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Scientific Reports Jun 2024Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of Johne's Disease, a chronic granulomatous enteritis of ruminants. MAP establishes an...
Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of Johne's Disease, a chronic granulomatous enteritis of ruminants. MAP establishes an infection in the host via the small intestine. This requires the bacterium to adhere to, and be internalised by, cells of the intestinal tract. The effector molecules expressed by MAP for this purpose remain to be fully identified and understood. Mammalian cell entry (mce) proteins have been shown to enable other Mycobacterial species to attach to and invade host epithelial cells. Here, we have expressed Mce1A, Mce1D, Mce3C and Mce4A proteins derived from MAP on the surface of a non-invasive Escherichia coli to characterise their role in the initial interaction between MAP and the host. To this end, expression of mce1A was found to significantly increase the ability of the E. coli to attach and survive intracellularly in human monocyte-like THP-1 cells, whereas expression of mce1D was found to significantly increase attachment and invasion of E. coli to bovine epithelial cell-like MDBK cells, implying cell-type specificity. Furthermore, expression of Mce1A and Mce1D on the surface of a previously non-invasive E. coli enhanced the ability of the bacterium to infect 3D bovine basal-out enteroids. Together, our data contributes to our understanding of the effector molecules utilised by MAP in the initial interaction with the host, and may provide potential targets for therapeutic intervention.
Topics: Mycobacterium avium subsp. paratuberculosis; Paratuberculosis; Animals; Humans; Cattle; Bacterial Proteins; Bacterial Adhesion; Epithelial Cells; Escherichia coli; Cell Line; THP-1 Cells
PubMed: 38942800
DOI: 10.1038/s41598-024-65592-2 -
Microbiological Research Jun 2024Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy. In this study, we investigated...
Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy. In this study, we investigated the potential protective effect of Lactobacillus rhamnosus GG (LGG) on radiation-induced intestinal injury and its underlying mechanisms. Mice were assigned to a control group, a 10 Gy total abdominal irradiation (TAI) group, or a group pretreated with 10 CFU LGG for three days before TAI. Small intestine and gut microbiota were analyzed 3.5 days post-exposure. LGG intervention improved intestinal structure, reduced jejunal DNA damage, and inhibited the inflammatory cGAS/STING pathway. Furthermore, LGG reduced M1 proinflammatory macrophage and CD8+ T cell infiltration, restoring the balance between Th17 and Treg cells in the inflamed jejunum. LGG also partially restored the gut microbiota. These findings suggest the possible therapeutic radioprotective effect of probiotics LGG in alleviating radiation-induced intestinal injury by maintaining immune homeostasis and reshaping gut microbiota.
PubMed: 38941923
DOI: 10.1016/j.micres.2024.127821 -
Diabetes Care Jun 2024The aim of this study was to investigate the impact of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the...
SGLT2 Inhibitor Dapagliflozin Increases Skeletal Muscle and Brain Fatty Acid Uptake in Individuals With Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Positron Emission Tomography Study.
OBJECTIVE
The aim of this study was to investigate the impact of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the skeletal muscle, brain, small intestine, and subcutaneous and visceral adipose tissue of individuals with type 2 diabetes by using positron emission tomography (PET).
RESEARCH DESIGN AND METHODS
In a 6-week randomized double-blind placebo-controlled trial, 53 patients with type 2 diabetes treated with metformin received either 10 mg dapagliflozin or placebo daily. Tissue FA uptake was quantified at baseline and end of treatment with PET and the long-chain FA analog radiotracer 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Treatment effects were assessed using ANCOVA, and the results are reported as least square means and 95% CIs for the difference between groups.
RESULTS
A total of 38 patients (dapagliflozin n = 21; placebo n = 17) completed the study. After 6 weeks, skeletal muscle FA uptake was increased by dapagliflozin compared with placebo (1.0 [0.07, 2.0] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.032), whereas uptake was not significantly changed in the small intestine or visceral or subcutaneous adipose tissue. Dapagliflozin treatment significantly increased whole-brain FA uptake (0.10 [0.02, 0.17] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.01), an effect observed in both gray and white matter regions.
CONCLUSIONS
Six weeks of treatment with dapagliflozin increases skeletal muscle and brain FA uptake, partly driven by a rise in free FA availability. This finding is in accordance with previous indirect measurements showing enhanced FA metabolism in response to SGLT2 inhibition and extends the notion of a shift toward increased FA use to muscle and brain.
