Severe Colitis Research Articles

Amlexanox targeted inhibition of TBK1 regulates immune cell function to exacerbate DSS-induced inflammatory bowel disease.

Amlexanox (ALX) is a small molecule drug for the treatment of inflammatory, autoimmune, metabolic and tumor diseases. At present, there are no studies on whether ALX has a therapeutic effect on inflammatory bowel disease (IBD). In this study, we used a mouse model of dextran sulfate sodium (DSS)-induced colitis to investigate the effect of ALX targeted inhibition of TBK1 on colitis. We found that the severity of colitis in mice was correlated with TBK1 expression. Notably, although ALX inhibited the activation of the TBK1-NF-κB/TBK1-IRF3 pro-inflammatory signaling pathway, it exacerbated colitis and reduced survival in mice. The results of drug safety experiments ruled out a relationship between this exacerbating effect and drug toxicity. In addition, ELISA results showed that ALX promoted the secretion of IL-1β and IFN-α, and inhibited the production of cytokines IL-6, TNF-α, IL-10, TGF-β and secretory IgA. Flow cytometry results further showed that ALX promoted T cell proliferation, activation and differentiation, and thus played a pro-inflammatory role; Also, ALX inhibited the generation of dendritic cells and the polarization of macrophages to M1 type, thus exerting anti-inflammatory effect. These data suggest that the regulation of ALX on the function of different immune cells is different, so the effect on the inflammatory response is bidirectional. In conclusion, our study demonstrates that simply inhibiting TBK1 in all immune cells is not effective for the treatment of colitis. Further investigation the anti-inflammatory mechanism of ALX on dendritic cells and macrophages may provide a new strategy for the treatment of IBD.

The association between erythema nodosum and pyoderma gangrenosum and pediatric inflammatory bowel disease.

The objectives of this study is to estimate rates and identify factors associated with erythema nodosum (EN) and pyoderma gangrenosum (PG) in pediatric patients with inflammatory bowel disease (IBD). This cohort study examined longitudinal visits of patients aged ≤ 21 years from the ImproveCareNow (ICN) registry. We evaluated the association of factors at the patient-level (demographics and IBD diagnosis age) and visit-level (IBD severity scores, markers and phenotypes, comorbidities, and treatment) with the presence of EN and PG, using longitudinal logistic regression models adjusted for time and within-patient clustering. A total of 285,913 visits from 32,497 patients aged ≤ 21 years from the ICN registry were analyzed. The occurrence of EN was 1.57% (95% confidence interval [95% CI]: 1.43%-1.71%) and the occurrence of PG was 0.90% (95% CI: 0.80%-1.00%). Co-occurrence of EN and PG was reported in 0.30% (95% CI: 0.25%-0.37%) patients. Both EN and PG were associated (p < 0.0001) with worse intestinal disease, lower remission, higher inflammatory markers, and extraintestinal manifestations (EIMs) arthritis and uveitis. EN and PG were associated with increased disease severity and other noncutaneous EIMs (arthritis and uveitis). A small subset of patients had developed both EN and PG.

Targeting Specific Kinase Substrates Rescues Increased Colitis Severity Induced by the Crohn's Disease-Linked LRRK2-N2081D Variant.

