Immunoregulatory Effects Research Articles

Relevance of mouse and human IBD patients-derived colon organoids to investigate intestinal macrophage differentiation.

The gastrointestinal tract is a remarkable example of complex biology, with a constant dialogue between the intestinal epithelium, in close contact with the microbiota, and the immune cells that protect the gut from infection. Organoids have revolutionized our approach to modelling the intestinal cellular compartment and have opened new avenues for unravelling the mechanisms involved in intestinal homeostasis and chronic pathogenesis such as inflammatory bowel disease. To date, few models have been established to explore the role of the colon, which is however the main site of inflammation in ulcerative colitis (UC). Here, we used conditioned media produced by colon organoids (OCM) from mice or human (control and UC patients) to investigate the relationship between macrophages and the colon epithelium. We addressed transcriptomic profiles of OCM-stimulated bone marrow-derived macrophages and found that these cells exhibited a unique anti-inflammatory signature distinct from that of conventional in vitro IL-4/IL-13 M2 differentiated macrophages. In addition, OCM induced a clear CD5 antigen-like-mediated immunoregulatory effect characterized by a significant reduction in LPS-induced iNOS expression. In line, OCM from human colons inhibited LPS-dependent inflammatory cytokine expression in human monocytes-derived macrophages. Interestingly, the inflammatory marker CD68 was reduced by OCM from control patients but not from UC patients, suggesting epithelial dysfunction in UC patients. Our results report new regulatory mechanisms in the colon and highlight the importance of developing new in vitro models to better characterize the relationship between the intestinal epithelium and immune mucosal cells.

Does Systematic Use of Small Doses of Vitamin D Have Anti-Inflammatory Effects and Effectively Correct Deficiency Among Healthy Adults?

Calcitriol, beyond its well-established role in calcium and phosphate homeostasis, contributes to immunological processes. No known vitamin D dosage regimen effectively corrects the deficiency while accounting for immunoregulatory effects. Therefore, the purpose of this assessment was to determine whether regular administration of low doses of vitamin D might correct deficiency and have immunoregulatory effects. A total of 35 healthy volunteers were asked to supplement with vitamin D daily at a dosage of 500 or 1000 IU, depending on the degree of deficiency, for 12 months. At the beginning of the study and after the end of the supplementation period, concentrations of 25(OH)D; PTH; total calcium; inorganic phosphorus; and the inflammatory cytokines IL-17, IL-10, TGF-β, and IFN-γ were determined in all participants. Correction of vitamin D deficiency was achieved with accompanying decreases in PTH and pro-inflammatory cytokine concentrations, while the concentration of anti-inflammatory cytokines remained stable. Therefore, regular vitamin D supplementation, even in small doses, effectively corrected the deficiency and had immunomodulatory effects.

An injectable multi-functional composite bioactive hydrogel for bone regeneration via immunoregulatory and osteogenesis effects

Bone defects represent a prevalent and significant challenge in clinical practice. Given the inflammatory microenvironment at injury sites and the requirement for endogenous cell and tissue infiltration, there is an urgent need for an ideal biomaterial that can modulate inflammation and promote bone regeneration. We developed an innovative injectable hydrogel (CH@PUE&MSN) designed for immunomodulation and bone regeneration through in situ self-assembly, incorporating puerarin and chitosan with mesoporous silica nanoparticles. In vitro experiments demonstrated that this multifunctional injectable hydrogel promotes tissue cell regeneration, reduces inflammation, inhibits osteoclast formation, induces the migration and differentiation of bone marrow mesenchymal stem cells, and facilitates bone regeneration. Furthermore, we conducted an extensive in vivo evaluation using a bone defect model, employing advanced imaging and histological analyses. Our findings indicate that this multifunctional injectable hydrogel is a promising bioactive material for bone regeneration and presents a novel strategy for the clinical management of bone defects.

Immunoregulatory and antiviral effect mediated by TLR7 and BMAP28 interaction in bovine alphaherpesvirus-infected respiratory primary cultures.