PubMed: 38941156
DOI: 10.2337/dc24-0470 -
Magyar Sebeszet Jun 2024Kompressziós vékonybél ileus esetét ismertetjük, amelyet a bélfodor nem gyakori, inflammatorikus természetű betegsége, mesenterialis panniculitis idézett elő....
BEVEZETÉS
Kompressziós vékonybél ileus esetét ismertetjük, amelyet a bélfodor nem gyakori, inflammatorikus természetű betegsége, mesenterialis panniculitis idézett elő. A magyar szakirodalomban ilyen közléssel nem találkoztunk.
ESETISMERTETÉS
A 91 éves férfi akut hasi panaszokkal került kórházba. A vizsgálatokkal vékonybél ileus derült ki. Ennek hátterében műtétkor malignitásra gyanús, bélfodri multinodularis elváltozást fedtünk föl. A biopsziából mesenterialis panniculitist diagnosztizáltunk. A ritka, több nyitott kérdéssel terhelt entitást mutatjuk be az irodalom és a saját észleleteink tükrében.
KÖVETKEZTETÉSEK
Számos differenciáldiagnosztikai eshetőség figyelembevételével a kórkép szövettanilag igazolható. A diagnózis felállítása után a további teendőket az egyéb leletek és az adott klinikai kontextus gondos elemzése fogja meghatározni.
Topics: Humans; Male; Aged, 80 and over; Intestinal Obstruction; Diagnosis, Differential; Panniculitis, Peritoneal; Intestine, Small; Ileus
PubMed: 38941150
DOI: 10.1556/1046.2024.20004 -
Frontiers in Immunology 2023Distinct, disease-associated intracellular miRNA (miR) expression profiles have been observed in peripheral blood mononuclear cells (PBMCs) of systemic lupus...
Inhibition of miRNA associated with a disease-specific signature and secreted via extracellular vesicles of systemic lupus erythematosus patients suppresses target organ inflammation in a humanized mouse model.
INTRODUCTION
Distinct, disease-associated intracellular miRNA (miR) expression profiles have been observed in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients. Additionally, we have identified novel estrogenic responses in PBMCs from SLE patients and demonstrated that estrogen upregulates toll-like receptor (TLR)7 and TLR8 expression. TLR7 and TLR8 bind viral-derived single-stranded RNA to stimulate innate inflammatory responses, but recent studies have shown that miR-21, mir-29a, and miR-29b can also bind and activate these receptors when packaged and secreted in extracellular vesicles (EVs). The objective of this study was to evaluate the association of EV-encapsulated small RNA species in SLE and examine the therapeutic approach of miR inhibition in humanized mice.
METHODS
Plasma-derived EVs were isolated from SLE patients and quantified. RNA was then isolated and bulk RNA-sequencing reads were analyzed. Also, PBMCs from active SLE patients were injected into immunodeficient mice to produce chimeras. Prior to transfer, the PBMCs were incubated with liposomal EVs containing locked nucleic acid (LNA) antagonists to miR-21, mir-29a, and miR-29b. After three weeks, blood was collected for both immunophenotyping and cytokine analysis; tissue was harvested for histopathological examination.
RESULTS
EVs were significantly increased in the plasma of SLE patients and differentially expressed EV-derived small RNA profiles were detected compared to healthy controls, including miR-21, mir-29a, and miR-29b. LNA antagonists significantly reduced proinflammatory cytokines and histopathological infiltrates in the small intestine, liver, and kidney, as demonstrated by H&E-stained tissue sections and immunohistochemistry measuring human CD3.
DISCUSSION
These data demonstrate distinct EV-derived small RNA signatures representing SLE-associated biomarkers. Moreover, targeting upregulated EV-encapsulated miR signaling by antagonizing miRs that may bind to TLR7 and TLR8 reveals a novel therapeutic opportunity to suppress autoimmune-mediated inflammation and pathogenesis in SLE.
Topics: Lupus Erythematosus, Systemic; Humans; Animals; MicroRNAs; Extracellular Vesicles; Mice; Disease Models, Animal; Female; Leukocytes, Mononuclear; Toll-Like Receptor 7; Inflammation; Toll-Like Receptor 8; Adult; Male; Middle Aged; Mice, SCID
PubMed: 38939646
DOI: 10.3389/fimmu.2023.1090177 -
Frontiers in Immunology 2024The comorbidity rate of inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) is high; nevertheless, the reasons behind this high rate remain unclear. Their...
