Intestinal Inflammatory Response Research Articles

Elucidating the role of gut microbiota dysbiosis in hyperuricemia and gout: Insights and therapeutic strategies

Hyperuricemia (HUA) is a condition associated with a high concentration of uric acid (UA) in the bloodstream and can cause gout and chronic kidney disease. The gut microbiota of patients with gout and HUA is significantly altered compared to that of healthy people. This article focused on the complex interconnection between alterations in the gut microbiota and the development of this disorder. Some studies have suggested that changes in the composition, diversity, and activity of microbes play a key role in establishing and progressing HUA and gout pathogenesis. Therefore, we discussed how the gut microbiota contributes to HUA through purine metabolism, UA excretion, and intestinal inflammatory responses. We examined specific changes in the composition of the gut microbiota associated with gout and HUA, highlighting key bacterial taxa and the metabolic pathways involved. Additionally, we discussed the effect of conventional gout treatments on the gut microbiota composition, along with emerging therapeutic approaches that target the gut microbiome, such as the use of probiotics and prebiotics. We also provided insights into a study regarding the gut microbiota as a possible novel therapeutic intervention for gout treatment and dysbiosis-related diagnosis.

Rosmarinic Acid Attenuates Salmonella enteritidis-Induced Inflammation via Regulating TLR9/NF-κB Signaling Pathway and Intestinal Microbiota.

Salmonella enteritidis (SE) infection disrupts the homeostasis of the intestinal microbiota, causing an intestinal inflammatory response and posing a great threat to human and animal health. The unreasonable use of antibiotics has led to an increase in the prevalence of drug-resistant SE, increasing the difficulty of controlling SE. Therefore, new drug strategies and research are urgently needed to control SE. Rosmarinic acid (RA) is a natural phenolic acid with various pharmacological activities, including antioxidant, anti-inflammatory and antibacterial properties. However, the protective effects and mechanism of RA on intestinal inflammation and the gut microbial disorders caused by SE have not been fully elucidated. In this study, RAW264.7 cells, MCECs and BALB/c mice were challenged with SE to assess the protective effects and mechanisms of RA. The results showed that RA enhanced the phagocytic ability of RAW264.7 cells, reduced the invasion and adhesion ability of SE in MCECs, and inhibited SE-induced inflammation in cells. Moreover, RA inhibited the activation of the NF-κB signaling pathway by upregulating TLR9 expression. Importantly, we found that RA provided protection against SE and increased the diversity and abundance of the intestinal microbiota in mice. Compared with infection control, RA significantly increased the abundance of Firmicutes and Acidibacteria and decreased the abundance of Proteobacteria, Epsilonbacteraeota and Bacteroidota. However, RA failed to alleviate SE-induced inflammation and lost its regulatory effects on the TLR9/NF-κB signaling pathway after destroying the gut microbiota with broad-spectrum antibiotics. These results indicated that RA attenuated SE-induced inflammation by regulating the TLR9/NF-κB signaling pathway and maintaining the homeostasis of the gut microbiota. Our study provides a new strategy for preventing SE-induced intestinal inflammation.

Differential analysis of sorting nexin 10 and sterol regulatory element-binding protein 2 expression in inflammatory bowel disease.

Sorting nexin 10 (SNX10) expression induces intestinal barrier dysfunction and inflammatory responses; in contrast, its inhibition promotes intestinal mucosal healing through sterol regulatory element-binding protein 2 (SREBP2)-mediated cholesterol synthesis. However, its regulatory mechanism for the pathogenesis of inflammatory bowel disease (IBD) remains unclear. In this study, we examined SNX10 and SREBP2 expression in ulcerative colitis (UC) and Crohn's disease (CD). A total of 30 and 28 patients with UC and CD, respectively, were recruited. The expression of SNX10 and SREBP2 in the colonic mucosa was measured by immunohistochemistry (IHC). We discovered that patients with CD had significantly higher expression levels of SNX10 and SREBP2 than patients with UC and healthy controls. In addition, the expression of SREBP2 in patients with UC was significantly higher than that in healthy controls. In our study, we indicated that SNX10 and SREBP2 may serve as biomarkers for identifying patients with UC and CD, thereby providing a clinical therapeutic strategy for the treatment of IBD by inhibiting SNX10.

