Gut dysbiosis modulates the immune response to factor VIII in murine hemophilia A

Abstract The development of neutralizing FVIII antibodies is the most serious complication of hemophilia A treatment. The currently known patient- and treatment-related risk factors for inhibitor development do not accurately predict this adverse event in all patients. The composition of the gut microbiota has been shown to influence immune-mediated diseases at distant anatomical sites (eg, lungs, brain, and joints). We demonstrate that a disrupted gut microbiota can be created in a mouse model of hemophilia A using a broad-spectrum antibiotic. Under controlled conditions, this sustained dysbiosis was associated with an increase in splenic B cells and the development of higher titer, FVIII-specific immunoglobulin G antibodies after FVIII challenge. Splenic and mesenteric lymph node cytokines, T cells, and dendritic cells were unaffected before administration of FVIII. However, the immune transcriptome of both aforementioned secondary lymphoid organs was significantly modified. Short-chain fatty acids (SCFAs), which are immunomodulatory microbial metabolites, were depleted in cecal contents of the dysbiotic mice. Furthermore, supplementation of the drinking water with butyrate, the most immunologically active SCFA, successfully achieved attenuation of the FVIII immune response. Collectively, data from this exploratory study suggest that the composition of the gut microbiota alters the FVIII immune response via the action of specific microbial metabolites on the immune cell transcriptome and that oral supplementation with butyrate effectively reduces the FVIII immune response.

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Integrated Transcriptional Profiling Analysis and Immune-Related Risk Model Construction for Intracranial Aneurysm Rupture

Frontiers in Neuroscience ◽

10.3389/fnins.2021.613329 ◽

2021 ◽

Vol 15 ◽

Author(s):

Dezhi Shan ◽

Xing Guo ◽

Guozheng Yang ◽

Zheng He ◽

Rongrong Zhao ◽

...

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

Signaling Pathway ◽

Immune Cell ◽

Risk Model ◽

Enrichment Analysis ◽

Cell Infiltration ◽

Enzyme Linked Immunosorbent Assay ◽

Immune Cell Infiltration ◽

Related Risk

Intracranial aneurysms (IAs) may cause lethal subarachnoid hemorrhage upon rupture, but the molecular mechanisms are poorly understood. The aims of this study were to analyze the transcriptional profiles to explore the functions and regulatory networks of differentially expressed genes (DEGs) in IA rupture by bioinformatics methods and to identify the underlying mechanisms. In this study, 1,471 DEGs were obtained, of which 619 were upregulated and 852 were downregulated. Gene enrichment analysis showed that the DEGs were mainly enriched in the inflammatory response, immune response, neutrophil chemotaxis, and macrophage differentiation. Related pathways include the regulation of actin cytoskeleton, leukocyte transendothelial migration, nuclear factor κB signaling pathway, Toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, and chemokine signaling pathway. The enrichment analysis of 20 hub genes, subnetworks, and significant enrichment modules of weighted gene coexpression network analysis showed that the inflammatory response and immune response had a causal relationship with the rupture of unruptured IAs (UIAs). Next, the CIBERSORT method was used to analyze immune cell infiltration into ruptured IAs (RIAs) and UIAs. Macrophage infiltration into RIAs increased significantly compared with that into UIAs. The result of principal component analysis revealed that there was a difference between RIAs and UIAs in immune cell infiltration. A 4-gene immune-related risk model for IA rupture (IRMIR), containing CXCR4, CXCL3, CX3CL1, and CXCL16, was established using the glmnet package in R software. The receiver operating characteristic value revealed that the model represented an excellent clinical situation for potential application. Enzyme-linked immunosorbent assay was performed and showed that the concentrations of CXCR4 and CXCL3 in serum from RIA patients were significantly higher than those in serum from UIA patients. Finally, a competing endogenous RNA network was constructed to provide a potential explanation for the mechanism of immune cell infiltration into IAs. Our findings highlighted the importance of immune cell infiltration into RIAs, providing a direction for further research.

