyps

Diagnostic Pathology ◽

10.1186/s13000-021-01089-0 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Jianwei Zhang ◽

Lei Han ◽

Feng Chen

Keyword(s):

Inflammatory Response ◽

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Mapk Pathway ◽

Inhibitory Effect ◽

Luciferase Reporter ◽

Western Blot Assay ◽

Protein Levels ◽

Tnf Α

Abstract Background Let-7a-5p is demonstrated to be a tumor inhibitor in nasopharyngeal carcinoma. However, the role of let-7a-5p in chronic rhinosinusitis with nasal polyps (CRSwNP) has not been reported. This study is designed to determine the pattern of expression and role of let-7a-5p in CRSwNP. Methods The expression level of let-7a-5p, TNF-α, IL-1β, and IL-6 in CRSwNP tissues and cells were detected by RT-qPCR. Western blot assay was carried out to measure the protein expression of the Ras-MAPK pathway. Dual luciferase reporter assay and RNA pull-down assay were used to explore the relationship between let-7a-5p and IL-6. Results Let-7a-5p was significantly downregulated in CRSwNP tissues and cells. Moreover, the mRNA expression of TNF-α, IL-1β and IL-6 was increased in CRSwNP tissues, while let-7a-5p mimic inhibited the expression of TNF-α, IL-1β and IL-6. Besides that, let-7a-5p was negatively correlated with TNF-α, IL-1β and IL-6 in CRSwNP tissues. In our study, IL-6 was found to be a target gene of let-7a-5p. Additionally, let-7-5p mimic obviously reduced the protein levels of Ras, p-Raf1, p-MEK1 and p-ERK1/2, while IL-6 overexpression destroyed the inhibitory effect of let-7a-5p on the Ras-MAPK pathway in CRSwNP. Conclusion We demonstrated that let-7a-5p/IL-6 interaction regulated the inflammatory response through the Ras-MAPK pathway in CRSwNP.

Download Full-text

The interplay between gut microbiota and the immune system in liver transplant recipients and its role in infections

Infection and Immunity ◽

10.1128/iai.00376-21 ◽

2021 ◽

Author(s):

Giuseppe Ancona ◽

Laura Alagna ◽

Andrea Lombardi ◽

Emanuele Palomba ◽

Valeria Castelli ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune System ◽

Liver Disease ◽

Gut Microbiota ◽

Liver Transplant ◽

Bacterial Infections ◽

Multidrug Resistant ◽

Transplant Recipients ◽

Liver Transplant Recipients

Liver transplantation (LT) is a life-saving strategy for patients with end-stage liver disease, hepatocellular carcinoma and acute liver failure. LT success can be hampered by several short-term and long-term complications. Among them, bacterial infections, especially due to multidrug-resistant germs, are particularly frequent with a prevalence between 19 and 33% in the first 100 days after transplantation. In the last decades, a number of studies have highlighted how gut microbiota (GM) is involved in several essential functions to ensure the intestinal homeostasis, becoming one of the most important virtual metabolic organs. GM works through different axes with other organs, and the gut-liver axis is among the most relevant and investigated ones. Any alteration or disruption of GM is defined as dysbiosis. Peculiar phenotypes of GM dysbiosis have been associated to several liver conditions and complications, such as chronic hepatitis, fatty liver disease, cirrhosis and hepatocellular carcinoma. Moreover, there is growing evidence of the crucial role of GM in shaping the immune response, both locally and systemically, against pathogens. This paves the way to the manipulation of GM as a therapeutic instrument to modulate the infectious risk and outcome. In this minireview we provide an overview of the current understanding on the interplay between gut microbiota and the immune system in liver transplant recipients and the role of the former in infections.

