Mouse Model Of Colitis Research Articles

Qin-Yu-Qing-Chang decoction reshapes colonic metabolism by activating PPAR-γ signaling to inhibit facultative anaerobes against DSS-induced colitis

BackgroundQin-Yu-Qing-Chang decoction (QYQC), an herbal formula from China, is extensively employed to manage ulcerative colitis (UC) and exhibits potential benefits for colonic function. Nevertheless, the fundamental molecular mechanisms of QYQC remain largely uncharted.MethodsThe primary constituents of QYQC were determined utilizing UHPLC-MS/MS analysis and the effectiveness of QYQC was assessed in a mouse model of colitis induced by dextran sulfate sodium. Evaluations of colon inflammatory responses and mucosal barrier function were thoroughly assessed. RNA sequencing, molecular docking, colonic energy metabolism, and 16S rRNA sequencing analysis were applied to uncover the complex mechanisms of QYQC in treating UC. Detect the signal transduction of the peroxisome proliferator-activated receptor-γ (PPAR-γ) both in the nucleus and cytoplasm. Furthermore, a PPAR-γ antagonist was strategically utilized to confirm the functional targets that QYQC exerts.ResultsUtilizing UHPLC-MS/MS, the principal constituents of the nine traditional Chinese medicinal herbs comprising QYQC were systematically identified. QYQC treatment substantially ameliorated colitis in mice, as evidenced by the improvement in symptoms and the reduction in colonic pathological injuries. Besides, QYQC treatment mitigated the inflammatory response and improved mucosal barrier function. Furthermore, QYQC enhanced the mitochondria citrate cycle (TCA cycle) by triggering PPAR-γ signaling and increasing the proportion of PPAR-γ entering the nucleus. This prevented the unconstrained expansion of facultative anaerobes, particularly pathogenic Escherichia coli (E. coli, family Enterobacteriaceae) and thus improved colitis. Results of molecular docking indicated that the representative chemical components of QYQC including Baicalin, Paeoniflorin, Mollugin, and Imperatorin bound well with PPAR-γ. The impact of QYQC on colitis was diminished in the presence of a PPAR-γ antagonist.ConclusionsIn summary, QYQC ameliorates UC by activating PPAR-γ signaling and increasing the proportion of PPAR-γ entering the nucleus, which enhances the energy metabolism of intestinal epithelial cells and thereby preventing the uncontrolled proliferation of facultative anaerobes.

Fresh bamboo juice regulates the diversity of intestinal microflora in mice by promoting the function of ILC2 cells to mediate intestinal protection

Background and aimUlcerative colitis (UC) is a growing global health concern, with current treatments facing challenges like drug dependence and side effects. Fresh bamboo juice (FBJ), known for its antimicrobial and potential immune-modulating properties, has shown promise as a natural therapeutic agent. The present study aimed to explore the protective effects of FBJ against colitis and further analyze the changes of gut microbiota composition, metabolite profiles, and underlying immune mechanisms. Materials and MethodsA colitis model in mice was established using DSS to investigate the effectiveness of FBJ. Intestinal tissue and fecal samples were also collected for 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS) analysis. Additionally, immunofluorescence and flow cytometry were employed to detect the proliferation and function of group 2 innate lymphoid cells (ILC2). Enzyme-linked immunosorbent assay (ELISA) was used to measure the cytokines secreted by immune cells. ResultsFBJ demonstrated significant therapeutic effects against DSS-induced colitis in mice. At the genus level, the abundance of Bacteroides, Akkermansia and unassigned bacteria in the bamboo juice group increased compared with the DSS group. In contrast, the abundance of Alloprevotella, Lactobacillus, Lachnospiraceae_NK4A136_group and Ruminococcaceae_UCG-014 significantly decreased. FBJ partially restored the balance of gut microbiota, as evidenced by the increased levels of beneficial bacteria. Metabolome analysis revealed significant alterations in fecal metabolites, including 3-Hydroxypyridine, Pyridoxine, SM(d18:1/16:0), and DL-Methionine sulfoxide were remarkably altered. Dysregulation of pathways such as Vitamin B6 metabolism, sphingolipid metabolism, and tyrosine metabolism was observed, which may contribute to protection against colitis. Flow cytometry and immunofluorescence showed a significant reduction in the proportion of ILC2 cells following FBJ treatment in the DSS group (1.82 % v.s. 3.18 %, P < 0.05). ELISA showed that the FBJ group had lower levels of IL-5, IL-6, IL-10, IL-13, IL-33, TNF-α, IFN-γ in intestinal tissue. ConclusionsOur findings demonstrate that FBJ exerts a protective effect against colitis, primarily by modulating the intestinal flora and metabolite profiles in mice with colitis. Furthermore, the observed alterations in bacterial flora and metabolites likely affect ILC2 function and cytokine production, thereby mediating the protective effects against colitis through modulation of the immune system.