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Habitual animal fat consumption in shaping gut microbiota and microbial metabolites

Food & Function ◽

10.1039/c9fo01490j ◽

2019 ◽

Vol 10 (12) ◽

pp. 7973-7982 ◽

Cited By ~ 2

Author(s):

Yi Wan ◽

Wenfeng Tong ◽

Renke Zhou ◽

Jie Li ◽

Jihong Yuan ◽

...

Keyword(s):

Fatty Acids ◽

Gut Microbiota ◽

Microbial Diversity ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Microbial Metabolites ◽

Animal Fat ◽

Fat Consumption ◽

Chain Fatty Acids

A diet with higher animal-based fat consumption is likely to be associated with moderately unfavorable impacts on gut microbial diversity, community, and regulation of fecal short-chain fatty acids.

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Microbial fermentation of flaxseed fibers modulates the transcriptome of GPR41-expressing enteroendocrine cells and protects mice against diet-induced obesity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00391.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. E453-E463 ◽

Cited By ~ 4

Author(s):

Tulika Arora ◽

Olga Rudenko ◽

Kristoffer Lihme Egerod ◽

Anna Sofie Husted ◽

Petia Kovatcheva-Datchary ◽

...

Keyword(s):

Gut Microbiota ◽

Protein Transport ◽

Fluorescent Protein ◽

Short Chain Fatty Acids ◽

Enteroendocrine Cells ◽

Chow Diet ◽

Enteroendocrine Cell ◽

Diet Induced Obesity ◽

Transcriptional Changes ◽

Cell Transcriptome

Dietary fibers, an integral part of the human diet, require the enzymatic activity of the gut microbiota for complete metabolism into short-chain fatty acids (SCFAs). SCFAs are important modulators of host metabolism and physiology and act in part as signaling molecules by activating G protein-coupled receptors (GPCRs), such as GPR41. Flaxseed fibers improve metabolism in rodents and mice, but their fermentation profiles, effects on enteroendocrine cells, and associated metabolic benefits are unknown. We fed GPR41-red fluorescent protein mice, an enteroendocrine reporter mouse strain, chow, high-fat diet (HFD), or HFD supplemented either with 10% nonfermentable fiber cellulose or fermentable flaxseed fibers for 12 wk to assess changes in cecal gut microbiota, enteroendocrine cell transcriptome in the ileum and colon, and physiological parameters. We observed that flaxseed fibers restructured the gut microbiota and promoted proliferation of the genera Bifidobacterium and Akkermansia compared with HFD. The shifts in cecal bacterial composition restored levels of the SCFAs butyrate similar to the chow diet, resulting in colonic but not ileal enteroendocrine cell transcriptional changes in genes related to cell cycle, mRNA, and protein transport compared with HFD. Consistent with the effects on enteroendocrine functions, flaxseed fibers also protected mice from diet-induced obesity, potentially by preventing a reduction in energy expenditure induced by an HFD. Our study shows that flaxseed fibers alter cecal microbial ecology, are fermented to SCFAs in the cecum, and modulate enteroendocrine cell transcriptome in the colon, which may contribute to their metabolically favorable phenotype.

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Effects of combined d-fagomine and omega-3 PUFAs on gut microbiota subpopulations and diabetes risk factors in rats fed a high-fat diet

Scientific Reports ◽

10.1038/s41598-019-52678-5 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Mercè Hereu ◽

Sara Ramos-Romero ◽

Cristina Busquets ◽

Lidia Atienza ◽

Susana Amézqueta ◽

...

Keyword(s):