Pig Milk Exosome Packaging ssc-miR-22-3p Alleviates Pig Intestinal Epithelial Cell Injury and Inflammatory Response by Targeting MAPK14

Inflammatory diseases of the intestinal tract in piglets severely impair the economic performance of pig farms. Pig milk exosomes can encapsulate miRNAs which can then enter the piglet intestine to play an immunomodulatory role. Previously, we comparatively analyzed and identified exosomal miRNAs in the colostrum and mature milk of Bamei and Landrace pigs, and we screened for ssc-miR-22-3p, which is associated with inflammation and immune response; however, the role played by ssc-miR-22-3p in the immune response in IPEC-J2 cells is not yet clear. In this study, we first constructed a pig intestinal inflammatory response model using Lipopolysaccharide (LPS) and Polyinosinic-polycytidylic acid (Poly (I:C)), and we investigated the role of ssc-miR-22-3p targeting MAPK14 in the regulation of LPS and Poly (I:C)-induced inflammatory injury in IPEC-J2 cells by RT-qPCR, cell counting kit-8 (CCK-8), EdU staining, lactate dehydrogenase (LDH) activity assay, and dual luciferase reporter gene assay. We successfully established LPS and Poly (I:C)-induced cell damage models in IPEC-J2 cells. The immune response of IPEC-J2 cells was stimulated by induction of IPEC-J2 cells at 10 μg/mL LPS and 20 μg/mL Poly (I:C) for 24 h. Overexpression of ssc-miR-22-3p decreased cytokine expression and promoted cell viability and proliferation. The functional enrichment analysis revealed that ssc-miR-22-3p targets genes enriched in the pathways of negative regulation of inflammatory response and bacterial invasion of epithelial cells. The validity of the binding site of ssc-miR-22-3p to MAPK14 was tested by a dual luciferase reporter gene. Pig milk exosome ssc-miR-22-3p promotes cell viability and proliferation by targeting MAPK14, and it alleviates LPS and Poly (I:C)-induced inflammatory responses in IPEC-J2 cells.

TIPE2 aggravates experimental colitis and disrupts intestinal epithelial barrier integrity by activating JAK2/STAT3/SOCS3 signal pathway

Ulcerative colitis (UC) is a chronic relapsing and progressive inflammatory disease of the colon. TIPE2 is a negative regulator of innate and adaptive immunity that maintains immune homeostasis. We found that TIPE2 was highly expressed in mucosa of mice with colitis. However, the role of TIPE2 in colitis remains unclear. We induced colitis in mice with dextran sulphate sodium (DSS) and treated them with TIPE2, and investigated the inflammatory activity of the colon in vivo by cytokines detection and histopathological analyses. We also measured inflammatory alteration and tight junctions induced by DSS in vitro. The results demonstrated that administration of TIPE2 promoted the severity of colitis in mice and human colon epithelial cells. Furthermore, TIPE2 aggravated intestinal epithelial barrier dysfunction by decreasing the expression of the tight junction proteins Occludin, Claudin-1 and ZO-1. In addition, TIPE2 exacerbated intestinal inflammatory response by inhibiting the expression of SOCS3, remarkably activating JAK2/STAT3 signaling pathway, and increasing the translocation of phosphorylated STAT3 into the nucleus. Silencing of Tipe2 attenuated the DSS-induced activation of JAK2/STAT3, thereby rescuing epithelial inflammatory injury and restoring barrier dysfunction. These results indicate that TIPE2 augments experimental colitis and disrupted the integrity of the intestinal epithelial barrier by activating the JAK2/STAT3/SOCS3 signaling pathway.

Effects of Cannabidiol Ingestion on Thermoregulatory and Inflammatory Responses to Treadmill Exercise in the Heat in Recreationally Active Males.