Varicellovirus bovinealpha 1 and 5 (formerly bovine alphaherpesvirus type 1 and 5, BoAHV-1 and BoAHV-5) are closely related and can be isolated from similar clinical conditions, including respiratory and nervous diseases, genital infections and abortion. Pathogens' activation of toll-like receptors (TLRs) induces the expression of proinflammatory cytokines and antimicrobial peptides such as cathelicidins. Cathelicidins are presumed to act as endogenous ligands of TLRs, stimulating, in turn, their activation. Cattle's innate immune responses mediated by TLRs and cathelicidins remain undefined. This work aimed to study the interaction mechanisms between TLR7 and a bovine cathelicidin (bovine myeloid antimicrobial peptide (BMAP)28 and their influence on the replication of BoAHV-1 and BoAHV-5. It was shown that in vitro infection by BoAHV-1 and BoAHV-5 induces the innate immune responses associated with TLR7 and BMAP28 in primary cultured bovine fetal lung cells. Pretreatment with TLR7 agonist (imiquimod) or an endogenous cathelicidin inductor (sodium butyrate) enhanced the innate immune response to BoAHV mediated by TLR7 signalling, BMAP28, TNFα, IFNβ and IFNγ. It exerted an antiviral effect, decreasing BoAHV replication. Inhibition of endosomal TLRs and downstream signalling molecules MAPK, NF-κβ, IKK-2, and JNK II counteracted these antiviral effects. Therefore, BMAP28 shows novel roles in modulating the immune response induced by TLR7 activation through signalling pathways involving kinases and NF-κβ. Enhancing TLR7 and endogenous cathelicidin expression could be a complementary tool for the prevention and/or control of BoAHV infections.

ZnCur nanoparticle-enhanced multifunctional hydrogel platform: Synergistic antibacterial and immunoregulatory effects for infected diabetic wound healing

ZnCur nanoparticle-enhanced multifunctional hydrogel platform: Synergistic antibacterial and immunoregulatory effects for infected diabetic wound healing

Immunomodulatory Acidic Polysaccharide from Jujube Fruit (Zizyphus jujuba Mill.): Insight into Their Chemical Characteristics and Modes of Action.

Jujube (Zizyphus jujuba Mill.) has been consumed globally as a fruit and a nutraceutical food for millennia. This study presents the isolation and purification of a novel water-soluble polysaccharide fraction, ZJMP-2, from Z. jujuba Mill. ZJMP-2 underwent characterization through Fourier transform infrared (FT-IR), high-performance gel permeation chromatography-laser light scattering (HPGPC-LLS), gas chromatography-mass spectrometry (GC-MS), scanning electron microscopy (SEM), atomic force microscopy (AFM), and nuclear magnetic resonance (NMR) analyses. It consists of glucose, galactose, arabinose, rhamnose, and galacturonic acid in molar ratios of 0.41:0.08:0.11:0.05:0.33 and boasts an average molecular weight of approximately 57.8 kDa. Its backbone features the structure →2)-α-l-Rhap-(1 → 4)-α-d-GalpA-(1 → 4)-α-d-GalpA-6OMe-(1 → 4)-α-d-GalpA-(1 → 3, 4)-α-d-Glcp-(1 →, with branching at →5)-α-l-Araf-(1 →, →4)-β-d-Galp-(1 →, and →4)-α-d-Glcp-(1→ at position O-3 of →3, 4)-α-d-Glcp-(1 →. These structural variations contribute to the pronounced immunoregulatory effects of ZJMP-2. Specifically, ZJMP-2 significantly elevated the expression levels of TLR4, NF-κB, and TRAF6 proteins, enhancing RAW264.7 cell activity, index of splenic lymphocytes, and the production of cytokines and NO, thereby activating macrophages and promoting lymphocyte proliferation. In vivo studies demonstrated that ZJMP-2 promoted the heart, spleen, and bone marrow indices, peripheral blood and spleen cell counts, and the number of heart and bone marrow cells in mice. These findings demonstrated that ZJMP-2 has potential as an immunomodulator and provides valuable insights for developing natural immunomodulators in the pharmaceutical industry.

Isolation, Structure, and Biological Activities of Exopolysaccharides from Actinomycetes: A Review.

In recent years, exopolysaccharides (EPSs) from actinomycetes have become a significant focus of research due to their diverse biological activities, including antitumor, antiviral, and immunoregulatory effects. This article reviews recent advancements in the study of EPSs from actinomycetes, summarizing findings from existing literature on extraction methods, structural characteristics, and biological activities. Various extraction methods can impact the purity and quality of EPSs obtained from actinomycetes. In addition, EPSs produced by different species of actinomycetes exhibit diverse structures, leading to variations in their biological activities. Future research should focus on optimizing current extraction methods or developing new techniques, exploring the relationship between structural characteristics and biological activities of EPSs, and elucidating their molecular mechanisms of action. Such efforts are essential for the comprehensive study and potential applications of EPSs from actinomycetes.

