scholarly journals DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Jia Tong Loh ◽  
Koon-Guan Lee ◽  
Alison P. Lee ◽  
Joey Kay Hui Teo ◽  
Hsueh Lee Lim ◽  
...  
Keyword(s):  
Immune System ◽  
Quiescent State ◽  
Adapter Protein ◽  
Wild Type ◽  
Complex Interplay ◽  
Intestinal Homeostasis ◽  
Microbial Dysbiosis ◽  
Stat3 Signaling ◽  
Normal Microbiota ◽  
Inflammatory Bowel

AbstractHow pathogenesis of inflammatory bowel disease (IBD) depends on the complex interplay of host genetics, microbiome and the immune system is not fully understood. Here, we showed that Downstream of Kinase 3 (DOK3), an adapter protein involved in immune signaling, confers protection of mice from dextran sodium sulfate (DSS)-induced colitis. DOK3-deficiency promotes gut microbial dysbiosis and enhanced colitis susceptibility, which can be reversed by the transfer of normal microbiota from wild-type mice. Mechanistically, DOK3 exerts its protective effect by suppressing JAK2/STAT3 signaling in colonic neutrophils to limit their S100a8/9 production, thereby maintaining gut microbial ecology and colon homeostasis. Hence, our findings reveal that the immune system and microbiome function in a feed-forward manner, whereby DOK3 maintains colonic neutrophils in a quiescent state to establish a gut microbiome essential for intestinal homeostasis and protection from IBD.

scholarly journals Extracellular Vesicles with Possible Roles in Gut Intestinal Tract Homeostasis and IBD

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Xin Chang ◽  
Shu-Ling Wang ◽  
Sheng-Bing Zhao ◽  
Yi-Hai Shi ◽  
Peng Pan ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune System ◽  
Extracellular Vesicles ◽  
Intestinal Tract ◽  
Intestinal Inflammation ◽  
Therapeutic Effects ◽  
Intestinal Homeostasis ◽  
Antimicrobial Materials ◽  
Intestinal Immune System ◽  
Inflammatory Bowel

The intestinal tract consists of various types of cells, such as epithelial cells, Paneth cells, macrophages, and lymphocytes, which constitute the intestinal immune system and play a significant role in maintaining intestinal homeostasis by producing antimicrobial materials and controlling the host-commensal balance. Various studies have found that the dysfunction of intestinal homeostasis contributes to the pathogenesis of inflammatory bowel disease (IBD). As a novel mediator, extracellular vesicles (EVs) have been recognized as effective communicators, not only between cells but also between cells and the organism. In recent years, EVs have been regarded as vital characters for dysregulated homeostasis and IBD in either the etiology or the pathology of intestinal inflammation. Here, we review recent studies on EVs associated with intestinal homeostasis and IBD and discuss their source, cargo, and origin, as well as their therapeutic effects on IBD, which mainly include artificial nanoparticles and EVs derived from microorganisms.

scholarly journals Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response

2018 ◽  
Vol 115 (13) ◽  
pp. E2960-E2969 ◽  
Author(s):  
Xinghua Gao ◽  
Qiuhua Cao ◽  
Yan Cheng ◽  
Dandan Zhao ◽  
Zhuo Wang ◽  
...  
Keyword(s):  
Immune System ◽  
Gut Microbiota ◽  
Chronic Stress ◽  
White Blood Cells ◽  
Underlying Mechanism ◽  
System Response ◽  
Stat3 Signaling ◽  
Mucin 2 ◽  
Inflammatory Bowel ◽  
Immune System Response

Chronic stress is known to promote inflammatory bowel disease (IBD), but the underlying mechanism remains largely unresolved. Here, we found chronic stress to sensitize mice to dextran sulfate sodium (DSS)-induced colitis; to increase the infiltration of B cells, neutrophils, and proinflammatory ly6Chi macrophages in colonic lamina propria; and to present with decreased thymus and mesenteric lymph node (MLN) coefficients. Circulating total white blood cells were significantly increased after stress, and the proportion of MLN-associated immune cells were largely changed. Results showed a marked activation of IL-6/STAT3 signaling by stress. The detrimental action of stress was not terminated in IL-6−/− mice. Interestingly, the composition of gut microbiota was dramatically changed after stress, with expansion of inflammation-promoting bacteria. Furthermore, results showed stress-induced deficient expression of mucin-2 and lysozyme, which may contribute to the disorder of gut microbiota. Of note is that, in the case of cohousing, the stress-induced immune reaction and decreased body weight were abrogated, and transferred gut microbiota from stressed mice to control mice was sufficient to facilitate DSS-induced colitis. The important role of gut microbiota was further reinforced by broad-spectrum antibiotic treatment. Taken together, our results reveal that chronic stress disturbs gut microbiota, triggering immune system response and facilitating DSS-induced colitis.