Exertional heat stress can induce systemic endotoxin exposure and a pro-inflammatory cascade, likely impairing thermoregulation. Cannabidiol (CBD) is protective in pre-clinical models of tissue ischaemia and inflammation. Therefore, this study examined the effects of CBD ingestion on exercise-induced thermoregulatory and inflammatory responses. In a randomised, double-blinded study, thirteen active males (age 25 ± 5 y; peak oxygen uptake [V̇O2peak] 50.4 ± 3.2 mL/kg/min) ingested 298 mg CBD or placebo 105 minutes before 1 h treadmill exercise (60-65% V̇O2peak) in 32 °C and 50% relative humidity. Core temperature, skin temperature, heart rate, subjective outcomes and sweat loss were assessed during/after exercise. Plasma osmolality, plasma volume changes and plasma markers of intestinal damage (I-FABP), monocyte activation (CD14) and inflammatory cytokine responses (IL-6, IL-8 and TNF-α) were assessed at baseline, pre-exercise, 20- and 90-min post-exercise. Core temperature (∆ 1.69 ± 0.48 °C [CBD] and 1.79 ± 0.53 °C [Placebo]) and I-FABP increased during exercise, with no differences between conditions (p > 0.050). Mean (95% CI) CD14 was 1776 (463 to 3090) pg/mL greater 90 min post-exercise in placebo (p = 0.049). Median (interquartile range) peak IL-6 concentration was -0.8 (-1.1, -0.3) pg/mL less in CBD (p = 0.050), whilst the between-conditions difference in IL-6 area under curve was -113 (-172, 27) pg/mL·270 min (p = 0.054). CBD did not affect thermoregulation during exertional heat stress but appeared to elicit minor immunosuppressive effects, reducing CD14 and IL-6 responses, warranting investigation in humans under more severe heat strain and other pro-inflammatory scenarios.

Oleanolic acid improves 5-fluorouracil-induced intestinal damage and inflammation by alleviating intestinal senescence

5-Fluorouracil (5-FU) is used as a standard first-line drug for colorectal cancer malignancy (CRC), but it brings a series of side effects such as severe diarrhea and intestinal damage. Our previous study found that a large number of senescent cells increased while 5-Fu induced intestinal damage, and anti-senescence drugs can alleviate its side effects of inflammatory damage. Oleanolic acid (OA) is a common pentacyclic triterpenoid mainly derived from food fungi and medicinal plants, and studies have shown that it mainly possesses hepatoprotective, enzyme-lowering, anti-inflammatory, and anti-tumor effects. But its role in senescence is still unclear. In the present study, we demonstrated for the first time that OA ameliorated 5-Fu-induced human umbilical vein endothelial cells (HUVECs) and human normal intestinal epithelial cells (NCM460) in a 5-Fu-induced cellular senescence model by decreasing the activity of SA-β-gal-positive cells, and the expression of senescence-associated proteins (p16), senescence-associated genes (p53 and p21), and senescence-associated secretory phenotypes (SASPs: IL-1β, IL-6, IL-8, IFN-γ and TNF-α). Meanwhile, in this study, in a BALB/c mouse model, we demonstrated that 5-FU induced intestinal inflammatory response and injury, which was also found to be closely related to the increase of senescent cells, and that OA treatment was effective in ameliorating these adverse phenomena. Furthermore, our in vivo and in vitro studies showed that OA could alleviate senescence by inhibiting mTOR. In colon cancer cell models, OA also enhanced the ability of 5-FU to kill HCT116 cells and SW480 cells. Overall, this study demonstrates for the first time the potential role of OA in counteracting the side effects of 5-FU chemotherapy, providing a new option for the treatment of colorectal cancer to progressively achieve the goal of high efficacy and low toxicity of chemotherapy.