Structure Elucidation and Immunostimulatory Activity Evaluation of a Galactoglucan from Alpinia officinarum Hance.

Alpinia officinarum Hance has a medicinal history of thousands of years in treating cough, diabetes, and gastrointestinal system diseases, and it is also a medicine food homology (MFH) plant in China. To evaluate the pharmacological activities of polysaccharides from the rhizomes of A. officinarum, polysaccharides were initially obtained by hot-water extraction and the ethanol precipitation method. A homogenous polysaccharide designated as AOP-w was isolated by a DE-52 column. The proposed structure was elucidated and the immunoregulatory effects on RAW 264.7 macrophage cells were evaluated. The results showed that AOP-w had a molecular weight of 5.26 kDa, and mainly consisted of galactose and glucose (molar ratio of 0.12:0.88). Its backbone comprised α-(1→4)-Glcp, α-(1→4,6)-Glcp and β-(1→3,4)-Galp residues, terminated by α-(1→6)-Glcp and T-Glcp residues. AOP-w was nontoxic to RAW 264.7 cells, but demonstrated promotion in cell proliferation within a 100 μg/mL concentration. The immunostimulatory effects of AOP-w were confirmed by the elevated NO production of AOP-w-treated cells. Moreover, the RNAseq was conducted and the results showed that AOP-w may activate the TNF and NF-κB signaling pathways by binding to Toll-like receptors, thereby affecting the immune modulatory activity of RAW264.7 cells. These results suggest a high potential of AOP-w from A. officinarum for immunotherapeutic applications.

Supplemental effects of Haematococcus pluvialis in a low-fish meal diet for Litopenaeus vannamei at varying temperatures: growth performance, innate immunity and gut bacterial community

This study examined the effects of Haematococcus pluvialis on the growth performance, innate immunity, and gut microbiota of Litopenaeus vannamei under different water temperature conditions. Feeding regimens included a 20% fishmeal diet (control), a low-fish meal (LFM) diet with 10% fishmeal and an LFM diet supplemented with 0.03% H. pluvialis. These diets were administered to six groups of L. vannamei at normal (30°C) (NT) and low (20°C) (LT) temperatures (NT_C, NT_LFM, NT_LFM_HP, LT_C, LT_LFM, and LT_LFM_HP) over 8 weeks. The weight gain rate of L. vannamei in group NT_LFM_HP was significantly higher compared to group NT_LFM. Astaxanthin levels and body pigmentation intensity in L. vannamei were significantly increased in the NT_LFM_HP and LT_LFM_HP groups. Moreover, hepatopancreatic antioxidant capacities, such as superoxide dismutase (SOD) activity and total antioxidant capacity (T-AOC), were lower in normal-temperature groups compared to the low-temperature groups. Nevertheless, antioxidant capacity was significantly higher in both the NT_LFM_HP and LT_LFM_HP groups compared to the control group. Meanwhile, the expression levels of antioxidants were significantly higher at lower temperatures compared to higher temperatures, with the NT_LFM_HP and LT_LFM_HP groups exhibiting the highest expression levels. Additionally, the mRNA levels of genes associated with the Toll and IMD pathways indicated immunoregulatory effects in the organism. The expression levels of immune genes were significantly higher at lower temperatures, especially in the NT_LFM_HP and LT_LFM_HP groups compared to the control groups. Notably, significant differences in gut microbial composition were observed in the NT_LFM_HP group compared to other groups, with variations influenced by temperature and fishmeal content. Specifically, Vibrionaceae abundance was significantly lower in the LT_LFM_HP group compared to the control group. The results also revealed that the abundance of Actinomarinales was significantly higher in low-temperature groups, with the LT_LFM_HP group displaying the greatest increase. Overall, these findings suggest that L. vannamei may be susceptible to reduced fishmeal levels, potentially impacting growth and immune function. Furthermore, H. pluvialis supplementation may assist L. vannamei in acclimating to prolonged low-temperature conditions.

A Comprehensive Review on Immunoregulatory Effects of Phytochemicals.