scholarly journals Metabolic Influences of Gut Microbiota Dysbiosis on Inflammatory Bowel Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Salma Sultan ◽  
Mohammed El-Mowafy ◽  
Abdelaziz Elgaml ◽  
Tamer A. E. Ahmed ◽  
Hebatoallah Hassan ◽  
...  
Keyword(s):  
Immune System ◽  
Gut Microbiota ◽  
Disease Progression ◽  
Short Chain Fatty Acids ◽  
Host Immune System ◽  
Microbial Dysbiosis ◽  
Medical Disorders ◽  
Inflammatory Bowel ◽  
The Impact ◽  
Gut Microbiota Dysbiosis

Inflammatory bowel diseases (IBD) are chronic medical disorders characterized by recurrent gastrointestinal inflammation. While the etiology of IBD is still unknown, the pathogenesis of the disease results from perturbations in both gut microbiota and the host immune system. Gut microbiota dysbiosis in IBD is characterized by depleted diversity, reduced abundance of short chain fatty acids (SCFAs) producers and enriched proinflammatory microbes such as adherent/invasive E. coli and H2S producers. This dysbiosis may contribute to the inflammation through affecting either the immune system or a metabolic pathway. The immune responses to gut microbiota in IBD are extensively discussed. In this review, we highlight the main metabolic pathways that regulate the host-microbiota interaction. We also discuss the reported findings indicating that the microbial dysbiosis during IBD has a potential metabolic impact on colonocytes and this may underlie the disease progression. Moreover, we present the host metabolic defectiveness that adds to the impact of symbiont dysbiosis on the disease progression. This will raise the possibility that gut microbiota dysbiosis associated with IBD results in functional perturbations of host-microbiota interactions, and consequently modulates the disease development. Finally, we shed light on the possible therapeutic approaches of IBD through targeting gut microbiome.

Natural Products: Experimental Efficient Agents for Inflammatory Bowel Disease Therapy

2020 ◽  
Vol 25 (46) ◽  
pp. 4893-4913 ◽  
Author(s):  
Fan Cao ◽  
Jie Liu ◽  
Bing-Xian Sha ◽  
Hai-Feng Pan
Keyword(s):  
Inflammatory Bowel Disease ◽  
Natural Products ◽  
Immune System ◽  
Bowel Disease ◽  
Therapeutic Potential ◽  
Adaptive Immune System ◽  
Receptor Protein ◽  
Intestinal Epithelia ◽  
Inflammatory Bowel ◽  
The Individual

: Inflammatory bowel disease (IBD) is a chronic, elusive disorder resulting in relapsing inflammation of intestine with incompletely elucidated etiology, whose two representative forms are ulcerative colitis (UC) and Crohn’s disease (CD). Accumulating researches have revealed that the individual genetic susceptibility, environmental risk elements, intestinal microbial flora, as well as innate and adaptive immune system are implicated in the pathogenesis and development of IBD. Despite remarkable progression of IBD therapy has been achieved by chemical drugs and biological therapies such as aminosalicylates, corticosteroids, antibiotics, anti-tumor necrosis factor (TNF)-α, anti-integrin agents, etc., healing outcome still cannot be obtained, along with inevitable side effects. Consequently, a variety of researches have focused on exploring new therapies, and found that natural products (NPs) isolated from herbs or plants may serve as promising therapeutic agents for IBD through antiinflammatory, anti-oxidant, anti-fibrotic and anti-apoptotic effects, which implicates the modulation on nucleotide- binding domain (NOD) like receptor protein (NLRP) 3 inflammasome, gut microbiota, intestinal microvascular endothelial cells, intestinal epithelia, immune system, etc. In the present review, we will summarize the research development of IBD pathogenesis and current mainstream therapy, as well as the therapeutic potential and intrinsic mechanisms of NPs in IBD.