LRRK2 contains a kinase domain where both the N2081D Crohn's disease (CD) risk and the G2019S Parkinson's disease (PD)-pathogenic variants are located. The mechanisms by which the N2081D variant increase CD risk, and how these adjacent mutations result in distinct diseases, remain unclear. To investigate the pathophysiology of the CD-linked LRRK2 N2081D variant, we generated a knock-in (KI) mouse model and compared its effects to those of the LRRK2-G2019S mutation. We find that Lrrk2 N 2081 D KI mice demonstrate heightened sensitivity to induced colitis, resulting in more severe inflammation and intestinal damage than Lrrk2 G2019S KI and wild-type mice. Analysis of Colon tissue revealed distinct mutation-dependent LRRK2 RAB substrate phosphorylation, with significantly elevated phosphorylated RAB10 levels in Lrrk2 N2081D mice. In cells, we demonstrate that the N2081D mutation activates LRRK2 through a mechanism distinct from that of LRRK2-G2019S. We further find that proinflammatory stimulation enhances LRRK2 kinase activity, leading to mutation-dependent differences in RAB phosphorylation and inflammatory responses in dendritic cells. Finally, we show that genetic knockout of Rab12 , but not pharmacological LRRK2 kinase inhibition, significantly reduced colitis severity in Lrrk2 N2081D mice. Our study characterizes the pathogenic mechanisms of LRRK2-linked CD, highlights important structural and functional differences between disease-associated LRRK2 variants, and suggests RAB proteins as promising therapeutic targets for modulating LRRK2 activity in CD treatment.

A Novel Microbial Dysbiosis Index and Intestinal Microbiota-Associated Markers as Tools of Precision Medicine in Inflammatory Bowel Disease Paediatric Patients.

Recent evidence indicates that the gut microbiota (GM) has a significant impact on the inflammatory bowel disease (IBD) progression. Our aim was to investigate the GM profiles, the Microbial Dysbiosis Index (MDI) and the intestinal microbiota-associated markers in relation to IBD clinical characteristics and disease state. We performed 16S rRNA metataxonomy on both stools and ileal biopsies, metabolic dysbiosis tests on urine and intestinal permeability and mucosal immunity activation tests on the stools of 35 IBD paediatric patients. On the GM profile, we assigned the MDI to each patient. In the statistical analyses, the MDI was correlated with clinical parameters and intestinal microbial-associated markers. In IBD patients with high MDI, Gemellaceae and Enterobacteriaceae were increased in stools, and Fusobacterium, Haemophilus and Veillonella were increased in ileal biopsies. Ruminococcaceae and WAL_1855D were enriched in active disease condition; the last one was also positively correlated to MDI. Furthermore, the MDI results correlated with PUCAI and Matts scores in ulcerative colitis patients (UC). Finally, in our patients, we detected metabolic dysbiosis, intestinal permeability and mucosal immunity activation. In conclusion, the MDI showed a strong association with both severity and activity of IBD and a positive correlation with clinical scores, especially in UC. Thus, this evidence could be a useful tool for the diagnosis and prognosis of IBD.

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.

Pregnancy outcomes among women with inflammatory bowel disease: A UK tertiary centre experience.

Optimal management of inflammatory bowel disease (IBD) in pregnancy is associated with better pregnancy outcomes. We describe management of IBD during pregnancy and maternal and fetal outcomes of patients from a tertiary UK IBD centre. This is a retrospective observational cohort study of all pregnancies occurring between 2015 and 2021 in a large tertiary IBD centre in the UK. IBD activity and management prior to, during and after pregnancy were recorded along with pregnancy and neonatal outcomes. Associations between IBD-focused interventions and any adverse pregnancy outcomes, as well as the association between IBD severity and treatments and adverse maternofetal outcomes were assessed. Pregnancies in 130 women with IBD were included for analysis. The mean maternal age at delivery was 30.5 (± 4.7) years. At conception, 73 women (56.2%) were in clinical remission and 24 (18.4%) were treated with a biologic agent. Active disease during pregnancy, measured by physician global assessment, was less frequent in women who were in clinical remission at conception, compared to those not in remission at conception (16/73 21.9% vs. 39/49 79.6%; data insufficient for eight women). Active IBD at conception was associated with pre-term birth (p = 0.04). Maternal corticosteroid use in any trimester was associated with low birth weight (T1 p = 0.02; T2 p = 0.005; T3 p = 0.007). Active disease (p = 0.008) and steroid use in the third trimester (p = 0.05) were both associated with neonatal infections up to sixmonths after birth. Women in clinical remission at the time of conception have favorable outcomes, consistent with prospective observational studies. Our observations emphasize the importance of high quality IBD care for women pre and post-partum in line with international recommendations.

