Severe Colitis Research Articles

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.

Mouse adaptation of human inflammatory bowel diseases microbiota enhances colonization efficiency and alters microbiome aggressiveness depending on the recipient colonic inflammatory environment

BackgroundUnderstanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis.ResultsOur study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10−/− mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10−/− mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10−/− host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10−/− mice than the distinct microbiota reassembled in non-inflamed WT hosts.ConclusionsOur findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer.9-8iLEe2BorBmu_z2q_8UWVideo

Nucleophosmin 1 promotes mucosal immunity by supporting mitochondrial oxidative phosphorylation and ILC3 activity

Nucleophosmin 1 (NPM1) is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Concurrent inflammatory bowel diseases (IBD) and MDS are common, indicating a close relationship between IBD and MDS. Here we examined the function of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 expression was reduced in patients with IBD. Npm1+/− mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote mitochondrial transcription factor A (TFAM) transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced the severity of dextran sulfate sodium-induced colitis. Thus, our findings indicate that NPM1 in ILC3s protects against IBD by regulating mitochondrial metabolism through a p65-TFAM axis.

The effect of novel paraprobiotic cocktail on dextran sodium sulfate induced acute colitis control focusing on autophagy signaling pathway.

Paraprobiotics are a non-viable form of probiotics that are reported to provide significant health benefits. Nevertheless, little is known about the beneficial effects of paraprobiotics on inflammatory bowel disease. Although probiotics show potential as therapeutic agents for a range of diseases, including inflammatory bowel disease (IBD), there are certain risks associated with their use. These risks include toxin production, hemolytic potential, antibiotic resistance, and the need to analyze metabolic activities. Hence Using paraprobiotic with the lower aforementioned risk would therefore be the preferable option. Here, we conducted an in vivo study to evaluate the preventive effect of our native paraprobiotic cocktail against dextran sulfate sodium (DSS)-induced murine colitis by affecting the autophagy signaling pathway. Four-week-old male C57Bl/6 mice were randomly divided into three groups after a two-week acclimation period with normal standard laboratory food diet. Mice were administered PBS (PBS group as control), PBS along with DSS (DSS group, as a control), and a cocktail of paraprobiotics along with DSS (Para group). The severity of colitis, length and histopathology of the colon were evaluated. In addition, the expression of autophagy was assessed using real-time PCR. The results showed that administration of the paraprobiotic cocktail to DSS-treated mice inhibited the severity of colitis symptoms, as evidenced by the inhibition of weight loss and DAI, as well as histopathological scores in the study colon, as well as shortening of colon length caused by DSS. In contrast to the DSS group, the cocktail was able to modulate inflammation through upregulation of autophagy-related genes (becline 1, atg5, atg7, atg12, and atg13). Although there are some limitations in our investigation, such as the dosage and duration of treatments, our native paraprobiotic blend effectively prevented the advancement of colitis. This suggests that it plays a vital role in regulating inflammation and preventing colitis by promoting the autophagy mechanism in cases where the consumption of probiotics may have negative consequences.

Exploring novel microbial metabolites and drugs for inhibiting Clostridioides difficile.

The most frequent infection associated with hospital settings is Clostridioides difficile, which can cause fatal diarrhea and severe colitis, toxic megacolon, sepsis, and leaky gut. Those who have taken antibiotics for other illnesses that affect the gut's healthy microbiota are more susceptible to C. difficile infection (CDI). Recently, some reports showed higher recurrence rates and resistance to anti-C. difficile, which may compromise the efficacy of CDI treatment. Our study is significant because it is anticipated to discover novel microbial metabolites and drugs with microbial origins that are safe for the intestinal flora, effective against C. difficile, and reduce the risk of recurrence associated with CDI.

Gut colonization with antibiotic-resistant Escherichia coli pathobionts leads to disease severity in ulcerative colitis

Escherichia coli is a Gram-negative commensal of human gut. Surprisingly, the role of E. coli in the pathogenesis of ulcerative colitis (UC) has not been explored until now. Human gut microbiota composition and meta-gut resistome were evaluated using metagenomics. Antibiotic susceptibility of E. coli isolates against different class of antibiotics was investigated. Further, the genome sequence analysis of E. coli isolates was performed to gain insight into the antimicrobial resistance (AMR) mechanism and virulence factors. Gut proteome of UC and non-UC was examined to understand the effect of resistant bacteria on host physiology. In UC patients, meta-gut resistome was found to be dominated by AMR genes (829) compared to healthy controls (HC) [518]. The metagenome study revealed a higher prevalence of AMR genes in the rural population (378 in HC; 607 in UC) compared to the urban (340 in HC; 578 in UC). Approximately, 40% of all E. coli isolates were multi-drug resistant (MDR), with higher prevalence in UC (43.75%) compared to HC (33.33%). Up-regulated expression of antimicrobial human proteins (lactotransferrin, azurocidin, cathepsin G, neutrophil elastase, and neutrophil defensin 3) and inflammatory mediator (Protein S100-A9 and Protein S100-A8) suggest microbial infection in UC gut. In addition to the conventional culturomics method, a multi-omics strategy provides deeper insights into the disease etiology, emergence of MDR pathobionts, and their roles in the disruption of the healthy gut environment in UC patients.