Toll-Like Receptor 2 Deficiency Exacerbates Dextran Sodium Sulfate-Induced Intestinal Injury through Marinifilaceae-Dependent Attenuation of Cell Cycle Signaling

Background: Ulcerative colitis (UC) is an intestinal disorder marked by chronic, recurring inflammation, yet its underlying mechanisms have not been fully elucidated. Methods: The current research dealt with examining the biological impacts of toll-like receptor 2 (TLR2) on dextran sulfate sodium (DSS)-triggered inflammation in the intestines of wild-type (WT) and TLR2-knockout (TLR2-KO) colitis mouse models. To elucidate the protective function of TLR2 in DSS-triggered colitis, RNA-sequencing (RNA-Seq) was carried out to compare the global gene expression data in the gut of WT and TLR2-KO mice. Further, 16S rRNA gene sequencing revealed notable variations in gut microbiota composition between WT and TLR2-KO colitis mice. Results: It was revealed that TLR2-KO mice exhibited increased susceptibility to DSS-triggered colitis. RNA-Seq results demonstrated that cell cycle pathway-related genes were notably downregulated in TLR2-KO colitis mice (enrichment score = 30, p &lt; 0.001). 16S rRNA gene sequencing revealed that in comparison to the WT colitis mice, the relative abundance of Marinifilacea (p = 0.006), Rikenellacea (p = 0.005), Desulfovibrionaceae (p = 0.045), Tannerellaceae (p = 0.038), Ruminococcaceae (p = 0.003), Clostridia (p = 0.027), and Mycoplasmataceae (p = 0.0009) was significantly increased at the family level in the gut of TLR2-KO colitis mice. In addition, microbiome diversity-transcriptome collaboration analysis highlighted that the relative abundance of Marinifilaceae was negatively linked to the expression of cell cycle signaling-related genes (p values were all less than 0.001). Conclusion: Based on these findings, we concluded that TLR2-KO exacerbates DSS-triggered intestinal injury by mitigating cell cycle signaling in a Marinifilaceae-dependent manner.

Evaluation of TNF-α and IFN-γ primed conditioned medium of mesenchymal stem cell in acetic acid-induced mouse model of acute colitis

IBD, an autoimmune-inflammatory disorder that affects people who are genetically prone to inflammation. There is a lot of interest in MSC-CM therapy, especially when primed with TNF-α + IFN-γ. Throughout the study, data were collected on the percentage of apoptotic cells, gene expression of ZO-1, Foxp3, GATA3, IDO-1, Muc2, T-bet, Notch1, TNFR2, and ROR-γt, colon weight and length, histopathological analysis, and DAI. TNF-α and IL-10 levels were assessed in addition to the NO level. The results suggest that primed MSC-CM improved DAI, mucosal deterioration, intestinal inflammation and NO concentration. The amount of TNF-α was decreased, but IL-10 and the colon’s percentage of apoptotic cells was increased. The mRNA expression of ZO-1, Foxp3, GATA3, IDO-1, and Muc2 genes increased greatly in the treatment groups, while the expression of T-bet, Notch1, TNFR2, and ROR-γt genes has decreased. These studies suggest that primed MSC-CM may combine with common treatments to improve responsiveness.

Neutrophil elastase-activated carbon dots for non-invasive early diagnosis of inflammatory bowel disease by near-infrared-II fluorescence imaging

Most near-infrared-II (NIR-II) fluorescent probes produce an “always-on” output with poor signal specificity for biomarkers. Neutrophil elastase (NE) is a critical factor in chronic inflammation or in the acute response to infection and injury, and NE activatable NIR-II fluorescent probes can aid in the early clinical diagnosis of inflammatory bowel disease (IBD). In this paper, we synthesized OPDG-PFA@PEI carbon dots (CDs) through a two-step reaction of solvothermal/surface covalent bond modification, which can “turn on” specific NIR-II fluorescence signals related to the level of NE produced by neutrophils and target sites of inflammation effectively, thus realizing the monitoring of in-situ NE in cells and in vivo. OPDG-PFA@PEI CDs fluorescent nanoprobe show high-performance real-time non-invasive NIR-II fluorescence imaging for early diagnostic evaluation of IBD in mouse models of DSS-induced IBD, providing a promising approach for the development of clinical non-invasive and more convenient early diagnosis of IBD.