Intestinal-level anti-inflammatory bioactivities of whole wheat: Rationale, design, and methods of a randomized, controlled, crossover dietary trial in adults with prediabetes

Randomized controlled trials (RCT) demonstrate that whole wheat consumption improves glycemia. However, substantial inter-individual variation is often observed, highlighting that dietary whole grain recommendations may not support the health of all persons. The objective of this report is to describe the rationale and design of a planned RCT aimed at establishing the gut microbiota and metabolome signatures that predict whole wheat-mediated improvements in glucose tolerance in adults with prediabetes. It is hypothesized that a controlled diet containing wheat bread (WHEAT; 160 g/day) compared with refined bread (WHITE) will improve glucose tolerance in a gut microbiota-mediated manner. Biospecimens will be collected before and after each 2-week study arm. Testing for oral glucose tolerance and gastrointestinal permeability will be performed post-intervention. Assessments will include oral glucose tolerance (primary outcome) and secondary outcomes including gut microbiota, targeted and untargeted metabolomics of fecal and plasma samples, intestinal and host inflammatory responses, and intestinal permeability. WHEAT is predicted to alleviate glucose intolerance by shifting microbiota composition to increase short-chain fatty acid-producing bacteria while reducing populations implicated in intestinal inflammation, barrier dysfunction, and systemic endotoxemia. Further, benefits from WHEAT are anticipated to correlate with gut-level and systemic metabolomic responses that can help to explain the expected inter-individual variability in glucose tolerance. Thus, knowledge gained from integrating multi-omic responses associating with glucose tolerance could help to establish a precision nutrition-based framework that can alleviate cardiometabolic risk. This framework could inform novel dietary whole grain recommendations by enhancing our understanding of inter-individual responsiveness to whole grain consumption.

Endoplasmic Reticulum Stress Contributes to Intestinal Injury in Intrauterine Growth Restriction Newborn Piglets.

Intrauterine growth retardation (IUGR) in piglets is associated with a high rate of morbidity and mortality after birth due to gut dysfunction, and the underlying mechanisms remain poorly understood. This study selected six pairs of IUGR newborn male piglets and normal birth weight newborn piglets (Large White × Landrace) to investigate differences in intestinal structure and digestive functions, intestinal ERS and apoptosis, intestinal barrier function, and inflammatory response. The results showed that IUGR significantly reduced the jejunal villi height (p < 0.05) and the ratio of villus-height-to-crypt-depth (p = 0.05) in neonatal piglets. Additionally, the microvilli in the jejunum of IUGR neonatal piglets were shorter than those in normal-weight piglets, and swelling of the mitochondria and expansion of the endoplasmic reticulum were observed. IUGR also significantly reduced serum glucose and lactase levels (p < 0.05) while significantly increasing mRNA levels of jejunal IRE1α, EIF2α, CHOP, Bax, Caspase9, Mucin2, Claudin-1, Occludin, ZO-1, Bcl-2, IL-6, and IFN-γ (p < 0.05), as well as GRP78 protein levels in neonatal piglets (p < 0.05). These findings suggest that IUGR impairs intestinal structure and barrier function in newborn piglets by enhancing intestinal inflammatory responses, activating intestinal ERS and the signaling pathways related to the unfolded protein response, thereby inducing ERS-related apoptosis.

Interplay between fluorine and cadmium on intestinal accumulation, oxidative stress, permeability and inflammatory response in rats

Fluorine (F) and Cadmium (Cd) have given rise to public concern regarding their adverse impacts on the environment and human beings. Yet, the toxic interplay between F and Cd on the intestine is still vague. Aiming to investigate the role of F on Cd-damaged intestine, a total of five groups of 30 SD rats were picked at random to be gavaged for 90 days: Control group (Ultra-pure water), Cd (Cd 1 mg/kg), Cd+LF (Cd 1 mg/kg+F 15 mg/kg), Cd+MF (Cd 1 mg/kg+F 45 mg/kg), and Cd+HF (Cd 1 mg/kg+F 75 mg/kg). It demonstrated that Cd enriched in the intestine and disordered intestinal barrier of rats. Interestingly, two side effects of F were observed resisting to the Cd toxicity. The Cd levels in colon contents were attenuated by 45.45 %, 28.11 %, and 19.54 % by F supplement, respectively. In the Cd+LF group, SOD, GSH-Px, and CAT activities elevated by 0.93, 1.76, and 1.78 times, respectively, and the MDA content reduced 0.67 times; the expressions of NQO1, SOD2, and GSH-Px mRNA markedly enhanced, as well as the Keap1 mRNA significantly decreased. Nevertheless, all indexes above in the Cd+HF group showed the opposite trends. Furthermore, LPS levels decreased by 45.93 % for the Cd+LF group and increased by 12.70 % in that the Cd+HF group. The ZO-1 expression in the Cd+LF group increased, whereas the Cd+HF group's expressions of Claudin-1, Occludin, and ZO-1 were all diminished by 35.46 %, 27.23 %, and 16.32 %, respectively. Moreover, the levels of TNF-α, IL-1β and TLR-4 decreased and IL-10 level promoted, while all showed opposite trends in the Cd+HF group. Collectively, it indicated there is a twofold interplay between F and Cd on intestinal damage and mainly depends on F dosages.