Risk Factors ◽

Gut Microbiota ◽

High Fat Diet ◽

Short Chain Fatty Acids ◽

Standard Diet ◽

Liver Inflammation ◽

Omega 3 ◽

Sprague Dawley ◽

High Fat ◽

Related Risk

Abstract Food contains bioactive compounds that may prevent changes in gut microbiota associated with Westernized diets. The aim of this study is to explore the possible additive effects of d-fagomine and ω-3 PUFAs (EPA/DHA 1:1) on gut microbiota and related risk factors during early stages in the development of fat-induced pre-diabetes. Male Sprague Dawley (SD) rats were fed a standard diet, or a high-fat (HF) diet supplemented with d-fagomine, EPA/DHA 1:1, a combination of both, or neither, for 24 weeks. The variables measured were fasting glucose and glucose tolerance, plasma insulin, liver inflammation, fecal/cecal gut bacterial subgroups and short-chain fatty acids (SCFAs). The animals supplemented with d-fagomine alone and in combination with ω-3 PUFAs accumulated less fat than those in the non-supplemented HF group and those given only ω-3 PUFAs. The combined supplements attenuated the high-fat-induced incipient insulin resistance (IR), and liver inflammation, while increasing the cecal content, the Bacteroidetes:Firmicutes ratio and the populations of Bifidobacteriales. The functional effects of the combination of d-fagomine and EPA/DHA 1:1 against gut dysbiosis and the very early metabolic alterations induced by a high-fat diet are mainly those of d-fagomine complemented by the anti-inflammatory action of ω-3 PUFAs.

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Motor Stereotypic Behavior Was Associated With Immune Response in Macaques: Insight From Transcriptome and Gut Microbiota Analysis

Frontiers in Microbiology ◽

10.3389/fmicb.2021.644540 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xuan Pan ◽

Fangyuan Liu ◽

Yang Song ◽

Hongrun Wang ◽

Lingyun Wang ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Gut Microbiota ◽

Molecular Mechanisms ◽

Rhesus Macaques ◽

Interaction Network ◽

Short Chain Fatty Acids ◽

Observation Data ◽

Psychiatric Diseases ◽

Blood Transcriptome

Motor stereotypic behaviors (MSBs) are common in captive rhesus macaques (Macaca mulatta) and human with psychiatric diseases. However, large gaps remain in our understanding of the molecular mechanisms that mediate this behavior and whether there are similarities between human and non-human primates that exhibit this behavior, especially at gene expression and gut microbiota levels. The present study combined behavior, blood transcriptome, and gut microbiota data of two groups of captive macaques to explore this issue (i.e., MSB macaques with high MSB exhibition and those with low: control macaques). Observation data showed that MSB macaques spent the most time on MSB (33.95%), while the CONTROL macaques allocated more time to active (30.99%) and general behavior (30.0%), and only 0.97% of their time for MSB. Blood transcriptome analysis revealed 382 differentially expressed genes between the two groups, with 339 upregulated genes significantly enriched in inflammation/immune response-related pathway. We also identified upregulated pro-inflammatory genes TNFRSF1A, IL1R1, and IL6R. Protein–protein interaction network analysis screened nine hub genes that were all related to innate immune response, and our transcriptomic results were highly similar to findings in human psychiatric disorders. We found that there were significant differences in the beta-diversity of gut microbiota between MSB and CONTROL macaques. Of which Phascolarctobacterium, the producer of short chain fatty acids (SCFAs), was less abundant in MSB macaques. Meanwhile, PICRUSTs predicted that SCFAs intermediates biosynthesis and metabolic pathways were significantly downregulated in MSB macaques. Together, our study revealed that the behavioral, gene expression levels, and gut microbiota composition in MSB macaques was different to controls, and MSB was closely linked with inflammation and immune response. This work provides valuable information for future in-depth investigation of MSB and human psychiatric diseases.

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Modulating the Microbiota as a Therapeutic Intervention for Type 2 Diabetes

Frontiers in Endocrinology ◽

10.3389/fendo.2021.632335 ◽

2021 ◽

Vol 12 ◽

Author(s):

M. Nazmul Huda ◽

Myungsuk Kim ◽

Brian J. Bennett

Keyword(s):