Christensenella minuta protects and restores intestinal barrier in a colitis mouse model by regulating inflammation

Christensenella minuta DSM 22607 has recently been suggested as a potential microbiome-based therapy for inflammatory bowel disease (IBD) because it displays strong anti-inflammatory effects both in vitro and in vivo. Here, we aimed to decipher the mechanism(s) underlying the DSM 22607-mediated beneficial effects on the host in a mouse model of chemically induced acute colitis. We observed that C. minuta plays a key role in the preservation of the epithelial barrier and the management of DNBS-induced inflammation by inhibiting interleukin (IL)-33 and Tumor necrosis factor receptor superfamily member 8 (Tnfrsf8) gene expression. We also showed that DSM 22607 abundance was positively correlated with Akkermansia sp. and Dubosiella sp. and modulated microbial metabolites in the cecum. These results offer new insights into the biological and molecular mechanisms underlying the beneficial effects of C. minuta DSM 22607 by protecting the intestinal barrier integrity and regulating inflammation.

Targeted V-type peptide-decorated nanoparticles prevent colitis by inhibiting endosomal TLR signaling and modulating intestinal macrophage polarization

Inflammatory bowel disease (IBD) has become a serious and challenging health problem globally without curative medical treatments. Mounting evidence suggests that intestinal macrophages and their phenotypes are key players in the pathogenesis of IBD. Modulating the phenotypes and functions of intestinal macrophages through targeted interventions could be a promising approach to manage detrimental gut inflammation in IBD. In this study, we rationally design and fabricate a novel class of V-type peptide-decorated nanoparticles, VP-NP, with potent anti-inflammatory activity. Such a design allows two functional motifs FFD in a single peptide molecule to enhance the bioactivity of the nanoparticles. As expected, VP-NP exhibits a strong inhibitory activity on endosomal Toll-like receptor (TLR) signaling. Surprisingly, VP-NP can inhibit M1 polarization while facilitating M2 polarization in mouse bone marrow-derived macrophages through regulating the key transcription factors NF-κB, STAT1 and PPAR-γ. Mechanistically, VP-NP is internalized by macrophages in the endosomes, where it blocks endosomal acidification to inhibit endosomal TLR signaling; the transcriptomic analysis reveals that VP-NP potently down-regulates many genes in TLR, NF-κB, JAK-STAT, and cytokine/chemokine signaling pathways associated with inflammatory responses. In a colitis mouse model, the intraperitoneally administered VP-NP effectively alleviates the disease activities by decreasing colon inflammation and injuries, pro-inflammatory cytokine production, and myeloid cell infiltration in the gut. Furthermore, VP-NP primarily targets intestinal macrophages and alters their phenotypes from inflammatory M1-type toward the anti-inflammatory M2-type. This study provides a new nanotherapeutic strategy to specifically regulate macrophage activation and phenotypes through a dual mechanism to control gut inflammation, which may augment current clinical treatments for IBD.

A high cholesterol diet aggravates experimental colitis through SREBP2-modulated endocytosis and degradation of occludin and Zo-1 proteins.