Endoscopic findings of immune checkpoint inhibitor-related gastrointestinal adverse events.

The use of immune checkpoint inhibitors (ICIs) for the treatment of various malignancies is increasing. Immune-related adverse events can occur after ICI administration, with gastrointestinal adverse events constituting a significant proportion of these events. When ICI-related diarrhea/colitis is suspected, endoscopic evaluation is recommended to differentiate it from other etiologies and assess the severity of colitis. The distribution of intestinal inflammation in ICI-related colitis demonstrates a high frequency of extensive colitis (23-86%). However, isolated right-sided colitis (3-8%) and ileitis (2-16%) are less prevalent. Endoscopic findings vary and predominantly encompass features indicative of inflammatory bowel disease, including aphthae, ulcers, diffuse or patchy erythema, mucosal edema, loss of vascular pattern, and friability. The presence of ulcers and extensive intestinal inflammation are associated with a reduced response to treatment. Microscopic inflammation can be observed even in endoscopically normal mucosa, underscoring the need for biopsies of seemingly normal mucosa. Histological findings present with acute/chronic inflammation and occasionally exhibit characteristics observed in inflammatory bowel disease, microscopic colitis, or ischemic colitis. The first-line therapeutic choice for ICI-related diarrhea/colitis with a common terminology criteria for adverse events grade of 2 or above is corticosteroids, whereas infliximab and vedolizumab are recommended for refractory cases.

The Role of Vitamin D Levels in Optimizing Treatment for Pediatric Inflammatory Bowel Disease (IBD) Patients and an Examination Into Different Factors That Influence IBD Treatment Outcomes.

Background Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), presents significant challenges, particularly in pediatric patients. Vitamin D deficiency has been associated with IBD, but its role in disease activity and remission remains unclear. This study investigates the relationship between serum vitamin D levels and IBD markers, including Pediatric Crohn's Disease Activity Index (PCDAI), Pediatric Ulcerative Colitis Activity Index (PUCAI), fecal calprotectin levels, and endoscopy findings. It also explores racial and ethnic disparities in these relationships. Methodology A retrospective study was conducted involving 51 pediatric patients with IBD from the Nemours Children's Health EMR system. Inclusion criteria required documented serum vitamin D levels at diagnosis and post-treatment, and at least one post-treatment assessment of PUCAI/PCDAI, calprotectin, or endoscopy. The study employed Spearman and Pearson correlation tests to analyze the associations between vitamin D levels and IBD markers. Ethnicity and race were analyzed using t-tests and chi-square tests. Results No statistically significant correlations were found between changes in serum vitamin D levels and IBD markers (endoscopy results, calprotectin levels, PUCAI/PCDAI scores) for both UC and CD. Analysis of racial and ethnic disparities revealed that Hispanic patients had significantly higher post-treatment calprotectin levels compared to non-Hispanics, although other markers showed no significant differences. Vitamin D levels did not significantly differ between racial or ethnic groups. Conclusions This study found no significant correlation between serum vitamin D levels and IBD activity markers in pediatric patients. Despite initial hypotheses, vitamin D levels do not appear to be useful in assessing IBD remission or disease state. Racial and ethnic disparities in IBD severity were observed, but further research with larger sample sizes and more consistent data collection is needed to draw more definitive conclusions.