Network Pharmacology Analysis and Retrospective Cohort Study Revealing the Effect of Qingyi Decoction on Intestinal Paralysis in Patients with Severe Acute Pancreatitis.

Intestinal dysfunction plays an important role in the clinical progress and prognosis of severe acute pancreatitis (SAP). Qingyi decoction (QYD) has shown beneficial effects on intestinal function recovery, but the prevention actions of the QYD on intestinal paralysis and its mechanism have not been fully explored. The possible molecular mechanism was unraveled by network pharmacology, including active ingredients and potential target prediction, as well as GO, KEGG, and REATCOME pathway enrichment analyses. The potential interactions between the main active ingredients of the QYD and core genes were explored by molecular docking. A retrospective cohort study on 137 patients with SAP from Tianjin Nankai Hospital was conducted to evaluate the preventive effect of QYD on intestinal paralysis. A total of 110 active ingredients in QYD were screened out, and 37 key targets were predicted by network pharmacology. GO, KEGG, and REATCOME enrichment analyses showed that bioinformatics annotation of the hub genes was mainly involved in intestinal epithelial functions and inflammatory response pathways. The main components of QYD possessed good affinity with IL-6, TNF, CASP3, CXCL8, and CRP by molecular docking. Patients who used QYD plus usual care seemed to have fewer intestinal paralysis rates, lower risk of renal insufficiency, ARDS and blood purification therapy, and shorter hospital and ICU stays. The multivariable regression analyses indicated that the mode of nasogastric and enemas administration of QYD (P = 0.010) and timely intervention with QYD (P = 0.045) were the independent protective factors for intestinal paralysis prevention in patients with SAP. In conclusion, QYD can be used as an effective adjuvant procedure to prevent the occurrence and development of intestinal paralysis in patients with SAP. The mechanisms may be involved in the anti-inflammatory response and maintenance of intestinal epithelial function.

Lactobacillus from fermented bamboo shoots prevents inflammation in DSS-induced colitis mice via modulating gut microbiome and serum metabolites

Fermented bamboo shoots (FBS) is a region-specific food widely consumed in Southwestern China, with Lactobacillus as the predominant fermenting bacteria. However, the probiotic potential of Lactobacillus derived from FBS reminds largely unexplored, especially for diseases with a low prevalence in areas consuming FBS, namely, inflammatory bowel disease. In this study, Lactiplantibacillus pentosus YQ001 and Lentilactobacillus senioris YQ005 were screening by in vitro probiotic tests to further investigate the probiotic-like bioactivity in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse. They exhibited more positive probiotic effects than Lactobacillus rhamnosus GG in preventing intestinal inflammatory response. The results revealed that both strains improved the abundance of deficient intestinal microbiota in UC mice, including Muribaculaceae and Akkermansia. In the serum metabolome, they modulated the DSS-disturbed levels of metabolites, with significant increment of cinnamic acid. Meanwhile, they reduced the expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) inflammatory factors and increased zonula occludens-1 (ZO-1), Occludin, and cathelicidin-related antimicrobial peptide (CRAMP) in the colon. Consequently, these results demonstrated that Lactobacillus spp. isolates derived from FBS showed promising probiotic activity based on the gut microbiome homeostasis modulation, anti-inflammation and intestinal barrier protection in UC mice.

Sirtuin 6 inhibits group 3 innate lymphoid cell function and gut immunity by suppressing IL-22 production.