Disrupted cholesterol homeostasis plays a critical role in the development of multiple diseases, such as cardiovascular disease and cancer. However, the role of cholesterol in inflammatory bowel disease (IBD) remains unclear. In the present study, we investigated whether and how high levels of cholesterol in the diet affect experimental colitis in mice. A normal diet supplemented with 1.25% cholesterol (high cholesterol diet) caused more severe colitis and aggravated the disruption of intestinal tight junction structure, accompanied by higher colonic tissue total cholesterol (TC) levels in a dextran sulfate sodium (DSS)-induced experimental colitis mouse model. Cholesterol aggravated DSS-induced intestinal epithelial barrier impairment and nuclear sterol regulatory element-binding protein 2 (nSREBP2) inhibition both in vivo and in vitro. In addition, nSREBP2 overexpression ameliorated cholesterol-induced intestinal epithelial barrier disruption in Caco2 cells. Interestingly, inhibition of SREBP2 disrupted intestinal epithelial barrier in the absence of cholesterol. Furthermore, SREBP2 regulated the protein expression of tight junction proteins (occludin/Zo-1) via modulating caveolin-1-mediated endocytosis and lysosomal degradation. Analysis of UK Biobank data indicated that, in fully adjusted models, higher serum TC concentrations were an independent protective factor for IBD incidence. The sterol regulatory element-binding factor 2 (SREBF2) gene rs2228313 (G/C) genetic variant was associated with the incidence of IBD and the CC genotype of SREBF2 rs2228313 was associated with higher serum TC levels and decreased the risk of IBD. In summary, a high cholesterol diet aggravates DSS-induced colitis in mice by down-regulating nSREBP2 expression, thereby promoting the endocytic degradation of tight junction proteins. In humans, SREBF2 gene single nucleotide polymorphism rs2228313 and serum TC levels are associated with IBD incidence.

Antibiotics damage the colonic mucus barrier in a microbiota-independent manner.

Antibiotic use is a risk factor for development of inflammatory bowel diseases (IBDs). IBDs are characterized by a damaged mucus layer, which does not separate the intestinal epithelium from the microbiota. Here, we hypothesized that antibiotics affect the integrity of the mucus barrier, which allows bacterial penetrance and predisposes to intestinal inflammation. We found that antibiotic treatment led to breakdown of the colonic mucus barrier and penetration of bacteria into the mucus layer. Using fecal microbiota transplant, RNA sequencing followed by machine learning, ex vivo mucus secretion measurements, and antibiotic treatment of germ-free mice, we determined that antibiotics induce endoplasmic reticulum stress in the colon that inhibits colonic mucus secretion in a microbiota-independent manner. This antibiotic-induced mucus secretion flaw led to penetration of bacteria into the colonic mucus layer, translocation of microbial antigens into circulation, and exacerbation of ulcerations in a mouse model of IBD. Thus, antibiotic use might predispose to intestinal inflammation by impeding mucus production.

Orally Deliverable Microalgal-Based Carrier with Selenium Nanozymes for Alleviation of Inflammatory Bowel Disease.

Excessive reactive oxygen species (ROS) is a hallmark of both the onset and progression of inflammatory bowel disease (IBD), where a continuous cycle of ROS and inflammation drives the progression of diseases. The design of oral antioxidant nanoenzymes for scavenging ROS has emerged as a promising strategy to intervene in IBD. However, the practical application of these nanoenzymes is limited due to their single catalytical property and significantly impacted by substantial leakage in the upper gastrointestinal tract. This study introduces a novel oral delivery system, SP@CS-SeNPs, combining natural microalgae Spirulina platensis (SP), which possesses superoxide dismutase (SOD)-like activity, with chitosan-functionalized selenium nanoparticles (CS-SeNPs) that exhibit catalase-like activity. The SP@CS-SeNPs system leverages the dual catalytic capabilities of these components to initiate a cascade reaction that first converts superoxide anion radicals (O2•-) into hydrogen peroxide (H2O2), and then catalyzes the decomposition of H2O2 into water and oxygen. This system not only utilizes the resistance of the microalgae carrier to gastric acid and its efficient capture by intestinal villi, thereby enhancing intestinal distribution and retention but also demonstrates significant anti-inflammatory effects and effective repair of the damaged intestinal barrier in a colitis mice model. These results demonstrate that this oral delivery system successfully combines the features of microalgae and nanozymes, exhibits excellent biocompatibility, and offers a novel approach for antioxidant nanozyme intervention in IBD.

Enteric-coated cerium dioxide nanoparticles for effective inflammatory bowel disease treatment by regulating the redox balance and gut microbiome

Reactive oxygen species (ROS) play crucial roles in the pathogenesis of inflammatory bowel disease (IBD) by disrupting the mucosal barrier and subsequently leading to the dysregulation of the gut microbiome. Therefore, ROS scavengers present a promising and comprehensive strategy for the effective IBD treatment. In the current work, we explored the therapeutic potential of cerium dioxide (CeO2) nano-enzyme, which is well-known for their potent antioxidant properties and capability to mimic natural antioxidant enzymes in the regulation of oxidative stress. We developed a novel enteric-coated nanomedicine (CeO2@S100) aiming at improving the oral delivery efficacy of CeO2 in the complex gastrointestinal environment. CeO2@S100 is composed of a CeO2 nanoparticle core and a protective polyacrylic acid resin shell (Eudragit S100), ensuring targeted delivery of the core specifically at inflamed intestinal sites due to the negative surface charge. In vivo experiments revealed CeO2@S100 significantly alleviates the IBD by balancing oxidative stress and regulating gut microbiota in a dextran sulfate sodium-induced mouse colitis model. The uncomplicated synthesis of CeO2@S100 highlights its promise for clinical use, presenting an effective and safe approach to managing IBD.