Subjective and objective sleep quality assessment in adolescent patients with inflammatory bowel disease

ObjectivesThere is a link between inflammatory bowel disease (IBD) and poor sleep quality that is presumed to be multifactorial. The purpose of this study was to identify factors that impact sleep quality in this group including clinical disease activity, depression, anxiety, quality of life, and disordered social media use through questionnaires. MethodsThis prospective study analyzed sleep quality in adolescent patients ages 13 to 18 with a diagnosis of IBD using objective data from wrist actigraphy and subjective report from the Pittsburgh Sleep Quality Index (PSQI). Additional screeners including the Short Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index, Pediatric Quality of Life Inventory Gastrointestinal Symptoms Module, Generalized Anxiety Disorder 7-item screener, Patient Health Questionnaire depression screener, and Social Media Disorder scale were also collected. ResultsTwenty-three subjects enrolled and 16 completed questionnaires. 62.5 % of participants were in clinical remission and the remaining 37.5 % had mild to severe clinical IBD activity. Poor subjective sleep quality was associated with a shorter duration of sleep time and an increased clinical disease activity score. Patients in clinical remission slept for a longer duration than those with mild IBD activity. ConclusionsThis study did not identify a significant relationship between sleep quality and psychosocial factors in the adolescent population with IBD, though their influence cannot be discounted. There was a connection between the presence of disease activity and shorter sleep duration. Similarly, PSQI scores correlated with sleep time but not sleep quality.

Integrating transcriptomics and proteomics to analyze the immune microenvironment of cytomegalovirus associated ulcerative colitis and identify relevant biomarkers

BackgroundIn recent years, significant morbidity and mortality in patients with severe inflammatory bowel disease (IBD) and cytomegalovirus (CMV) have drawn considerable attention to the status of CMV infection in the intestinal mucosa of IBD patients and its role in disease progression. However, there is currently no high-throughput sequencing data for ulcerative colitis patients with CMV infection (CMV + UC), and the immune microenvironment in CMV + UC patients have yet to be explored.MethodThe xCell algorithm was used for evaluate the immune microenvironment of CMV + UC patients. Then, WGCNA analysis was explored to obtain the co-expression modules between abnormal immune cells and gene level or protein level. Next, three machine learning approach include Random Forest, SVM-rfe, and Lasso were used to filter candidate biomarkers. Finally, Best Subset Selection algorithms was performed to construct the diagnostic model.ResultsIn this study, we performed transcriptomic and proteomic sequencing on CMV + UC patients to establish a comprehensive immune microenvironment profile and found 11 specific abnormal immune cells in CMV + UC group. After using multi-omics integration algorithms, we identified seven co-expression gene modules and five co-expression protein modules. Subsequently, we utilized various machine learning algorithms to identify key biomarkers with diagnostic efficacy and constructed an early diagnostic model. We identified a total of eight biomarkers (PPP1R12B, CIRBP, CSNK2A2, DNAJB11, PIK3R4, RRBP1, STX5, TMEM214) that play crucial roles in the immune microenvironment of CMV + UC and exhibit superior diagnostic performance for CMV + UC.ConclusionThis 8 biomarkers model offers a new paradigm for the diagnosis and treatment of IBD patients post-CMV infection. Further research into this model will be significant for understanding the changes in the host immune microenvironment following CMV infection.

A novel deletion in the BLOC1S6 Gene Associated with Hermansky-Pudlak syndrome type 9 (HPS-9)