BACKGROUND
The comorbidity rate of inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) is high; nevertheless, the reasons behind this high rate remain unclear. Their similar genetic makeup probably contributes to this comorbidity.
METHODS
Based on data obtained from the genome-wide association study of IBD and RA, we first assessed an overall genetic association by performing the linkage disequilibrium score regression (LDSC) analysis. Further, a local correlation analysis was performed by estimating the heritability in summary statistics. Next, the causality between the two diseases was analyzed by two-sample Mendelian randomization (MR). A genetic overlap was analyzed by the conditional/conjoint false discovery rate (cond/conjFDR) method.LDSC with specific expression of gene analysis was performed to identify related tissues between the two diseases. Finally, GWAS multi-trait analysis (MTAG) was also carried out.
RESULTS
IBD and RA are correlated at the genomic level, both overall and locally. The MR results suggested that IBD induced RA. We identified 20 shared loci between IBD and RA on the basis of a conjFDR of <0.01. Additionally, we identified two tissues, namely spleen and small intestine terminal ileum, which were commonly associated with both IBD and RA.
CONCLUSION
Herein, we proved the presence of a polygenic overlap between the genetic makeup of IBD and RA and provided new insights into the genetic architecture and mechanisms underlying the high comorbidity between these two diseases.
Topics: Arthritis, Rheumatoid; Humans; Genome-Wide Association Study; Inflammatory Bowel Diseases; Genetic Predisposition to Disease; Linkage Disequilibrium; Polymorphism, Single Nucleotide; Mendelian Randomization Analysis; Comorbidity
PubMed: 38938570
DOI: 10.3389/fimmu.2024.1359857 -
Journal of Extracellular Biology Sep 2023Extracellular vesicles (EVs) recently emerged as important players in the pathophysiology of parasitic infections. While the protist parasite can produce EVs, their...
Extracellular vesicles (EVs) recently emerged as important players in the pathophysiology of parasitic infections. While the protist parasite can produce EVs, their role in giardiasis remains obscure. can disrupt gut microbiota biofilms and transform commensal bacteria into invasive pathobionts at sites devoid of colonizing trophozoites via unknown mechanisms. We hypothesized that EVs could modify gut bacterial behaviour via a novel mode of trans-kingdom communication. Our findings indicate that EVs exert bacteriostatic effects on HB101 and TW1, increasing their swimming motility. EVs also decreased the biofilm-forming ability of HB101 but not by TW1, supporting the hypothesis that these effects are, at least in part, bacteria-selective. HB101 and TW1 exhibited increased adhesion/invasion onto small intestine epithelial cells when exposed to EVs. EVs labelled with PKH67 revealed colocalization with HB101 and TW1 bacterial cells. Small RNA sequencing revealed a high abundance of ribosomal RNA (rRNA)- and transfer RNA (tRNA)-derived small RNAs, short-interfering RNAs (siRNAs) and micro-RNAs (miRNAs) within EVs. Proteomic analysis of EVs uncovered the presence of RNA chaperones and heat shock proteins that can facilitate the thermal stability of EVs and its sRNA cargo, as well as protein-modifying enzymes. In vitro, RNase heat-treatment assays showed that total RNAs in EVs, but not proteins, are responsible for modulating bacterial swimming motility and biofilm formation. small RNAs of EVs, but not proteins, were responsible for the increased bacterial adhesion to intestinal epithelial cells induced upon exposure to EVs. Together, the findings indicate that EVs contain a heat-stable, RNase-sensitive cargo that can trigger the development of pathobiont characteristics in Enterobacteria, depicting a novel trans-kingdom cross-talk in the gut.
PubMed: 38938375
DOI: 10.1002/jex2.109 -
Journal of Pediatric Gastroenterology... Jun 2024For children with constipation and fecal incontinence treated with antegrade continence enemas (ACE), a fluoroscopic study with contrast administered via...
BACKGROUND
For children with constipation and fecal incontinence treated with antegrade continence enemas (ACE), a fluoroscopic study with contrast administered via appendicostomy/cecostomy can define the anatomy of the colon and simulate the flush to investigate associated symptoms or inadequate response. These studies can at times show retrograde flow into the small intestine. Our objective was to investigate the significance of this finding.
METHODS
We reviewed studies at our institution with contrast administered via appendicostomy/cecostomy in children treated with ACE, identifying those demonstrating retrograde flow of contrast. We recorded demographics, medical history, interventions, and outcomes.