Type 2 Diabetes ◽

Gut Microbiota ◽

Fecal Microbiota Transplantation ◽

Disease Status ◽

Short Chain Fatty Acids ◽

Host Cells ◽

Low Grade ◽

Microbial Metabolites ◽

Microbial Composition

Mounting evidence suggested that the gut microbiota has a significant role in the metabolism and disease status of the host. In particular, Type 2 Diabetes (T2D), which has a complex etiology that includes obesity and chronic low-grade inflammation, is modulated by the gut microbiota and microbial metabolites. Current literature supports that unbalanced gut microbial composition (dysbiosis) is a risk factor for T2D. In this review, we critically summarize the recent findings regarding the role of gut microbiota in T2D. Beyond these associative studies, we focus on the causal relationship between microbiota and T2D established using fecal microbiota transplantation (FMT) or probiotic supplementation, and the potential underlying mechanisms such as byproducts of microbial metabolism. These microbial metabolites are small molecules that establish communication between microbiota and host cells. We critically summarize the associations between T2D and microbial metabolites such as short-chain fatty acids (SCFAs) and trimethylamine N-Oxide (TMAO). Additionally, we comment on how host genetic architecture and the epigenome influence the microbial composition and thus how the gut microbiota may explain part of the missing heritability of T2D found by GWAS analysis. We also discuss future directions in this field and how approaches such as FMT, prebiotics, and probiotics supplementation are being considered as potential therapeutics for T2D.

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Gut Microbiota Metabolites in Major Depressive Disorder. Deep Insights into Their Pathophysiological Role and Potential Translational Applications

Metabolites ◽

10.3390/metabo12010050 ◽

2022 ◽

Vol 12 (1) ◽

pp. 50

Author(s):

Miguel A. Ortega ◽

Miguel Angel Alvarez-Mon ◽

Cielo García-Montero ◽

Oscar Fraile-Martinez ◽

Luis G. Guijarro ◽

...

Keyword(s):

Major Depressive Disorder ◽

Gut Microbiota ◽

Depressive Disorder ◽

Disease Status ◽

Short Chain Fatty Acids ◽

Human Organism ◽

Microbial Metabolites ◽

Clinical Value ◽

Major Depressive ◽

Health And Disease

The gut microbiota is a complex and dynamic ecosystem essential for the proper functioning of the organism, affecting the health and disease status of the individuals. There is continuous and bidirectional communication between gut microbiota and the host, conforming to a unique entity known as “holobiont”. Among these crosstalk mechanisms, the gut microbiota synthesizes a broad spectrum of bioactive compounds or metabolites which exert pleiotropic effects on the human organism. Many of these microbial metabolites can cross the blood–brain barrier (BBB) or have significant effects on the brain, playing a key role in the so-called microbiota-gut-brain axis. An altered Microbiota-Gut-Brain (MGB) axis is a major characteristic of many neuropsychiatric disorders, including major depressive disorder (MDD). Significative differences between gut eubiosis and dysbiosis in mental disorders like MDD with their different metabolite composition and concentrations are being discussed. In the present review, the main microbial metabolites (short-chain fatty acids -SCFAs-, bile acids, amino acids, tryptophan -trp- derivatives, and more), their signaling pathways and functions will be summarized to explain part of MDD pathophysiology. Conclusions from promising translational approaches related to microbial metabolome will be addressed in more depth to discuss their possible clinical value in the management of MDD patients.

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A review: Potential of resveratrol and its analogues to mitigate diseases via gut microbial modulation

Journal of Food Bioactives ◽

10.31665/jfb.2020.12248 ◽

2020 ◽

Vol 12 ◽

Author(s):

Yen-Chun Koh ◽

You-Tsz Lien ◽

Yu-Ting Chou ◽

Chi-Tang Ho ◽

Min-Hsiung Pan

Keyword(s):

Disease Prevention ◽

Gut Microbiota ◽

Microbial Growth ◽

Short Chain Fatty Acids ◽

Microbial Metabolites ◽

Major Focus ◽

Microbial Dysbiosis ◽

Microbial Infections ◽

Clinical Models ◽

Potential Strategy

The stilbenoids form a group of bioactive phenolic compounds found in various plant species whose original functions are to act as protective compounds against microbial infections and toxins. Among the stilbenoids, resveratrol is the most well-studied and has been shown to exert multiple benefits in disease prevention. The bioavailability of resveratrol is one of the major limitations in its role as a disease-prevention agent; however, it has exhibited biological activity in animals and clinical models. Gut microbiota may play a role in overcoming limited bioavailability via microbial transformations. On the other hand, the modulatory effects of stilbenoids on gut microbial dysbiosis induced by several diseases can be crucial in disease alleviation. In addition to gut microbial metabolites, such as SCFAs (short-chain fatty acids), stilbenoids can be used to inhibit microbial growth, making their use a potential strategy in preventing disease progression. In this review, the interactions of stilbenoids (with a major focus on resveratrol and pterostilbene) and gut microbiota will be discussed to clarify the importance of gut microbiota in the strategy of “disease prevention via phytochemicals.”