BackgroundHermansky-Pudlak Syndrome (HPS), a rare autosomal recessive disorder, is characterized by oculocutaneous albinism, bleeding diathesis, and sometimes severe lung problems and inflammatory bowel disease. Symptoms include skin and hair pigmentation variations, along with visual impairments. Variants in eleven genes encoding protein complexes essential for membrane trafficking and intracellular endosomal transport pathways underlie various recognized HPS subtypes. This study focuses on HPS-9, a subtype of Hermansky-Pudlak Syndrome caused by a variant in the BLOC1S6 gene, which is a subunit of the BLOC1 complex. In this study, a novel Copy Number Variation (CNV) in the aforementioned gene in an Iranian family is reported. The study aims to better understand the etiology of HPS-9 symptoms by identifying and confirming the variant and determining whether the gene is expressed despite the deletion. There have only been five reports of this syndrome in the literature thus far. Our novel CNV represents a significant contribution to understanding the genetic basis of HPS-9.ResultsThis study investigates a male patient presenting with albinism. Whole Exome Sequencing (WES) identified a homozygous deletion of approximately 350 bp using CNV analysis. The deletion affects the intronic region of the BLOC1S6 gene, causing uncertainties in defining the exact boundaries due to WES limitations. Primer walking and GAP-PCR techniques were used to define the deletion boundaries. Subsequent assessments of this variant across other family members helped identify homozygous affected members and heterozygous carriers. The absence of BLOC1S6 expression in the affected individual was confirmed through Real-time PCR experiments. These findings underscore the importance of understanding the implications for the patient’s healthcare and potential therapeutic approaches.ConclusionThis study introduces a case of Hermansky-Pudlak Syndrome Type 9 (HPS-9) caused by a homozygous deletion in the BLOC1S6 gene. We identified an approximately 7-kb deletion encompassing exon 1 and the intronic region of the gene. The absence of BLOC1S6 expression, confirmed via Real-time PCR, highlights the importance of studying the pathogenicity of the deletion and its impact on the patient’s health. Our findings contribute to the sparse knowledge on HPS-9 and underscore the need for further exploration into the genetic causes of this rare disorder.

Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti-Tumor Necrosis Factors

Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic condition characterized by relapsing and remitting inflammation of the gastrointestinal tract. The pathogenesis involves a complex interplay of genetic, environmental, and immune factors. Treatment paradigms have evolved significantly over the past few decades, with the introduction of biologics, particularly anti-TNF (tumor necrosis factor) agents, marking a significant advancement. Anti-TNF therapies, including infliximab, adalimumab, golimumab, and certolizumab pegol, have efficacy in inducing and maintaining remission, promoting mucosal healing, and improving the quality of life in moderate to severe IBD patients. The early and appropriate use of these agents can mitigate disease progression and reduce the dependency on corticosteroids, enhancing long-term patient outcomes. Nevertheless, these therapies are expensive and are associated with potential adverse effects, including increased risk of infections and malignancies. This review discusses the mechanisms, clinical efficacy, safety profiles, and therapeutic positioning of anti-TNF agents in IBD management, integrating current Korean treatment guidelines.

Psidium guajava Seed Oil Reduces the Severity of Colitis Induced by Dextran Sulfate Sodium by Modulating the Intestinal Microbiota and Restoring the Intestinal Barrier.

The oil derived from Psidium guajava seeds (TKSO) exhibits an abundance of diverse unsaturated fatty acids, notably oleic, linoleic, and α-linolenic acids, conferring substantial health advantages in addressing metabolic irregularities and human diseases. This research endeavor focused on elucidating the impacts of TKSO on colonic inflammatory responses and intestinal microbiota alterations in a murine model of colitis induced by dextran sulfate sodium (DSS), demonstrated that substantial supplementation with TKSO reduces the severity of colitis induced by DSS. Furthermore, TKSO effectively attenuated the abundance and expression of proinflammatory mediators while augmenting the expression of tight junction proteins in DSS-challenged mice. Beyond this, TKSO intervention modulated the intestinal microbial composition in DSS-induced colitis mice, specifically by enhancing the relative presence of Lactobacillus, Norank_f_Muribaculaceae, and Lachnospiraceae_NK4A136_group, while concurrently diminishing the abundance of Turicibacter. Additionally, an analysis of short-chain fatty acids (SCFAs) revealed noteworthy elevations in acetic, propionic, isobutyric, and butyric acids, and total SCFAs levels in TKSO-treated mice. In summary, these findings underscore the potential of TKSO to reduce the severity of colitis induced by DSS in mice through intricate modulation of the intestinal microbiota, metabolite profiles, and intestinal barrier repair, thereby presenting a promising avenue for the development of therapeutic strategies against intestinal inflammatory conditions.

Peripheral Blood Eosinophilia at Diagnosis of Inflammatory Bowel Disease Is Associated with Severe Disease Course; A Nationwide Study From the epi-IIRN Cohort.