Download Full-text

ON THE QUESTION OF THE PATHOGENESIS OF HIV-INFECTION: THE ROLE OF IMMUNE ACTIVATION IN PROGRESSION OF DISEASE

Epidemiology and Infectious Diseases (Russian Journal) ◽

10.17816/eid40663 ◽

2012 ◽

Vol 17 (3) ◽

pp. 47-52

Author(s):

G. R. Khasanova ◽

I. G. Mustafin ◽

V. A. Anokhin

Keyword(s):

Immune System ◽

Gut Microbiota ◽

Hiv Infection ◽

Immune Activation ◽

Opportunistic Pathogens ◽

Rate Of Progression ◽

Progression Of Disease ◽

Modern Knowledge

Hyperactivaion of immme system is considered by most investigators as importantfactor, contributing to progression of HIV-infection and development ofAIDS. In the review modern knowledge about mechanisms and results of activation of immune system during HIV-infection are presented. HIV itself, opportunistic pathogens and components of gut microbiota, first of all, endotoxins ofgram-negative bacteria are considered as probable "activators" of immune system. High levels of endotoxin and markers of immune activation are associated with an even greater rate of progression of HIV-infection.

Download Full-text

Clinical significance of miR-129-5p in patients with neonatal sepsis and its regulatory role in the LPS-induced inflammatory response

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2020.5184 ◽

2020 ◽

Author(s):

Meng Li ◽

Xiaoyang Huang ◽

Qingcui Zhuo ◽

Jinghui Zhang ◽

Xiuli Ju

Keyword(s):

Inflammatory Response ◽

Clinical Significance ◽

Neonatal Sepsis ◽

Close Association ◽

Disease Diagnosis ◽

Diagnostic Value ◽

Regulatory Role ◽

Value Analysis ◽

Tnf Α

Neonatal sepsis (NS) occurs in neonates within 28 days, especially preterm infants. The dysregulation of miRNAs is widely detected in NS. The study investigated the expression changes and clinical significance of miR-129-5p in NS patients and further explored the regulatory role of miR-129-5p in the LPS-induced inflammatory response in monocytes. A total of 75 neonates with NS and 84 neonates without NS were recruited. qRT-PCR was used for the measurement of miR-129-5p expression. The receiver operating characteristic (ROC) curve was constructed for diagnostic value analysis. ELISA was used to detect the concentration of inflammatory cytokines. Monocytes were isolated from the blood of neonates to investigate the role of miR-129-5p in the LPS-induced inflammatory response in vitro. miR-129-5p was low expressed in the serum of NS cases compared with controls. Serum miR-129-5p had a diagnostic value for NS with a sensitivity of 82.7% and specificity of 79.8%. There was close association for serum miR-129-5p with TNF-α (r = -0.652, p < 0.001) and IL-8 (r = -0.700, p < 0.001) levels in NS patients. Overexpression of miR-129-5p reversed the increasing trend of TNF-α and IL-8 induced by LPS, whereas miR-129-5p downregulation aggravated the increase of TNF-α and IL-8 induced by LPS in monocytes. MiR-129-5p was downregulated in the serum of NS patients, and it might be a promising biomarker for disease diagnosis. Overexpression of miR-129-5p alleviated the inflammatory response of NS.

Download Full-text

Proinflammatory responses in SARS-CoV-2 infected and soluble spike glycoprotein S1 subunit activated human macrophages

10.1101/2021.06.14.448426 ◽

2021 ◽

Author(s):

Kim Chiok ◽

Kevin Hutchison ◽

Lindsay Grace Miller ◽

Santanu Bose ◽

Tanya A Miura

Keyword(s):

Virus Infection ◽

Inflammatory Response ◽

Virus Replication ◽

Inflammatory Mediators ◽

Inflammatory Responses ◽

Activated Macrophages ◽

Human Macrophages ◽

Tnf Α ◽

Proinflammatory Responses

Critically ill COVID-19 patients infected with SARS-CoV-2 display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We used SARS-CoV-2 infected and glycosylated soluble SARS-CoV-2 Spike S1 subunit (S1) treated THP-1 human-derived macrophage-like cell line to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication, virus infection resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that S1 is a key viral component inducing inflammatory response in macrophages, independently of virus replication. Thus, virus-infected or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.