Lif Deficiency Leads to Iron Transportation Dysfunction in Ameloblasts

2021 ◽  
pp. 002203452110119
Author(s):  
L. Fan ◽  
Y.J. Ou ◽  
Y.X. Zhu ◽  
Y.D. Liang ◽  
Y. Zhou ◽  
...  
Keyword(s):  
Tooth Development ◽  
Iron Status ◽  
Acid Resistance ◽  
Blue Staining ◽  
Maturation Stage ◽  
Wild Type ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Stem Cell Pluripotency ◽  
Underlying Mechanisms

Leukemia inhibitory factor (LIF), a member of the interleukin 6 family of cytokines, is involved in skeletal metabolism, blastocyst implantation, and stem cell pluripotency maintenance. However, the role of LIF in tooth development needs to be elucidated. The aim of the present study was to investigate the effect of Lif deficiency on tooth development and to elucidate the functions of Lif during tooth development and the underlying mechanisms. First, it was found that the incisors of Lif-knockout mice had a much whiter color than those of wild-type mice. Although there were no structural abnormalities or defective mineralization according to scanning electronic microscopy and computed tomography analysis, 3-dimensional images showed that the length of incisors was shorter in Lif−/− mice. Microhardness and acid resistance assays showed that the hardness and acid resistance of the enamel surface of Lif−/− mice were decreased compared to those of wild-type mice. In Lif−/− mice, whose general iron status was comparable to that of the control mice, the iron content of the incisors was significantly reduced, as confirmed by energy-dispersive X-ray spectroscopy (EDS) and Prussian blue staining. Histological staining showed that the cell length of maturation-stage ameloblasts was shorter in Lif−/− mice. Likewise, decreased expression of Tfrc and Slc40a1, both of which are crucial proteins for iron transportation, was observed in Lif−/− mice and Lif-knockdown ameloblast lineage cell lines, according to quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and Western blot. Moreover, the upregulation of Tfrc and Slc40a1 induced by Lif stimulation was blocked by Stattic, a signal transducer and activator of transcription 3 (Stat3) signaling inhibitor. These results suggest that Lif deficiency inhibits iron transportation in the maturation-stage ameloblasts, and Lif modulates expression of Tfrc and Slc40a1 through the Stat3 signaling pathway during enamel development.

scholarly journals Functions of Dendritic Cells and Its Association with Intestinal Diseases

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 583
Author(s):  
Ze-Jun Yang ◽  
Bo-Ya Wang ◽  
Tian-Tian Wang ◽  
Fei-Fei Wang ◽  
Yue-Xin Guo ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Dendritic Cells ◽  
Immune System ◽  
Regulatory Mechanism ◽  
Intestinal Tumors ◽  
Regulatory Relationship ◽  
Intestinal Diseases ◽  
Inflammatory Bowel ◽  
Plasmacytoid Dcs

Dendritic cells (DCs), including conventional DCs (cDCs) and plasmacytoid DCs (pDCs), serve as the sentinel cells of the immune system and are responsible for presenting antigen information. Moreover, the role of DCs derived from monocytes (moDCs) in the development of inflammation has been emphasized. Several studies have shown that the function of DCs can be influenced by gut microbes including gut bacteria and viruses. Abnormal changes/reactions in intestinal DCs are potentially associated with diseases such as inflammatory bowel disease (IBD) and intestinal tumors, allowing DCs to be a new target for the treatment of these diseases. In this review, we summarized the physiological functions of DCs in the intestinal micro-environment, their regulatory relationship with intestinal microorganisms and their regulatory mechanism in intestinal diseases.

scholarly journals Gut microbiota differs between children with Inflammatory Bowel Disease and healthy siblings in taxonomic and functional composition: a metagenomic analysis

2017 ◽  
Vol 312 (4) ◽  
pp. G327-G339 ◽  
Author(s):  
Rebecca L. Knoll ◽  
Kristoffer Forslund ◽  
Jens Roat Kultima ◽  
Claudius U. Meyer ◽  
Ulrike Kullmer ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Gut Microbiota ◽  
Bowel Disease ◽  
Virulence Genes ◽  
Metagenomic Sequencing ◽  
Fecal Microbiome ◽  
Microbial Dysbiosis ◽  
Healthy Siblings ◽  
Inflammatory Bowel ◽  
Sibling Study

