Relationships among gut microbiota, plasma metabolites, and juvenile idiopathic arthritis: a mediation Mendelian randomization study

ObjectiveThe objective of this study is to investigate the causal relationship between gut microbiota and juvenile idiopathic arthritis, and to identify and quantify the potential role of plasma metabolites as mediators.MethodsUsing summary-level data from genome-wide association studies, a two-sample Mendelian randomization was conducted involving 131 gut microbiota genus, 1,400 plasma metabolites, and juvenile idiopathic arthritis. Additionally, a two-step approach was employed to quantify the proportion of the effect of gut microbiota on juvenile idiopathic arthritis mediated by plasma metabolites. Effect estimation primarily utilized Inverse Variance Weighting, with further validation using Bayesian weighted Mendelian randomization.ResultsIn our MR analysis, a positive correlation was observed between Rikenellaceae and the risk of juvenile idiopathic arthritis, while Dorea showed a negative correlation with juvenile idiopathic arthritis risk. Mediation analysis indicated that Furaneol sulfate levels acted as a mediator between Dorea and juvenile idiopathic arthritis, with an indirect effect proportion of 19.94, 95% CI [8.86–31.03%].ConclusionOur study confirms a causal relationship between specific microbial genus and juvenile idiopathic arthritis, and computes the proportion of the effect mediated by plasma metabolites, offering novel insights for clinical interventions in juvenile idiopathic arthritis

The interplay of BDNF-TrkB with NMDA receptor in propofol-induced cognition dysfunction

Abstract Background The aim of the present study was to verify whether propofol impaired learning and memory through the interplay of N-methyl-D-aspartate (NMDA) receptor with brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway. Methods 120 Sprague-Dawley (SD) rats were randomly assigned into eight groups. Experimental drugs including saline, intralipid, propofol, N-methyl-D-aspartate (NMDA), 7,8-dihydroxyflavone (7,8-DHF), K252a and MK-801. Spatial learning and memory of rats were tested by the Morris water maze (MWM) test. The mRNA and protein expression were determined by immunohistochemistry, RT-PCR and western blot. Finally, hippocampus cells proliferation and apoptosis were examined by PCNA immunohistochemistry and TUNEL respectively. Results The memory and learning was diminished in the propofol exposure group, however, the impaired memory and learning of rats were improved with the addition of NMDA and 7,8-DHF, while the improvement of memory and learning of rats were reversed with the addition of K252a and MK-801. In addition, the mRNA and protein expression levels and hippocampus cells proliferation were the same trend with the results of the MWM test, while apoptosis in hippocampus was reversed. Conclusion The propofol can impair memory and learning of rats and induce cognition dysfunction through the interplay of NMDA receptor and BDNF-TrkB-CREB signaling pathway

Epigenetic Mechanisms Contribute to the Expression of Immune Related Genes in the Livers of Dairy Cows Fed a High Concentrate Diet

<div><p>Purpose</p><p>Epigenetic modifications critically regulate the expression of immune-related genes in response to inflammatory stimuli. It has been extensively reported that a high concentrate (HC) diet can trigger systemic inflammation in dairy cows, yet it is unclear whether epigenetic regulation is involved in the expression of immune genes in the livers of dairy cows. This study aimed to investigate the impact of epigenetic modifications on the expression of immune-related genes.</p><p>Experimental Design</p><p>In eight mid-lactating cows, we installed a rumen cannula and catheters of the portal and hepatic veins. Cows were randomly assigned to either the treatment group fed a high concentrate (HC) diet (60% concentrate + 40% forage, <i>n = 4</i>) or a control group fed a low concentrate (LC) diet (40% concentrate + 60% forage, <i>n = 4</i>).</p><p>Results</p><p>After 10 weeks of feeding, the rumen pH was reduced, and levels of lipopolysaccharide (LPS) in the rumen, and portal and hepatic veins were notably increased in the HC group compared with the LC group. The expression levels of detected immune response-related genes, including Toll-like receptor 4 (TLR4), cytokines, chemokines, and acute phase proteins, were significantly up-regulated in the livers of cows fed a HC diet. Chromatin loosening at the promoter region of four candidate immune-related genes (TLR4, LPS-binding protein, haptoglobin, and serum amyloid A3) was elicited, and was strongly correlated with enhanced expression of these genes in the HC group. Demethylation at the promoter region of all four candidate immune-related genes was accompanied by chromatin decompaction.</p><p>Conclusion</p><p>After HC diet feeding, LPS derived from the digestive tract translocated to the liver via the portal vein, enhancing hepatic immune gene expression. The up-regulation of these immune genes was mediated by epigenetic mechanisms, which involve chromatin remodeling and DNA methylation. Our findings suggest that modulating epigenetic mechanisms could provide novel ways to treat systemic inflammatory responses elicited by the feeding of a HC diet.</p></div