Download Full-text

MiR-22-3p suppresses sepsis-induced acute kidney injury by targeting PTEN

Bioscience Reports ◽

10.1042/bsr20200527 ◽

2020 ◽

Vol 40 (6) ◽

Author(s):

Xudong Wang ◽

Yali Wang ◽

Mingjian Kong ◽

Jianping Yang

Keyword(s):

Acute Kidney Injury ◽

Inflammatory Response ◽

Periodic Acid ◽

Kidney Injury ◽

Luciferase Reporter ◽

Tunel Staining ◽

Tnf Α

Abstract Background: Septic acute kidney injury is considered as a severe and frequent complication that occurs during sepsis. The present study was performed to understand the role of miR-22-3p and its underlying mechanism in sepsis-induced acute kidney injury. Methods: Rats were injected with adenovirus carrying miR-22-3p or miR-NC in the caudal vein before cecal ligation. Meanwhile, HK-2 cells were transfected with the above adenovirus following LPS stimulation. We measured the markers of renal injury (blood urea nitrogen (BUN), serum creatinine (SCR)). Histological changes in kidney tissues were examined by hematoxylin and eosin (H&E), Masson staining, periodic acid Schiff staining and TUNEL staining. The levels of IL-1β, IL-6, TNF-α and NO were determined by ELISA assay. Using TargetScan prediction and luciferase reporter assay, we predicted and validated the association between PTEN and miR-22-3p. Results: Our data showed that miR-22-3p was significantly down-regulated in a rat model of sepsis-induced acute kidney injury, in vivo and LPS-induced sepsis model in HK-2 cells, in vitro. Overexpression of miR-22-3p remarkably suppressed the inflammatory response and apoptosis via down-regulating HMGB1, p-p65, TLR4 and pro-inflammatory factors (IL-1β, IL-6, TNF-α and NO), both in vivo and in vitro. Moreover, PTEN was identified as a target of miR-22-3p. Furthermore, PTEN knockdown augmented, while overexpression reversed the suppressive role of miR-22-3p in LPS-induced inflammatory response. Conclusions: Our results showed that miR-22-3p induced protective role in sepsis-induced acute kidney injury may rely on the repression of PTEN.

Download Full-text

Grain dust-induced lung inflammation is reduced byRhodobacter sphaeroidesdiphosphoryl lipid A

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1998.274.1.l26 ◽

1998 ◽

Vol 274 (1) ◽

pp. L26-L31 ◽

Cited By ~ 10

Author(s):

Paul J. Jagielo ◽

Timothy J. Quinn ◽

Nilofer Qureshi ◽

David A. Schwartz

Keyword(s):

Inflammatory Response ◽

Airway Inflammation ◽

Lipid A ◽

Partial Agonist ◽

Inhibitory Effect ◽

Sterile Saline ◽

Endotoxin Activity ◽

Tnf Α ◽

Grain Dust

To further determine the importance of endotoxin in grain dust-induced inflammation of the lower respiratory tract, we evaluated the efficacy of pentaacylated diphosphoryl lipid A derived from the lipopolysaccharide of Rhodobacter sphaeroides (RsDPLA) as a partial agonist of grain dust-induced airway inflammation. RsDPLA is a relatively inactive compound compared with lipid A derived from Escherichia coli (LPS) and has been demonstrated to act as a partial agonist of LPS-induced inflammation. To assess the potential stimulatory effect of RsDPLA in relation to LPS, we incubated THP-1 cells with RsDPLA (0.001–100 μg/ml), LPS (0.02 μg endotoxin activity/ml), or corn dust extract (CDE; 0.02 μg endotoxin activity/ml). Incubation with RsDPLA revealed a tumor necrosis factor (TNF)-α stimulatory effect at 100 μg/ml. In contrast, incubation with LPS or CDE resulted in TNF-α release at 0.02 μg/ml. Pretreatment of THP-1 cells with varying concentrations of RsDPLA before incubation with LPS or CDE (0.02 μg endotoxin activity/ml) resulted in a dose-dependent reduction in the LPS- or CDE-induced release of TNF-α with concentrations of RsDPLA of up to 10 μg/ml but not at 100 μg/ml. To further understand the role of endotoxin in grain dust-induced airway inflammation, we utilized the unique LPS inhibitory property of RsDPLA to determine the inflammatory response to inhaled CDE in mice in the presence of RsDPLA. Ten micrograms of RsDPLA intratracheally did not cause a significant inflammatory response compared with intratracheal saline. However, pretreatment of mice with 10 μg of RsDPLA intratracheally before exposure to CDE (5.4 and 0.2 μg/m3) or LPS (7.2 and 0.28 μg/m3) resulted in significant reductions in the lung lavage concentrations of total cells, neutrophils, and specific proinflammatory cytokines compared with mice pretreated with sterile saline. These results confirm the LPS-inhibitory effect of RsDPLA and support the role of endotoxin as the principal agent in grain dust causing airway inflammation.