We conducted this nationwide study to evaluate the association between peripheral blood eosinophilia (PBE) and long-term outcomes in children and adults with inflammatory bowel diseases (IBD). Data from the epi-IIRN cohort, a validated population-based IBD database, included patients diagnosed between 2005-2020 who had an eosinophil count at diagnosis, and those of non-IBD controls. PBE was defined as an eosinophil count of >0.5 X109/L Severe disease course was defined as corticosteroid dependency, use of ≥2 biologics from different classes, or surgery. Time-to-outcomes, including severe disease course, was determined by Cox proportional hazard models. Included were 28,133 patients (15,943 Crohn's disease [CD] and 12,190 ulcerative colitis [UC]), and 28,724 non-IBD controls. The prevalence of PBE was 13% in the IBD group and 5% in controls (P < .001). PBE was more prevalent in UC (16.1%) compared to CD (10.6%, OR=1.52 (95%CI 1.42-1.63); P < .001) and in pediatric-onset (23.5%) compared to adult-onset (11%) IBD (OR=2.14 (1.97-2.31); P <.001). In a multivariate analysis, PBE was a predictor of severe disease course in IBD (hazard ratio [HR]=1.49, 95%CI 1.38-1.62, P < .001). PBE also predicted time-to-hospitalization (HR=1.24, 95%CI 1.19-1.30), use of corticosteroids (HR=1.32, 95%CI 1.28-1.36), corticosteroid dependency (HR=1.37, 95%CI 1.31-1.43), and need of biologics (HR=1.27, 95%CI 1.21-1.33). In this largest nationwide study, PBE predicted severe IBD course. These findings support the use of PBE as a marker of adverse outcome of IBD and as a potential target for future therapies.

Quality of life after colectomy and ileo-jpouch-anal anastomosis in paediatric patients with ulcerative colitis.

Ulcerative Colitis (UC) is an Inflammatory Bowel Disease (IBD). Surgery is required in cases of severe acute colitis, massive hemorrhage, toxic megacolon, and perforation; in such cases colectomy and JpouchIleoanal anastomosis (IPAA) are performed. The aim of this study was to evaluate functional outcome, and patient satisfaction and Quality of Life (QoL) after surgery. Questionnaires were administered to 24 patients with UC undergoing surgery from 2011 to 2022. Mean age at IPAA was 10.8years. Twenty patients underwent IPAA in 3 operations, 4 patients in 2. All patients underwent laparoscopic surgery. 6months after surgery mean level of satisfaction was 8.7/10, perception of health status was 7.4. Twenty-three patients (95.8%) recommended IPAA. For 20 patients (83.3%) surgery did not cause delay in education, while 14 patients (58.3%) played sport. The lowest number of evacuations was 9.2 per day, the highest 13.3. Seventeen patients (70.8%) had no incontinence and 15 patients (62.5%) were not affected by pouchitis. After 12months mean satisfaction level raised up to 9.2/10, perception of health status to 8.5. School absences decreased and no other patients showed any delay in education. Seventeen (70.8%) patients played sports. The number of evacuations decreased: the lowest number was 5.1 per day, the highest 7.5. Twenty patients (83.3%) were continent and 12 (50%) did not use antibiotics. Most patients show a good functional outcome in defecation frequency and continence, which has improved through time, number of pouchitis episodes has increased. Patients appear satisfied after surgery.