The levels of mRNA expression (relative copy number) in the livers of cows from treatment and control groups.

<p>^a Values are mean ± SEM</p><p>^&copy number[×10⁴]</p><p>^$acute phase protein (APP)</p><p>*<i>p</i> <0.05</p><p>**<i>p</i> <0.01 <i>vs</i> control.</p><p>The levels of mRNA expression (relative copy number) in the livers of cows from treatment and control groups.</p

The expression of TLR4 protein in the livers of cows fed two different diets.

<p>The average relative TLR4 protein expression levels compared with reference β-actin protein levels is presented. Black filled bar, treatment group fed a HC diet (n = 4, mean ± SEM); white filled bar, control group fed a LC diet (n = 4, mean ± SEM). The significance of the changes in TLR4 protein expression levels is indicated (*<i>p</i><0.05, **<i>p</i><0.01).</p

A map of the target promoter region of candidate genes and the distribution of relevant transcription factor binding sites in the corresponding promoter regions of those genes.

<p>Numbers refer to the transcriptional start position (TSP, +1), indicated by bold black arrows, and the 5’-position of exon 1 (black box). The gray boxes in the TLR4, Hp, and αS1-casein promoter regions indicate repeat elements. The position of the various transcription factors and restriction enzyme recognition sites are indicated by the respective symbols. The positions of primers used for CHART-PCR and the methylation assays are denoted by light black arrows. The promoter structure of αS1-casein has been described by Vanselow <i>et al</i>. The TSP of the SAA3 promoter was reported by Marilynn <i>et al</i>. The target promoter regions of candidate genes were identified by BLAST analyses as DNA-sequences that are 5’-upstream of the mRNA sequence deposited in the following NCBI files: NM_174198 (TLR4), NM_001038674 (LBP), NM_001040470 (Hp), and NW_003104637 (SAA3).</p

The correlation between the degree of chromatin compaction and the percentage of promoter methylation.

<p>The individual degrees of chromatin compaction (axis of abscissa) are plotted against the percentages of promoter methylation for the respective genes, as shown in panels A–E. Black squares, treated cows fed a HC diet; white circles, control cows fed a LC diet; R², coefficient of correlation; <i>p</i>, significance of correlation.</p

LPS concentrations in the rumen, and portal and hepatic veins of cows from treatment and control groups.

<p>^a Values are mean ± SEM</p><p>^# [×10⁴]</p><p>Tr, Treatment; Ti, Time; <i>p</i>, significant level.</p><p>LPS concentrations in the rumen, and portal and hepatic veins of cows from treatment and control groups.</p

The correlation between chromatin compaction and mRNA expression.

<p>The graph shows the individual degrees of chromatin compaction (axis of abscissa) compared with the relevant mRNA copy numbers (axis of ordinate) for each respective gene, which are presented in panels A–E. Black rhombs, treated cows fed a HC diet; white circles, control cows fed a LC diet; R², coefficient of correlation; <i>p</i>, significance of correlation.</p

A comparison of promoter methylation in the liver of cows from treatment and control groups.

<p>^a Values are mean ± SEM</p><p>*<i>p</i> < 0.05</p><p>**<i>p</i> < 0.01 <i>vs</i> control.</p><p>A comparison of promoter methylation in the liver of cows from treatment and control groups.</p