Development of dual GPBAR1 agonist and RORγt inverse agonist for the treatment of inflammatory bowel diseases

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic disorders characterized by dysregulated immune response and persistent inflammation. Recent studies suggest that bile acid receptors, particularly GPBAR1, and the transcription factor RORγt play critical roles in modulating intestinal inflammation. This study evaluates the therapeutic potential of PBT002, a dual GPBAR1 agonist and RORγt inverse agonist, in IBD models. The effects of PBT002 were assessed through in vitro and in vivo experiments. Macrophages and T lymphocytes obtained from the buffy coat were exposed to PBT002 to evaluate its immunomodulatory activity. The beneficial effects in vivo were evaluated in mouse models of colitis induced by TNBS, DSS or DSS + IL-23 using also a Gpbar1 knock-out male mice. PBT002 exhibited an EC50 of 1.2 µM for GPBAR1 and an IC50 of 2.8 µM for RORγt. In in vitro, PBT002 modulated macrophage polarization towards an anti-inflammatory M2 phenotype and reduced Th17 cell markers while increasing Treg markers. In the TNBS-induced colitis model, PBT002 reduced weight loss, CDAI, and colon damage, while it modulated cytokine gene expression towards an anti-inflammatory profile. In GPBAR1-/-, the anti-inflammatory effects of PBT002 were attenuated, indicating partial GPBAR1 dependence. RNA sequencing revealed significant modulation of inflammatory pathways by PBT002. In DSS+IL-23 induced colitis, PBT002 mitigated disease exacerbation, reducing pro-inflammatory cytokine levels and immune cell infiltration. In conclusion, PBT002, a GPBAR1 agonist and RORγt inverse agonist, modulates both the innate and adaptive immune responses to reduce inflammation and disease severity in models of IBD.

Blood pressure alteration associated with abnormal body electrolyte and water balance in colitis mice.

Previous studies reported that there is an association between abnormal body fluid balance and prognosis in colitis patients. However, it remains to be clarified the effects of colitis on characteristics of body electrolytes or water content, including alternation in blood pressure. In this study, we examined the effects of colon injury on body water balance and blood pressure in the dextran sodium sulfate (DSS)-induced colitis mouse model. We evaluated body electrolytes and water content, blood pressure, and urea-associated water conservation in DSS mice. By 5 days after the treatment, DSS mice exhibited diarrhea but relatively maintained body weight and total body sodium, potassium, and water content by increases in water intake and hepatic ureagenesis. On 7 days after DSS treatment, when colitis becomes severe, DSS mice significantly decreased food and water intake, and body weight but significantly increased relative total body sodium, potassium, and water content per dry mass. Notably, DSS induced more total body dry mass loss relative to water loss. These body electrolytes and water accumulation on day 7 were associated with a reduction in urinary osmole excretion and urine volume accompanied by renal urea accumulation. DSS mice significantly increased blood pressure by day 5 and then decreased on day 7. These findings suggest that body electrolyte and fluid imbalance and alternations in blood pressure in colitis vary with the stage and severity of the condition. Assessment and correction of electrolyte and water content at the tissue level would be important to improve the prognosis of colitis.

Lactobacillus gasseri ATCC33323 affects the intestinal mucosal barrier to ameliorate DSS-induced colitis through the NR1I3-mediated regulation of E-cadherin.