Polysaccharides from Dendrobium devonianum ameliorate Salmonella typhimurium-induced ulcerative colitis by modulating ClostridiumXlVa, purine and tryptophan metabolism

Given the escalating severity of colitis caused by Salmonella infection and the growing challenge of drug resistance, there is an urgent demand for novel and effective treatment strategies with minimal side effects. Herein, we explored the potential therapeutic effects of polysaccharides on Ulcerative Colitis (UC). Our results showed that both purified polysaccharide from Dendrobium devonianum (DVP-1) and Crude polysaccharides from Dendrobium devonianum (CP) pre-treatment could prevent colon shortening and spleen enlargement, and alleviate colonic tissue damage. Western blot and RT-qPCR analyses revealed that DVP-1 and CP downregulated pro-inflammatory mediators while upregulating the expression of the anti-inflammatory mediator and tight junction proteins. Besides, 16S rRNA sequencing analysis showed that DVP-1 modulated gut dysbiosis by increasing the relative abundance of ClostridiumXlVa, and reducing the relative abundance of Alloprevotella. Additionally, DVP-1 and CP significantly increased the concentrations of tryptophan metabolites while decreasing purine metabolites. Taken together, these findings suggest that DVP-1 and CP yield potential benefits in alleviating UC primarily through restoring intestinal barrier function and regulating intestinal microbiota.

Dietary Porphyra tenera ameliorated dextran sodium sulfate-induced colitis in mice via modulating gut microbiota dysbiosis

Bioactive components from Porphyra tenera (PT) have been reported to confer various health benefits. The role of PT in inflammatory bowel disease (IBD) has not been fully investigated. This study aimed to explore the anti-inflammatory properties of PT on dextran sodium sulfate (DSS)-treated mice. PT supplementation attenuated the severity of colitis in DSS-treated mice, evidenced by the reduction of disease activity index (DAI), restoration of colonic histological damage and suppression of abnormal inflammatory response. Sequencing analysis indicated that intake of PT alleviated DSS-induced gut microbiota dysbiosis, accompanied by reversing the generation of short-chain fatty acids (SCFAs) and bile acids (BAs). Overall, our findings demonstrated that supplementation of PT attenuated the severity of intestinal inflammation and ameliorated gut microbiota dysbiosis in a murine colitis model, which provided a rationale for further application of edible seaweeds for preventing inflammation-related disorders in humans.

Sodium orthovanadate protects against ulcerative colitis and associated liver damage in mice: insights into modulations of Nrf2/Keap1 and NF-κB pathways.

Ulcerative colitis (UC) is a prominent category of disease that is associated with bowel inflammation, it can occur at any period of life and is prevalently rising on a global scale. Dextran sulfate sodium (DSS) has been extensively used to develop colitis due to its ability to mimic human UC, providing consistent and reproducible inflammation, ulceration, and disruption of the epithelial barrier in the colon. Chronic inflammation in the gut can lead to alterations in the gut-liver axis, potentially impacting liver function over time, while direct evidence linking diversion colitis to liver damage is limited. Thus, the present study aims to assess the gut and liver damage against DSS and the possible molecular mechanisms. Forty-seven animals were randomly assigned to six groups. Ulcerative colitis was induced using 2.5% w/v DSS in three alternate cycles, each lasting 7 days, with 1-week remission periods in between. SOV (5 and 10 mg/kg, orally) and the standard drug 5-aminosalicylic acid (100 mg/kg, orally) were administered from the start of the 2nd DSS cycle until the end of the experiment. Biochemical parameters, ELISA, histopathological, and immunohistochemical analyses have been conducted to assess damage in the colon and liver. SOV significantly reduced colitis severity by lowering the DAI score, oxidative stress markers (LPS, IL-1β, MPO, nitrite), and restoring liver biomarkers (SGPT, SGOT). Histopathological findings supported these protective benefits in the liver and gut. Moreover, immunohistochemical analysis showed SOV enhanced the expression of the cytoprotective mediator Nrf2/Keap-1 and reduced the expression of inflammatory mediators NF-κB and IL-6. Present findings concluded that SOV demonstrated a dose-dependent effect against UC through anti-inflammatory and antioxidant pathways, with the highest dose of SOV 10 mg/kg having more significant (p < 0.001) results than the low dose of 5 mg/kg.