An efficient immune system in the host body plays a crucial role in the preservation of normal biological and immune reactions and processes, as well as the intrinsic environment. This is because the immune system is responsible for fighting off foreign invaders. A healthy immune system strengthens the body's defense against infections, illnesses, and other unwelcome pathogens, thereby reducing the risk of allergic reactions and autoimmune diseases. Innate immune cells and acquired immune system components interact in a corrective fashion to produce optimal immune responses. In recent years, researchers have begun to focus on the immune system as a potential primary target of toxicity from chemical, pharmacological, and environmental exposure. Sex, age, stress, malnutrition, alcohol, genetic variability, lifestyles, environmental pollutants, and chemotherapy are just a few of the many elements that might modify the host's immunological responses. The production, amplification, attenuation, or suppression of immunological responses are all examples of immunomodulation. There are a wide variety of synthetic and traditional treatments available, and many of them cause major side effects and develop pathogenic resistance very quickly. Natural substances called phytochemicals play a crucial role in regulating the body's immune system. Risk factors for immune response changes are discussed, as is the immunomodulatory action of phytochemicals like glycosides, alkaloids, phenolic acids, flavonoids, saponins, tannins, sterols, and steroids.

MSCs-derived ECM functionalized hydrogel regulates macrophage reprogramming for osteoarthritis treatment by improving mitochondrial function and energy metabolism

Osteoarthritis (OA) is a degenerative disease that affects the entire joint, with synovial inflammation being a major pathological feature. Macrophages, as the most abundant immune cells in the synovium, have an M1/M2 imbalance that is closely related to the occurrence and development of OA. Mesenchymal stem cells (MSCs) have been shown to effectively suppress inflammation in the treatment of OA, but they still pose issues such as immune rejection and tumorigenicity. The extracellular matrix (ECM), as a major mediator of MSCs' immunoregulatory effects, offers a cell-free therapy to circumvent these risks. In this study, we developed an ECM-functionalized hydrogel by combining MSC-derived ECM with gelatin methacryloyl (GelMA). To enhance the immunomodulatory potential of MSCs, we pre-stimulated MSCs with the inflammatory factor interleukin-6 (IL-6) present in OA. In vitro results showed that the ECM-functionalized hydrogel promoted M2 macrophage polarization and inhibited the expression of various inflammatory genes, strongly indicating the hydrogel's powerful immunoregulatory capabilities. In an in vivo rat OA model, the ECM-functionalized hydrogel significantly reduced synovial inflammation and cartilage matrix degradation, alleviating the progression of OA. Furthermore, we utilized proteomics and transcriptomics analysis to reveal that the hydrogel accomplished macrophage metabolic reprogramming by regulating mitochondrial function and energy metabolism, thereby reducing inflammation. These findings suggest that the ECM-functionalized hydrogel is a promising biomaterial-based strategy for treating OA by targeting key pathological mechanisms.

Protective Role of Selenium-Binding Protein 1 (SELENBP1) in Patients with Ulcerative Colitis.

The expression of selenium-binding protein 1 (SELENBP1), a molecule responsible for the absorption of selenium in the colon, is crucial for its immunoregulatory effect, but this phenomenon has not been studied in patients with UC. The present study aimed to determine the clinical outcome of SELENBP1 expression in colonic tissue from patients with UC. The relative mRNA expression of SELENBP1 was analyzed in 34 patients with UC and 20 controls. Statistical analyses were performed with SPSS 19. SELENBP1 gene expression was significantly lower in patients with active UC than those with UC in remission (p = 0.003) and within the controls (p = 0.04). Overexpression of the SELENBP1 gene was associated with a more benign clinical course characterized by initial activity and more than two years of prolonged remission (OR 23.7, p = 0.003) and an intermittent clinical course (OR 47.5, p = 0.001), mild histological activity (OR 0.11; 95% CI: 1.00-1.41, p = 0.05) and severe histological activity (OR 0.08, 95% CI: 0.008-0.866, p = 0.02). SELENBP1-positive cells were found mainly in the submucosa's inflammatory infiltrate and muscular and adventitia's internal layers from patients with active UC compared to those in the control group (p ≤ 0.001). The upregulation of SELENBP1 was associated with a benign clinical course of UC. This is the first report suggesting the immunoregulatory role of SELENBP1 in patients with UC.