RESULTS
We identified 162 studies (52% male, median age 10.7 years) with contrast via appendicostomy (76%) or cecostomy (24%). Diagnoses included anorectal malformation (38%), spinal cord anomaly (26%), functional constipation (24%), colonic dysmotility (18%), and Hirschsprung disease (12%). Fifty-nine (36%) studies showed retrograde flow: 28/59 children (48%) were not responding adequately and 21/59 (36%) had symptoms with ACE. Children with retrograde flow were more likely to have symptoms with ACE than those without (36% vs. 15%, p < 0.01). Fourteen children underwent interventions for this finding, including administering flushes more distally (4/8 responded), changing positioning of the child during flush administration, (1/2 responded), and slowing administration (1/1 responded). Retrograde flow was associated with younger age (p < 0.01), not sex or underlying diagnosis.
CONCLUSION
Identifying retrograde flow during studies with contrast administered via appendicostomy/cecostomy can be useful for children with a poor response or symptoms associated with ACE, as adjustments to the mechanics of the flush can alleviate those symptoms.
LEVEL OF EVIDENCE
Prognostic study, Level III.
PubMed: 38937991
DOI: 10.1002/jpn3.12297 -
Advanced Science (Weinheim,... Jun 2024Genetically lean and obese individuals have distinct intestinal microbiota and function. However, the underlying mechanisms of the microbiome heterogeneity and its...
Genetically lean and obese individuals have distinct intestinal microbiota and function. However, the underlying mechanisms of the microbiome heterogeneity and its regulation on epithelial function such as intestinal stem cell (ISC) fate remain unclear. Employing pigs of genetically distinct breeds (obese Meishan and lean Yorkshire), this study reveals transcriptome-wide variations in microbial ecology of the jejunum, characterized by enrichment of active Lactobacillus species, notably the predominant Lactobacillus amylovorus (L. amylovorus), and lactate metabolism network in obese breeds. The L. amylovorus-dominant heterogeneity is paralleled with epithelial functionality difference as reflected by highly expressed GPR81, more proliferative ISCs and activated Wnt/β-catenin signaling. Experiments using in-house developed porcine jejunal organoids prove that live L. amylovorus and its metabolite lactate promote intestinal organoid growth. Mechanistically, L. amylovorus and lactate activate Wnt/β-catenin signaling in a GPR81-dependent manner to promote ISC-mediated epithelial proliferation. However, heat-killed L. amylovorus fail to cause these changes. These findings uncover a previously underrepresented role of L. amylovorus in regulating jejunal stem cells via Lactobacillus-lactate-GPR81 axis, a key mechanism bridging breed-driven intestinal microbiome heterogeneity with ISC fate. Thus, results from this study provide new insights into the role of gut microbiome and stem cell interactions in maintaining intestinal homeostasis.
PubMed: 38937989
DOI: 10.1002/advs.202400058 -
The Kobe Journal of Medical Sciences Jun 2024Intussusception is a common cause of intestinal obstruction in infants aged 6-18 months. However, intussusception in preterm neonates (IPN) is an exceedingly rare...
Intussusception is a common cause of intestinal obstruction in infants aged 6-18 months. However, intussusception in preterm neonates (IPN) is an exceedingly rare disorder. The etiology of IPN remains unclear, but common prenatal injuries, such as those causing intestinal hypoxia/hypoperfusion, dysmotility, and strictures, have been proposed as possible contributing factors. Diagnosis is often delayed because the symptoms closely resemble those of necrotizing enterocolitis (NEC). Given the divergent treatments for IPN and NEC, establishing an early and accurate diagnosis is crucial. IPN is predominantly located in the small intestine (91.6%), and ultrasonography proves useful in its diagnosis. We present a case of a very preterm infant who developed intussusception triggered by acquired cytomegalovirus (aCMV) infection, necessitating surgical treatment. The cause of intussusception in this case was diagnosed as aCMV enteritis because no organic lesions were observed in the advanced part of the intussusception. The presence of CMV was confirmed by CMV-DNA-PCR examination of the resected intestinal tract. Intestinal edema and decreased intestinal peristalsis due to aCMV enteritis are likely the primary causes of the intussusception.
Topics: Humans; Intussusception; Cytomegalovirus Infections; Infant, Newborn; Infant, Extremely Premature; Male; Female; Enteritis; Infant, Premature, Diseases
PubMed: 38936880
DOI: 10.24546/0100489974