Lower fecal microbiota transplantation ameliorates ulcerative colitis by eliminating oral-derived Fusobacterium nucleatum and virulence factor

BackgroundRecently, the oral oncobacterium Fusobacterium nucleatum (F. nucleatum), has been linked with ulcerative colitis (UC). Here, we aim to investigate whether Fecal Microbiota Transplantation (FMT) can alleviate UC by restoring gut microbiota and eliminating oral-derived F. nucleatum and virulence factor fadA.MethodC57BL/6J mice were randomly divided into a healthy control group (HC), Dextran Sulfate Sodium group (DSS), oral inoculation group (OR), upper FMT group (UFMT), and lower FMT group (LFMT). Disease activity index, body weight, survival rate, and histopathological scores were used to measure the severity of colitis. The function of the intestinal mucosal barrier was evaluated by performing immunohistochemical staining of the tight junction protein Occludin. Real-time PCR was used to assess the relative abundance of the nusG gene and the virulence gene fadA. Cytokine levels were detected by ELISA. Full-length sequencing of 16S rRNA was used to analyze the changes and composition of gut microbiota.FindingsOral incubation of F. nucleatum further exacerbated the severity of colitis and gut dysbiosis. Peptostreptococcaceae, Enterococcaceae, and Escherichia coli were significantly enriched in OR mice. However, LFMT mice showed an obvious decrease in disease activity and were more effective in restoring gut microbiota and eliminating F. nucleatum than UFMT mice. Bacteroidota, Lachnospiraceae, and Prevotellaceae were mainly enriched bacteria in LFMT mice. In addition, Genera such as Lactobacillus, Allobaculum, and Bacteroidales were found negative correlation with TNF-α, IL-1β, and IL-6. Genera like Romboutsia, Escherichia Shigella, Enterococcus, and Clostridium were found positively correlated with TNF-α, IL-1β, and IL-6.ConclusionsOral incubation of F. nucleatum further exacerbates the severity and dysbiosis in DSS-induced colitis mice. Besides, lower tract FMT can ameliorate colitis by restoring the gut microbiota diversity and eliminating F. nucleatum and virulence factor fadA.

A Family of Cyclic Lipopeptides Found in Human Isolates of Bacillus Ameliorates Acute Colitis via Direct Agonism of Toll-Like Receptor 2 in a Murine Model of Inflammatory Bowel Disease

BackgroundThe Bacillus-derived cyclic lipopeptides (surfactin, iturin, and fengycin) form potent Heterogeneous Lipopeptide Micelle (HeLM) complexes. HeLM is a small molecule that has been shown to have immunomodulatory effects. However, how HeLM regulates inflammation is not clear, moreover its application to Inflammatory Bowel Disease (IBD), specifically Ulcerative Colitis (UC), has not been tested before.AimsTo use a murine model of IBD and determine the effects of HeLM and related molecular mechanisms of action.MethodsColitis was induced in mice by administration of 4% Dextran Sodium Sulfate. Three preparations were tested against negative and positive controls: Purified HeLM, the wild-type strain that produces it, and an isogenic mutant that does not produce HeLM. Clinical, biochemical, and histological scoring systems were used to assess the severity of colitis. RT-qPCR and cell cultures were used to determine the levels of molecular signaling. Fecal samples were processed for metagenomic analysis.ResultsPurified HeLM, and the wild-type strain, significantly decreased the severity of colitis as determined by the disease activity index (DAI), mouse colitis histology index (MCHI), fecal calprotectin, and colonic length. This effect was not seen in the mutant. HeLM was found to be an agonist to TLR-2, seemingly activating the Toll-Like Receptor 2/IL-10 pathway, with subsequent downregulation of inflammatory cytokines (TNF-α, IL-1β, and IL-6). At higher concentrations HeLM inhibited lipopolysaccharide ligands from activating TLR-4. The reduction in colitis was not due to microbiome modulation, as had previously been hypothesized.ConclusionOur results indicate that HeLM ameliorates colitis by TLR-2-induced IL-10 production and possibly via the inhibition of lipopolysaccharide.