Download Full-text

Sepsis and the Microbiome: A Vicious Cycle

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa682 ◽

2020 ◽

Author(s):

William D Miller ◽

Robert Keskey ◽

John C Alverdy

Keyword(s):

Immune Response ◽

Immune System ◽

Gut Microbiota ◽

Enteral Feeding ◽

Gut Microbiome ◽

Antibiotic Stewardship ◽

Vicious Cycle ◽

Fecal Transplant ◽

Suspected Infection

Abstract Although sepsis has been characterized as a dysregulated immune response to an ongoing or suspected infection, the role of the microbiome as a key influencer of the septic response is emerging. The unavoidable disruption of the microbiome while treating sepsis with antibiotics can itself result in immune system dysregulation, further exacerbating the course and outcome of sepsis. Alterations in the gut microbiome as a result of sepsis and its treatment have been implicated in the organ dysfunction typical of sepsis across a wide variety of tissues including the lung, kidney and brain. A number of microbiota directed interventions are currently under investigation in the setting of sepsis including fecal transplant, the administration of dietary fiber in enteral feeding products and the use of antibiotic scavengers that are directed at attenuating the effects of antibiotics on the gut microbiota while allowing them to concentrate at the primary sites of infection. Taken together, the emerging role of the gut microbiome in sepsis touches various elements of the pathophysiology of sepsis and its treatment, and provides yet another reason to consider the judicious use of antibiotics via antibiotic stewardship programs.

Download Full-text

The Gut Microbiota in Multiple Sclerosis: An Overview of Clinical Trials

Cell Transplantation ◽

10.1177/0963689719873890 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1507-1527 ◽

Cited By ~ 16

Author(s):

Giovanni Schepici ◽

Serena Silvestro ◽

Placido Bramanti ◽

Emanuela Mazzon

Keyword(s):

Multiple Sclerosis ◽

Immune System ◽

Gut Microbiota ◽

Fecal Microbiota Transplantation ◽

Fecal Microbiota ◽

System A ◽

Relapsing Remitting ◽

The Central Nervous System ◽

Review Reports

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative disease that affects the central nervous system. A recent study showed that interaction between the immune system and the gut microbiota plays a crucial role in the development of MS. This review reports the clinical studies carried out in recent years that aimed to evaluate the composition of the microbiota in patients with relapsing–remitting MS (RR-MS). We also report what is available in the literature regarding the effectiveness of fecal microbiota transplantation and the role of the diet in restoring the intestinal bacterial population. Studies report that patients with RR-MS have a microbiota that, compared with healthy controls, has higher amounts of Pedobacteria, Flavobacterium, Pseudomonas, Mycoplana, Acinetobacter, Eggerthella, Dorea, Blautia, Streptococcus and Akkermansia. In contrast, MS patients have a microbiota with impoverished microbial populations of Prevotella, Bacteroides, Parabacteroides, Haemophilus, Sutterella, Adlercreutzia, Coprobacillus, Lactobacillus, Clostridium, Anaerostipes and Faecalibacterium. In conclusion, the restoration of the microbial population in patients with RR-MS appears to reduce inflammatory events and the reactivation of the immune system.

Download Full-text