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Free microbial metabolites from healthy and dysbiotic gut microbiota differentially regulate intestinal immune response

10.26226/morressier.6170a2077c09fc044a974299 ◽

2021 ◽

Author(s):

Namrata Iyer

Keyword(s):

Immune Response ◽

Gut Microbiota ◽

Microbial Metabolites

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EBV miRNAs are potent effectors of tumor cell transcriptome remodeling in promoting immune escape

10.1101/2020.12.21.423766 ◽

2020 ◽

Author(s):

Nathan Ungerleider ◽

Whitney Bullard ◽

Mehmet Kara ◽

Xia Wang ◽

Claire Roberts ◽

...

Keyword(s):

Immune Response ◽

Tumor Cell ◽

Pathway Analysis ◽

Mirna Expression ◽

Immune Cell ◽

Noncoding Rnas ◽

Affinity Constant ◽

Cell Phenotype ◽

Cell Transcriptome ◽

Mirna Targeting

ABSTRACTEpstein Barr virus (EBV) contributes to the tumor phenotype through a limited set of primarily non-coding viral RNAs, including 31 mature miRNAs. Here we investigated the impact of EBV miRNAs on remodeling the tumor cell transcriptome. Strikingly, EBV miRNAs displayed exceptionally abundant expression in primary EBV-associated Burkitt’s Lymphomas (BLs) and Gastric Carcinomas (GCs). To investigate viral miRNA targeting, we used the high-resolution approach, CLASH in GC and a BL cell models. Affinity constant calculations of targeting efficacies for CLASH hits showed that viral miRNAs bind their targets more effectively than their host counterparts, as did Kaposi’s sarcoma-associated herpesvirus (KSHV) and murine gammaherpesvirus 68 (MHV68) miRNAs. Using public BL and GC RNA-seq datasets, we found that high EBV miRNA targeting efficacies translates to enhanced reduction of target expression. Pathway analysis of high efficacy EBV miRNA targets showed enrichment for innate and adaptive immune responses. Inhibition of the immune response by EBV miRNAs was functionally validated in vivo through the finding of inverse correlations between EBV miRNAs and immune cell infiltration and T-cell diversity in TCGA GC dataset. Together, this study demonstrates that EBV miRNAs are potent effectors of the tumor transcriptome that play a role in suppressing the host immune response.AUTHOR SUMMARYBurkitt’s Lymphoma and gastric cancer are both associated with EBV, a prolific DNA tumor virus that latently resides in nearly all human beings. Despite mostly restricting viral gene expression to noncoding RNAs, EBV has important influences on the fitness of infected tumor cells. Here, we show that the miRNA class of viral noncoding RNAs are a major viral contributor to remodeling the tumor cell regulatory machinery in patient tumor samples. First, an assessment of miRNA expression in clinical tumor samples showed that EBV miRNAs are expressed at unexpectedly high levels relative to cell miRNAs. Using a highly specific miRNA target identification approach, CLASH, we comprehensively identified both viral and cellular microRNA targets and the relative abundance of each microRNA-mRNA interaction. We also show that viral microRNAs bind to and alter the expression of their mRNA targets more effectively than their cellular microRNA counterparts. Pathway analysis of the most effectively targeted mRNAs revealed enrichment of immune signaling pathways and we show a corresponding inverse correlation between EBV miRNA expression and infiltrating immune cells in EBV positive primary tumors. Altogether, this study shows that EBV miRNAs are key regulators of the tumor cell phenotype and the immune cell microenvironment.

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