Immunostimulatory activity of sea buckthorn polysaccharides via TLR2/4-mediated MAPK and NF-κB signaling pathways in vitro and in vivo

SP0.1–1, derived from Sea buckthorn (Hippophae rhamnoides L.), has been discovered to exhibit unique antioxidant activity. In this study, we investigated the immunomodulatory activity and mechanisms of SP0.1–1 on macrophage RAW 264.7 cells in vitro and immunosuppressive mice induced by cyclophosphamide in vivo. The results indicated SP0.1–1 strengthened the immune functions via promoting the proliferation of RAW264.7 cells and phagocytic activity, along with stimulating the release of NO, ROS and cytokines including TNF-α, IL-6, IL-1β and IFN-γ. Western blot and molecular docking analysis demonstrated that SP0.1–1 attached to the prime receptors TLR2 and TLR4 in RAW264.7 cells, and triggered the activation of MyD88-mediated MAPK and NF-κB signaling pathways, thereby exerting the immune response in RAW264.7 cells. However, the intervention of specific inhibitors against TLR2, TLR4, JNK, ERK, p38 and NF-κB blocked the TLR-mediated MAPK and NF-κB signaling pathways and downregulated the levels of NO and the aforementioned cytokines, thus suppressing the activation of macrophages. Therefore, it can be speculated that SP0.1–1 activated the macrophages principally via the TLR2/4-MyD88-mediated MAPK and NF-κB signaling pathways. Additionally, SP0.1–1 could protect against the cyclophosphamide-induced immunosuppression in mice, manifested by the improvement of body weight, immune organ indices, phagocytic index, and the relievement of spleen damage, along with the enhancement of cytokines TNF-α, IL-6, IFN-γ and immunoglobulin IgG and IgM. These findings will shed light on the molecular mechanism of SP0.1–1 on the immunoregulatory effect, and lay the foundation for exploiting a potential immunostimulatory agent of SP0.1–1.

Cefiderocol has immunoregulative effects in LPS-induced vitro experimental model via inhibiting inflammation and ferroptosis

BackgroundCefiderocol is a new catecholamine-containing siderophore cephalosporin. It, however, remains unclear how cefiderocol modulates the immune response of the host. ObjectivesThis study elucidated whether cefiderocol exerts immunoprotective effects in an in vitro experimental model induced with lipopolysaccharide (LPS). MethodsMouse macrophage RAW 264.7 cells were exposed to LPS (100 ng/mL) or LPS + cefiderocol (40 mg/L) to assess the immunomodulatory effect of cefiderocol in vitro. ELISA was performed on cell culture supernatants to estimate cytokine levels. Ferroptosis level was also quantified by detecting intracellular reactive oxygen species (ROS) and iron levels through flow cytometry analysis. Malondialdehyde (MDA) and glutathione (GSH) levels were estimated by ELISA. We conducted western blotting assay for evaluating key ferroptosis pathway proteins. ResultsCefiderocol alleviated LPS-induced inflammation by reducing IL-6, TNF-α, and IL-1β production levels and enhancing the IL-10 production level. Further analysis to determine the underlying mechanism revealed that cefiderocol inhibited ferroptosis; this was confirmed by reduced ROS, MDA, and Fe2+ ion levels; increased GSH levels; upregulated expression of solute carrier family 7 member 11, glutathione peroxidase 4, nuclear factor erythroid 2-related factor 2, and ferroptosis suppressor protein 1; and downregulated expression of acyl-CoA synthetase long-chain family member 4. ConclusionsCefiderocol may play a key role in reducing inflammation by decreasing inflammatory cytokine release and suppressing ferroptosis.

Comparative study on physicochemical characterization and immunomodulatory activities of neutral and acidic Lycium barbarum polysaccharides

Lycium barbarum polysaccharides (LBPs) are recognized as key bioactive constituents of Lycium barbarum with diverse biological activities. However, current research on LBPs is largely confined to crude extracts, offering limited insight into the structural properties underlying their biological effects. In this study, we separated crude LBP into acidic LBP (ALBP) and neutral LBP (NLBP), which exhibited distinct physicochemical properties. ALBP, consisting of 76.18 % galacturonic acid (GalA), demonstrated crystallinity, thermal stability and gelatinous characteristics. In contrast, NLBP, with only 3.16 % GalA, displayed a more porous structure and superior fluidity. Furthermore, functional analysis revealed that NLBP exhibited enhanced immunoregulatory effects by activating dendritic cells and repolarizing macrophages. In a B16F10 melanoma-bearing C57BL/6 J mice model, NLBP significantly inhibited tumor growth with an inhibition rate of 66.7 % through macrophage repolarization. The findings highlight the distinct biological effects of NLBP and ALBP, providing a theoretical foundation for the refined utilization of LBP.