Group 3 innate lymphoid cells (ILC3s) are enriched in the intestinal mucosa and play important roles in host defense against infection and inflammatory diseases. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)- dependent deacetylase and has been shown to control intestinal epithelial cell differentiation and survival. However, the role of SIRT6 in ILC3s remains unknown. To investigate the role of SIRT6 in gut ILC3s, we generated SIRT6 conditional knockout mice by crossing Rorccre and Sirt6flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection and dextran sodium sulfate-induced colitis models were used to determine the role of SIRT6 in gut defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses. Here we show that SIRT6 inhibits IL-22 expression in intestinal ILC3s in a cell-intrinsic manner. Deletion of SIRT6 in ILC3s does not affect the cell numbers of total ILC3s and subsets, but results in increased IL-22 production. Furthermore, ablation of SIRT6 in ILC3s protects mice against Citrobacter rodentium infection and dextran sodium sulfate-induced colitis. Our results suggest that SIRT6 may play a role in ILC3 function by regulating gut immune responses against bacterial infection and inflammation. Our finding provided insight into the relation of epigenetic regulators with IL-22 production and supplied a new perspective for a potential strategy against inflammatory bowel disease.

Transfer from ciliate to zebrafish: Unveiling mechanisms and combined effects of microplastics and heavy metals

The impacts and toxicological mechanisms of microplastics (MPs) or heavy metals on aquatic ecosystems have been the subject of extensive research and initial understanding. However, the combined toxicity of co-pollutants on organisms and cumulative toxic effects along the food chain are still underexplored. In this study, the ciliate protozoan Paramecium caudatum and zebrafish Danio rerio were used to represent the microbial loop and the higher trophic level, respectively, to illustrate the progressive exposure of MPs and cadmium (Cd2+). The findings indicate that MPs (ca. 1 ×105 items/L) containing with Cd2+ (below 0.1 µg/L) could permeate the bodies of zebrafish through trophic levels after primary ingestion by ciliates. This could cause adverse effects on zebrafish, including alterations in bioindicators (total sugar, triglycerides, lactate, and glycogen) associated with metabolism, delayed hepatic development, disruption of intestinal microbiota, DNA damage, inflammatory responses, and abnormal cellular apoptosis. In addition, the potential risks associated with the transfer of composite pollutants through the microbial loop into traditional food chain were examined, offering novel insights on the evaluation of the ecological risks associated with MPs. As observed, understanding the bioaccumulation and toxic effects of combined pollutants in zebrafish holds crucial implications for food safety and human health.

Polygonum hydropiper Compound Extract Inhibits Clostridium perfringens-Induced Intestinal Inflammatory Response and Injury in Broiler Chickens by Modulating NLRP3 Inflammasome Signaling.

Necrotic enteritis (NE) is a critical disease affecting broiler health, with Clostridium perfringens as its primary pathogen. Polygonum hydropiper compound extract (PHCE), formulated based on traditional Chinese veterinary principles, contains primarily flavonoids with antibacterial, anti-inflammatory, and antioxidant properties. However, PHCE's efficacy against Clostridium perfringens-induced NE and its underlying mechanism remain unclear. This study employed network pharmacology and molecular docking to predict PHCE's potential mechanisms in treating NE, followed by determining its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Clostridium perfringens (C. perf). Subsequently, the effects of various PHCE doses on intestinal damage, antioxidant capacity, and inflammatory factors in C. perf-infected broilers were assessed. Network pharmacology and molecular docking suggested that PHCE's therapeutic mechanism for NE involves the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome signaling pathway, with flavonoids such as quercetin, kaempferol, and isorhamnetin as key active components. PHCE exhibited an MIC of 3.13 mg/mL and an MBC of 12.5 mg/mL against C. perf. High PHCE doses effectively reduced intestinal damage scores in both the jejunum and ileum, accompanied by attenuated intestinal pathological changes. Additionally, the high dose significantly increased superoxide dismutase (SOD) levels while decreasing malondialdehyde (MDA), hydrogen peroxide (H2O2), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) in the jejunum and ileum (p < 0.01 or p < 0.05). PHCE also modulated the expression of caspase-1, IL-1β, gasdermin D (GSDMD), and NLRP3 mRNA, key components of the NLRP3 inflammasome signaling pathway, in both intestinal segments. These findings collectively indicate that PHCE protects against C. perf-induced oxidative stress and inflammatory damage in NE. By enhancing antioxidant capacity, PHCE likely reduces oxidative stress and inflammatory responses, subsequently modulating NLRP3 inflammasome signaling pathway key factor expression. Overall, this research provides valuable insights into the protective mechanism of the herbal compound PHCE and its potential benefits for avian health.