Current treatment for pediatric inflammatory bowel disease (IBD) patients is often ineffective, with serious side effects. Manipulating the gut microbiota via fecal microbiota transplantation (FMT) is an emerging treatment approach but remains controversial. We aimed to assess the composition of the fecal microbiome through a comparison of pediatric IBD patients to their healthy siblings, evaluating risks and prospects for FMT in this setting. A case-control (sibling) study was conducted analyzing fecal samples of six children with Crohn’s disease (CD), six children with ulcerative colitis (UC) and 12 healthy siblings by metagenomic sequencing. In addition, lifetime antibiotic intake was retrospectively determined. Species richness and diversity were significantly reduced in UC patients compared with control [Mann-Whitney U-test false discovery rate (MWU FDR) = 0.011]. In UC, bacteria positively influencing gut homeostasis, e.g., Eubacterium rectale and Faecalibacterium prausnitzii, were significantly reduced in abundance (MWU FDR = 0.05). Known pathobionts like Escherichia coli were enriched in UC patients (MWU FDR = 0.084). Moreover, E. coli abundance correlated positively with that of several virulence genes (SCC > 0.65, FDR < 0.1). A shift toward antibiotic-resistant taxa in both IBD groups distinguished them from controls [MWU Benjamini-Hochberg-Yekutieli procedure (BY) FDR = 0.062 in UC, MWU BY FDR = 0.019 in CD). The collected results confirm a microbial dysbiosis in pediatric UC, and to a lesser extent in CD patients, replicating associations found previously using different methods. Taken together, these observations suggest microbiotal remodeling therapy from family donors, at least for children with UC, as a viable option. NEW & NOTEWORTHY In this sibling study, prior reports of microbial dysbiosis in IBD patients from 16S rRNA sequencing was verified using deep shotgun sequencing and augmented with insights into the abundance of bacterial virulence genes and bacterial antibiotic resistance determinants, seen against the background of data on the specific antibiotic intake of each of the study participants. The observed dysbiosis, which distinguishes patients from siblings, highlights such siblings as potential donors for microbiotal remodeling therapy in IBD.

scholarly journals P009 Disease classifier and microbial dysbiosis index tools cross-predict various pathogenic conditions due to general microbial signal

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S129-S129
Author(s):  
H Abbas Egbariya ◽  
T Braun ◽  
R Hadar ◽  
O Gal-Mor ◽  
N Shental ◽  
...  
Keyword(s):  
Random Forest ◽  
Disease Control ◽  
Control Cohort ◽  
Sequencing Data ◽  
Microbial Dysbiosis ◽  
Trained Classifier ◽  
The Status ◽  
Inflammatory Bowel ◽  
General Response ◽  
Log Ratio

Abstract Background Microbial dysbiosis is widely described in inflammatory bowel disease (IBD), and has been shown to predict IBD state. However, many other diseases including neuro-psychiatric, metabolic, and malignancies, most of which do not result in gut inflammation, are also linked with gut microbial alteration. Since most studies focus on a single disease, the extent of similarity between different diseases is usually not examined. Methods We reanalyzed raw sequencing data from 12,838 human gut V4 16Sseq samples, spanning 59 case-controls comparisons and 28 unique diseases. Novel statistical approach was applied to reduce the effect of the different cohorts; all samples were processed uniformly, and differentially expressed amplicon sequence variants (ASVs) were identified within each cohort. The resulting behavior (direction of change and effect size) of each ASV were then combined across all studies. We used random forest as our classifier and generated non-specific dysbiosis index (NSDI). Results For the disease prediction, each cohort was randomly subsampled to 23 healthy and 23 disease samples. Random forest classifier was trained on one disease/control cohort, and the trained classifier was then used to predict the status of a different disease/control cohort. Disease classifiers performed well in identifying many sick vs. healthy states but failed to differentiate between different diseases. For example, a classifier trained on IBD cohort classified relatively good also disease/control in lupus, schizophrenia, or Parkinson’s from different cohorts. We show this cross-identification is due to a large number of shared disease-associated bacteria and utilize these bacteria to define a novel non-specific dysbiosis index (NSDI). After, we identified 114 non-disease specific ASVs (86 up and 28 down regulated ASVs across diseases in comparison to controls), we calculate the per-sample NSDI by rank-transforming the bacteria within the sample and computing the normalized log ratio of the sum of the ranks of the 86 down and 28 up regulated ASVs. The resulting NSDI is shown to perform better than the previously published CD dysbiosis index (Gevers et al, 2014; PMID: 24629344) indicating that NSDI can successfully differentiate between most cases and controls across a wide variety of diseases. Conclusion A robust non-specific general response of the gut microbiome is detected across different diseases, some of which is shared with IBD. Classifiers trained on a single disease may identify the general non-specific signal and therefore care should be taken when interpreting the classifier predictions. Finally, our NSDI can be used to prioritize the per-sample degree of dysbiosis.

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