Setting "cold" tumors on fire: Cancer therapy with live tumor-targeting bacteria.

Immunotherapy with checkpoint blockade has shown remarkable efficacy in many patients with a variety of different types of cancer. However, the majority of patients with cancer have yet to benefit from this revolutionary therapy. Studies have shown that checkpoint blockade works best against immune-inflamed tumors characterized by the presence of tumor-infiltrating lymphocytes (TILs). In this review, we summarize studies using live tumor-targeting bacteria to treat cancer and describe various strategies to engineer the tumor-targeting bacteria for maximized immunoregulatory effects. We propose that tumor-localized infections by such engineered bacteria can create an immune microenvironment in favor of a more effective antitumor immunity with or without other therapies, such as immune checkpoint blockade (ICB). Finally, we will briefly outline some exemplary oncology clinical trials involving ICB plus live therapeutic bacteria, with a focus on their ability to modulate antitumor immune responses.

Transcriptomic and proteomic analysis of the jejunum revealed the effects and mechanism of protocatechuic acid on alleviating Salmonella typhimurium infection in chickens

Salmonella typhimurium is a common cause of gastroenteritis, which infects animals and human. Protocatechuic acid has anti-inflammatory, immunoregulatory and anti-pathogenic effects, and is expected to be an effective choice for alleviating Salmonella infection and intestinal injury. A total of 180 1-d female, yellow-feathered chickens were randomly allocated into 3 treatment groups, the controls (Ctr), the Salmonella-challenged treatment (Sal) and the protocatechuic acid treatment (PA). Birds were fed a basal diet for 18 d, with birds in PA supplemented with 600 mg/kg protocatechuic acid. On 14 and 16 d, birds in Sal and PA were orally challenged with 109 CFU S. typhimurium, while birds in Ctr received an equal amount of PBS. The results showed that protocatechuic acid improved growth performance and jejunal structure in Salmonella-infected chickens (P < 0.05). In addition, protocatechuic acid suppressed (P < 0.05) the secretion of plasmal IgG, IL-1β, and IFN-β, and jejunal mucosal IL-6, IFN-β, complement protein 3 and 4. Mechanistically, the transcriptomic results showed that dietary protocatechuic acid inhibited acute inflammatory response and activated the signaling pathways of cytokine-cytokine receptor interaction, complement and coagulation cascades. Results of proteomic showed that protocatechuic acid inhibited the positive regulation of dendritic cell cytokine production and I-κB kinase/NF-κB signaling, as well as cytokine-cytokine receptor interaction and MAPK signaling pathways, and activated the mTOR signaling pathways. These results were critical to both suppressing the secretion of inflammatory cytokines and restoring the intestinal function. Dietary protocatechuic acid (600 mg/kg) was effective to alleviate Salmonella infection, as it suppressed the levels of cytokines and complement protein by inhibiting MAPK, I-κB kinase/NF-κB and enhancing the mTOR signaling pathway, thus offset the decline in weight loss and intestinal injury caused by infection.

Lacticaseibacillus rhamnosus LRa05 alleviates cyclophosphamide-induced immunosuppression and intestinal microbiota disorder in mice.

Probiotics play a crucial role in regulating the gut microbiota and enhancing immune response. Oral administration of probiotics modulates intestinal microbiota composition and immune homeostasis. In this study, we investigated the immunoregulatory effect of Lacticaseibacillus rhamnosus LRa05 on cyclophosphamide (CTX)-induced immunosuppressive mice. The results showed that oral administration of LRa05 reduced weight loss, restored immune organ indices, and maintained the structural integrity of the intestinal tissue in CTX-treated mice. Moreover, oral administration of LRa05 exhibited immune-modulating properties by promoting the secretion of cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-10, and secretory immunoglobulin A) in serum. Moreover, the analysis of 16S rRNA amplicon sequencing revealed that LRa05 increased gut microbiota diversity and regulated its composition. In detail, LRa05 intervention restored the Firmicutes/Bacteroidota ratio and significantly increased the relative abundance of Lachnospiraceae_NK4A136_group, Oscillibacter, Alloprevotella, Parasutterella, and Roseburia in immunocompromised mice. Conversely, the abundances of Helicobacter, Bacteroides, and unclassified_Desulfovibrionaceae were significantly decreased after administration of LRa05. Based on these findings, orally administered LRa05 could effectively maintain intestinal microbiota homeostasis and regulate immunity, suggesting the potential of L. rhamnosus LRa05 as a candidate probiotic strain in the application of dietary supplement. PRACTICAL APPLICATION: Supplement with L. rhamnosus LRa05 can improve immunity, regulate gut microbiota and promote body health.