Vitamin E and GPX4 cooperatively protect treg cells from ferroptosis and alleviate intestinal inflammatory damage in necrotizing enterocolitis

BackgroundThe notable decline in the number of Tregs within Necrotizing enterocolitis (NEC) intestinal tissues，contribute to excessive inflammation and necrosis, yet the precise underlying factors remain enigmatic. Ferroptosis, a novel cell death stemming from a disrupted lipid redox metabolism, is the focus of this investigation. Specifically, this study delves into the ferroptosis of Treg cells in the context of NEC and observes the protective effects exerted by vitamin E intervention, which aims to mitigate ferroptosis of Treg cells. MethodsTo investigate the reduction of Treg cells in NEC intestine, we analyzed its association with ferroptosis from multiple angles. We constructed a mouse with a specific knockout of Gpx4 in Treg cells, aiming to examine the impact of Treg cell ferroptosis on NEC intestinal injury and localized inflammation. Ultimately, we employed vitamin E treatment to mitigate ferroptosis in NEC intestine's Treg cells, monitoring the subsequent amelioration in intestinal inflammatory damage. ResultsThe diminution of Treg cells in NEC is attributed to ferroptosis stemming from diminished GPX4 expression. Gpx4-deficient Treg cells exhibit impaired immunosuppressive function and are susceptible to ferroptosis. This ferroptosis of Treg cells exacerbates intestinal damage and inflammatory response in NEC. Notably, Vitamin E can inhibit the ferroptosis of Treg cells, subsequently alleviating intestinal damage and inflammation in NEC. Additionally, Vitamin E bolsters the anti-lipid peroxidation capability of Treg cells by upregulating the expression of GPX4. ConclusionIn the context of NEC, the ferroptosis of Treg cells represents a significant factor contributing to intestinal tissue damage and an exaggerated inflammatory response. GPX4 is pivotal for the viability and functionality of Treg cells. Vitamin E exhibits the capability to mitigate the ferroptosis of Treg cells, thereby enhancing their number and function, which plays a crucial role in mitigating intestinal tissue damage and inflammatory response in NEC.

Anti-Inflammatory Effects of miR-369-3p via PDE4B in Intestinal Inflammatory Response.

Cyclic nucleotide phosphodiesterases (PDEs) consist of a family of enzymes expressed in several types of cells, including inflammatory cells, that play a pivotal role in inflammation. Several studies have demonstrated that the inhibition of PDE4 results in a reduced inflammatory response via PKA and CREB signaling. Hence, PDE4 suppression improves the inflammatory feedback typical of several diseases, such as inflammatory bowel disease (IBD). In our previous studies, we have demonstrated that miR-369-3p regulates inflammatory responses, modulating different aspects of the inflammatory process. The aim of this study was to demonstrate an additional anti-inflammatory effect of miR-369-3p targeting PDE4B, one of the widely expressed isoforms in immune cells. We found that miR-369-3p was able to reduce the expression of PDE4B, elevating the intracellular levels of cAMP. This accumulation increased the expression of PKA and pCREB, mitigating the release of pro-inflammatory cytokines and promoting the release of anti-inflammatory cytokines. To prove that PDE4B is a good therapeutic target in IBD, we also demonstrate that the expression of PDE4B was increased in UC patients compared to healthy controls, affecting the immune infiltrate. PDE4B is considered an important player in inflammatory progression; hence, our results show the ability of miR-369-3p to ameliorate inflammation by targeting PDE4B, supporting its future application as a new therapeutic approach in IBD.