Inflammatory bowel disease (IBD) is an immune system disorder primarily characterized by colitis, the exact etiology of which remains unclear. Traditional treatment approaches currently yield limited efficacy and are associated with significant side effects. Extensive research has indicated the potent therapeutic effects of probiotics, particularly Lactobacillus strains, in managing colitis. However, the mechanisms through which Lactobacillus strains ameliorate colitis require further exploration. In our study, we selected Lactobacillus gasseri ATCC33323 from the intestinal microbiota to elucidate the specific mechanisms involved in modulation of colitis. Experimental findings in a DSS-induced colitis mouse model revealed that L. gasseri ATCC33323 significantly improved physiological damage in colitic mice, reduced the severity of colonic inflammation, decreased the production of inflammatory factors, and preserved the integrity of the intestinal epithelial structure and function. It also maintained the expression and localization of adhesive proteins while improving intestinal barrier permeability and restoring dysbiosis in the gut microbiota. E-cadherin, a critical adhesive protein, plays a pivotal role in this protective mechanism. Knocking down E-cadherin expression within the mouse intestinal tract significantly attenuated the ability of L. gasseri ATCC33323 to regulate colitis, thus confirming its protective role through E-cadherin. Finally, transcriptional analysis and in vitro experiments revealed that L. gasseri ATCC33323 regulates CDH1 transcription by affecting NR1I3, thereby promoting E-cadherin expression. These findings contribute to a better understanding of the specific mechanisms by which Lactobacillus strains alleviate colitis, offering new insights for the potential use of L. gasseri as an alternative therapy for IBD, particularly in dietary supplementation.

Magnolol-loaded polydopamine-chitosan coated pH-responsive nanoparticles for alleviation of ulcerative colitis

This study designed and developed a novel three-layer electrostatic, slow-releasing nanoparticle drug delivery system for the treatment of ulcerative colitis. The nanoparticles were composed of layers of zein-based polydopamine, chitosan and cellulose acetate phthalate to form a polyelectrolyte multilayer core−shell nanoparticle structure. The anti-inflammatory natural product magnolol was chosen to be the model drug for the study. The nanoparticles (260.50 ± 23.90 nm) were prepared with layer-by-layer coating and then assessed in vitro and in vivo using a mouse model of ulcerative colitis. The in vitro data confirmed the slow-releasing and pH-dependent characteristics of particles. Quantitative analysis of the in vivo distribution of Mag in mice showed significantly higher concentrations in colonic tissue than in the upper gastrointestinal tract (854.6 ng/g vs 291.5–351.1 ng/g, respectively). Histological and pro-inflammatory cytokine analysis indicated that the nanoparticles had a significant anti-inflammatory effect and were protective against DSS-induced structural damage of the colonic mucosal structure. These results confirm that this nano-delivery system could increase the levels of Mag reaching the colon, resulting in greater efficacy than free Mag in treating UC in this mouse model.

Umbelliprenin attenuates comorbid behavioral disorders in acetic acid-induced colitis in mice: mechanistic insights into hippocampal oxidative stress and neuroinflammation.

Inflammatory bowel disease (IBD) is often accompanied by psychiatric disorders. Emerging evidence suggests that neuroinflammation and oxidative stress contribute to the psychiatric symptoms associated with IBD. Umbelliprenin (UMB) possesses several pharmacological properties, including anti-inflammatory and antioxidant effects. This study aimed to investigate the protective effects of UMB on comorbid behavioral disorders in a mouse model of experimental colitis, focusing on its potential anti-neuroinflammatory and antioxidant activities. After inducing colitis with acetic acid, male NMRI mice were treated for 7 consecutive days with UMB, saline, or dexamethasone. Behavioral assessments included the forced swimming test (FST), splash test, open field test (OFT), and elevated plus maze (EPM). Histopathological changes in the colon were evaluated, and total antioxidant capacity (TAC), malondialdehyde (MDA) levels, and the expression of inflammatory genes (TNFα, IL1β, and TLR4) were measured in the hippocampus. Colitis was associated with increased immobility time in the FST, reduced entries and time spent in the open arms of the EPM, decreased grooming behavior in the splash test, and reduced time spent in the central zone of the OFT. Colitis also resulted in a reduction in TAC and an increase in MDA levels and inflammatory gene expression in the hippocampus. UMB treatment mitigated the behavioral disorders associated with colitis, reduced neuroinflammation and oxidative stress in the hippocampus, and alleviated histopathological alterations in the colon. In conclusion, UMB may reduce behavioral disorders induced by colitis by decreasing oxidative stress and neuroinflammation in the hippocampus.