Intermittent fasting reduces inflammation and joint damage in a murine model of rheumatoid arthritis: insights from transcriptomic and metagenomic analyses

BackgroundIntermittent fasting (IF) has shown benefits in various pathological conditions. Although its anti-inflammatory potential has been recognized, its effects on the mechanism underlying rheumatoid arthritis (RA) remain insufficiently characterized. This study aimed to investigate the effects of IF in a murine model of RA.MethodsCollagen-induced arthritis (CIA) was developed in sixteen male DBA/1 mice, randomly assigned to two groups, with one undergoing IF every other day for four weeks. The effects of IF on joint inflammation and remodeling were evaluated clinically, histologically, and through tomography. Transcriptomic changes were characterized using expression microarrays, validated by RT-qPCR, and confirmed by immunohistochemistry. Additionally, modifications in gut microbiota were assessed through 16 S sequencing.ResultsMice subjected to IF significantly reduced the incidence and severity of clinical arthritis. Histological and radiographic assessments confirmed a decrease in inflammation and joint damage. Transcriptomic analysis revealed that IF led to the upregulation of 364 genes and the downregulation of 543 genes, with notable reductions in inflammatory signaling pathways associated with RA-related genes, including Cd72, Cd79a, Ifna, Il33, and Bglap 2. Notably, IL33 emerged as a pivotal mediator in the inflammatory processes mitigated by fasting. Key regulators associated with IF effects, such as CEBPA, FOXO1, HIF1A, PPARG, and PPARA, were identified, indicating a complex interplay between metabolic and inflammatory pathways. Furthermore, differential expression of microRNAs and lncRNAs, including miR-15b, miR-103-2, miR-302a, miR-6985, and miR- 5624, was observed. Metagenomic analysis indicated that IF enhanced the abundance and diversity of the gut microbiome, explicitly promoting anti-inflammatory bacterial populations, notably within the genus Ruminococcaceae.ConclusionOur findings suggest that IF exerts significant anti-inflammatory and immunoregulatory effects in the context of CIA. Given its non-risky nature, further investigation into the potential benefits of IF in patients with RA is warranted.Clinical trial numberNot applicable.

Umbilical Cord Mesenchymal Stem Cell Secretome: A Potential Regulator of B Cells in Systemic Lupus Erythematosus.

Autoimmune diseases represent a severe personal and healthcare problem that seeks novel therapeutic solutions. Mesenchymal stem cells (MSCs) are multipotent cells with interesting cell biology and promising therapeutic potential. The immunoregulatory effects of secretory factors produced by umbilical cord mesenchymal stem cells (UC-MSCs) were assessed on B lymphocytes from 17 patients with systemic lupus erythematosus (SLE), as defined by the 2019 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE, and 10 healthy volunteers (HVs). Peripheral blood mononuclear cells (PBMCs) from patients and HVs were cultured in a UC-MSC-conditioned medium (UC-MSCcm) and a control medium. Flow cytometry was used to detect the surface expression of CD80, CD86, BR3, CD40, PD-1, and HLA-DR on CD19+ B cells and assess the percentage of B cells in early and late apoptosis. An enzyme-linked immunosorbent assay (ELISA) quantified the production of BAFF, IDO, and PGE2 in PBMCs and UC-MSCs. Under UC-MSCcm influence, the percentage and mean fluorescence intensity (MFI) of CD19+BR3+ cells were reduced in both SLE patients and HVs. Regarding the effects of the MSC secretome on B cells in lupus patients, we observed a decrease in CD40 MFI and a reduced percentage of CD19+PD-1+ and CD19+HLA-DR+ cells. In contrast, in the B cells of healthy participants, we found an increased percentage of CD19+CD80+ cells and decreased CD80 MFI, along with a decrease in CD40 MFI and the percentage of CD19+PD-1+ cells. The UC-MSCcm had a minimal effect on B-cell apoptosis. The incubation of patients' PBMCs with the UC-MSCcm increased PGE2 levels compared to the control medium. This study provides new insights into the impact of the MSC secretome on the key molecules involved in B-cell activation and antigen presentation and survival, potentially guiding the development of future SLE treatments.