Impact of Coffee Consumption on Subjective Perception and Inflammatory Markers in Patients with Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic conditions marked by persistent inflammation, impacting patients' quality of life. This study assessed differences in coffee consumption between CD and UC patients and its potential effects on the subjective perception and objective changes in inflammation markers in these two categories of patients. Using questionnaires, coffee consumption patterns, and perceived symptom effects were evaluated. Biological samples were collected to measure the following inflammatory markers: leukocytes, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fecal calprotectin (FC). Among 148 patients, 60% reported regular coffee consumption, with no significant difference between CD and UC patients. While 45.93% perceived no impact on symptoms, 48% of those reporting exacerbation continued their regular coffee consumption. FC values were significantly lower in coffee consumers than in non-consumers (p < 0.05), particularly in those consuming natural coffee (p < 0.001), and the case was observed for UC patients (p < 0.05). No significant differences were observed in other inflammatory markers, regardless of coffee type, frequency, or milk addition. This study highlights the commonality of coffee consumption among IBD patients and the association of lower FC levels with coffee consumption, especially in UC patients, suggesting that coffee may influence intestinal inflammatory responses.

Roseburia intestinalis-derived extracellular vesicles ameliorate colitis by modulating intestinal barrier, microbiome, and inflammatory responses.

Inflammatory bowel disease (IBD) is a chronic disorder characterized by recurrent gastrointestinal inflammation, lacking a precise aetiology and definitive cure. The gut microbiome is vital in preventing and treating IBD due to its various physiological functions. In the interplay between the gut microbiome and human health, extracellular vesicles secreted by gut bacteria (BEVs) are key mediators. Herein, we explore the role of Roseburia intestinalis (R)-derived EVs (R-EVs) as potent anti-inflammatory mediators in treating dextran sulfate sodium-induced colitis. R was selected as an optimal BEV producer for IBD treatment through ANCOM analysis. R-EVs with a 76nm diameter were isolated from R using a tangential flow filtration system. Orally administered R-EVs effectively accumulated in inflamed colonic tissues and increased the abundance of Bifidobacterium on microbial changes, inhibiting colonic inflammation and prompting intestinal recovery. Due to the presence of Ile-Pro-Ile in the vesicular structure, R-EVs reduced the DPP4 activity in inflamed colonic tissue and increased the active GLP-1, thereby downregulating the NFκB and STAT3 via the PI3K pathway. Our results shed light on the impact of BEVs on intestinal recovery and gut microbiome alteration in treating IBD.

Parthanatos initiated by ROS-induced DNA damage is involved in intestinal epithelial injury during necrotizing enterocolitis

Necrotizing enterocolitis (NEC) involves intestinal epithelial damage and inflammatory response and is associated with high morbidity and mortality in infants. To improve therapeutic prospects, elucidating underlying molecular mechanisms of intestinal epithelial damage during NEC is of the essence. Poly (ADP-ribose) polymerase 1 (PARP1)-dependent parthanatos is a programmed inflammatory cell death. In the present study, the presence of parthanatos-associated proteins PARP1 and poly (ADP-ribose) (PAR), along with high expression of DNA damage-associated biomarkers, 8-hydroxy-2’-deoxyguanosine (8-OHdG) and phosphorylation of histone H2AX (γH2AX), were discovered in the intestinal tissues of NEC infants. Additionally, the upregulated expression of PARP1 and PAR in NEC intestinal tissues correlated distinctly with clinical indices indicative of NEC incidence and severity. Furthermore, we demonstrated that inhibiting the expression of parthanatos-associated proteins, by either pharmacological blockage using 3-aminobenzamide (3-AB), an inhibitor of PARP1, or genetic knockout using Parp1-deficient mice, resulted in substantial improvements in both histopathological severity scores associated with intestinal injury and inflammatory reactions. Moreover, in an in vitro NEC model, reactive oxygen species (ROS)-induced DNA damage promoted the formation of PAR and nuclear translocation of apoptosis-inducing factor (AIF), thus activating PARP1-dependent parthanatos in Caco-2 cells and human intestinal organoids. Our work verifies a previously unexplored role for parthanatos in intestinal epithelial damage during NEC and suggests that inhibition of parthanatos may serve as a potential therapeutic strategy for intervention of NEC.