Berberine and magnolol exert cooperative effects on ulcerative colitis in mice by self-assembling into carrier-free nanostructures

The risk of ulcerative colitis (UC) is increasing worldwide with limited success using classical drugs, which has underscored the development of novel agents. Recently, carrier-free molecular assembly has been proven to be an effective drug delivery system, but it has yet to be examined for UC drug development using phytochemicals. Based on traditional Chinese medicine compatibility and potential medicinal uses, a pair of natural compounds, berberine (BBR) and magnolol (MAG), were found to self-assemble into nanostructures in aqueous solutions. Spectral analysis revealed that the assembly mechanisms of BBR and MAG were mediated through charge interactions and π-π stacking. Pharmacokinetic studies and animal imaging showed that BBR-MAG self-assembly (BM) effectively promoted the oral bioavailability and biodistribution of BBR in the colon. BM exhibited superior effects in regulating inflammatory factors, maintaining colon barrier integrity, and regulating gut microbiota in a dextran sulfate sodium salt-induced colitis mouse model. Additionally, no apparent signs of toxicity were observed, suggesting that BM has a favorable safety profile. This study presents a new strategy for UC management and highlights the cooperative effects of combined phytochemicals.Graphical

PARP1 inactivation increases regulatory T / Th17 cell proportion in intestinal inflammation. Role of HMGB1

Inflammatory bowel diseases (IBD) are chronic relapsing disorders with increasing prevalence. Knowledge gaps still limit the possibility to develop more specific and effective therapies. Using a dextran sodium sulfate colitis mouse model, we found that inflammation increased the total number and altered the frequencies of leukocytes within colon mesenteric lymph nodes (cMLNs). Although the inflammation reduced the frequency of regulatory T (Treg) cells, their absolute numbers were increased. Increased frequency of colitogenic Th17 cells was also observed. Noteworthy, untreated mice lacking Poly(ADP-ribose)-Polimerase-1 functional gene (PARP-1KO) displayed higher frequency of Treg cells and lower percentage of Th17 cells in cMLNs. In colitic PARP-1KO mice the inflammation driven expansion of the Foxp3 Treg population was more pronounced than in WT mice. Conversely, colitis increased Th17 cells to a lower extent in PARP-1KO mice compared with WT mice, resulting in a more protective Treg/Th17 cell ratio. Consequently PARP-1KO mice developed less severe colitis with reduced expression of inflammatory cytokines. In ex vivo experiments PARP-1KO and WT CD11c dendritic cells (DCs) promoted naïve CD4 T cell differentiation differently, the former sustaining more efficiently the generation of Treg cells, the latter that of Th17 cells. Addition of HMGB1 B box or of dipotassium glycyrrhizate, which sequesters extracellular HMGB1, revealed a role for this alarmin in the regulation exerted by PARP-1 on the stimulating vs. tolerogenic function of DCs during colitis. Moreover, a higher percentage of CD11c DC from PARP-1KO mice expressed CD103, a marker associated with the ability of DC to induce Treg cells, compared with WT DC. Conversely, PARP-1KO DC were including a reduced percentage of CX3CR1+ DC, described to induce Th17 cells. These findings were observed in both splenic and colon lamina propria DC.

Dysregulated myeloid differentiation in colitis is induced by inflammatory osteoclasts in a TNFα-dependent manner

Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn’s disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.

Lactobacillus johnsonii colonizing in mice intestine contributes to control the gut barrier function via regeneration of the crypt in DSS‐treated mice

AbstractBackgroundUnbalanced gut microbiota is considered to cause dysfunction of the gut barrier function. Lactobacillus johnsonii MG, isolated from mouse feces as gut associating lactobacilli, enhanced gut barrier function in Caco‐2 cells via interaction with JAM‐2 in tight junctions. In this study, the anti‐inflammatory effects of L. johnsonii MG were investigated in a colitis mouse model developed by treating mice with 3% dextran sulfate sodium (DSS) for 9 days.ResultsMG treatment of colitis mice resulted in fast recovery of the body weight and showed significant improvement in the disease activity index and histopathological scores. The histomorphological score increased by DSS treatment was significantly improved in the MG‐treated group. In the intestine, the expression of Ocln, Zo1, Itga6, Lama3, and Jam2 genes, which are involved in tight junction functions, were significantly upregulated in MG‐treated colitis mice. In the microflora analysis, the abundance of Ruminococcaceae, Bacteroides, and Lachnospiraceae were reduced in DSS‐treated mice and recovered by MG treatment.ConclusionWe reported the potential of L. johnsonii MG in the regeneration of crypts and integrity of matrix proteins in the gut of mice with colitis through its association with tight junctions. The experimental results provide new insights into the probiotic effect of tight junction associating L. johnsonii MG.