Peroxiredoxin 3 Deficiency Exacerbates DSS-Induced Acute Colitis via Exosomal miR-1260b-Mediated Barrier Disruption and Proinflammatory Signaling.

Aims: Peroxiredoxin3 (Prdx3) is an intracellular antioxidant enzyme that is specifically localized in mitochondria and protects against oxidative stress by removing mitochondrial reactive oxygen species (ROS). The intestinal epithelium provides a physical and biochemical barrier that segregates host tissues from commensal bacteria to maintain intestinal homeostasis. An imbalance between the cellular antioxidant defense system and oxidative stress has been implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the role of Prdx3 in the intestinal epithelium under intestinal inflammation has not been elucidated. To investigate the potential role of Prdx3 in intestinal inflammation, we used intestinal epithelial cell (IEC)-specific Prdx3-knockout mice. Results: IEC-specific Prdx3-deficient mice showed more severe colitis phenotypes with greater degrees of body weight loss, colon shortening, barrier disruption, mitochondrial damage, and ROS generation in IECs. Furthermore, exosomal miR-1260b was dramatically increased in Prdx3-knockdown colonic epithelial cells. Mechanistically, Prdx3 deficiency promoted intestinal barrier disruption and inflammation via P38-mitogen-activated protein kinase/NFκB signaling. Innovation: This is the first study to report the protective role of Prdx3 in acute colitis using IEC-specific conditional knockout mice. Conclusion: Our study sheds light on the role of exosome-loaded miRNAs, particularly miR-1260b, in IBD. Targeting miR-1260b or modulating exosome-mediated intercellular communication may hold promise as potential therapeutic strategies for managing IBD and restoring intestinal barrier integrity.

The effect of the probiotic bacteria &lt;i&gt;Akkermansia Muciniphila&lt;/i&gt; in intestinal homeostasis and dss-induced inflammation in mice

Akkermansia muciniphila is a Gram-negative anaerobic bacterium, a component of the normal human intestinal microbiota. A decrease in the presence of this bacterium is associated with pathologies, including metabolic disorders, intestinal inflammation and colorectal cancer. A. muciniphila is a probiotic approved for patients with diabetes and obesity. In recent years, A. muciniphila was studied in the control of intestinal inflammation and colorectal cancer. The exact mechanisms of A. muciniphila action remain unclear, while the use of different administration protocols shows different effects in mouse models of colitis and colorectal cancer. We reported that A. muciniphila has distinct effects on intestinal mucin production depending on viable or pasteurized form of bacteria. Another factor affecting the outcome of the A. muciniphila administration is the number of bacteria. To address how the dose of bacteria may affect the severity of acute intestinal inflammation wild-type mice were subjected to daily oral injections with 10⁸ CFU or 109 CFU of viable A. muciniphila for two weeks; the control group was injected with PBS. After that, groups were subjected to the induction of acute colitis by adding 7% DSS to drinking water for five days. 8 days after the onset of colitis induction, a morphometric assessment of the colitis severity was performed. Mice given a high dose of A. muciniphila (109 CFU) were found to be protected from developing severe colitis. RT-PCR analysis of colon samples from mice receiving a high dose of bacteria showed an increase in the gene expression of antimicrobial peptides, IL-17A, IL-17F. Interestingly, the protective effect of A. muciniphila was observed only in a high dose group, but not in a low dose group. Our data suggest that A. muciniphila provides the protective effect in colitis and highlight the importance of selecting the dose of the bacterium for proper interpretation.

Comparison of short-term outcomes and defecatory function following robotic and conventional laparoscopic surgery for stapled-ileal pouch-anal anastomosis-a retrospective cohort study.

This study assessed the potential advantages of robotic-assisted Stapled ileal pouch-anal anastomosis (Ro Stapled-IPAA) in ulcerative colitis (UC) compared to conventional laparoscopic surgery (Lap), with a focus on short-term outcomes and postoperative defecatory function, an aspect not previously explored. Out of a total of 132 patients who underwent proctocolectomy or residual rectal resection, consecutive patients undergoing minimally invasive Stapled-IPAA for UC at our hospital from May 2014 to May 2024 were included. The Ro approach was chosen for individuals with severe colitis extending into the anal canal, deeper rectal cancers (beyond T1), and cases requiring residual rectal resection, taking advantage of its benefits. Perioperative outcomes, including anastomosis height, operative time, intraoperative blood loss, complication rate, postoperative hospital stay, and defecatory function using Wexner scores and anorectal manometry before proctocolectomy and 6 months after stoma closure, were compared between the Ro and Lap groups. 33 patients (Lap, n=21; Ro, n=12) were included. The Ro group demonstrated a significantly lower anastomosis height (0.5 vs. 3.0 cm, P<0.001), reduced intraoperative blood loss (35 vs. 118mL, P=0.032), shorter postoperative hospital stay (8 vs. 10.5d), and no cases of anastomotic leakage (0% vs. 14.3%), as compared to the Lap group. Pouch failure occurred in 14% of Lap group; none were observed in the Ro group. Wexner scores favored the Ro group at 12 months after stoma closure (0 vs. 8 points), and there was better maximum voluntary squeeze pressure (302mmHg vs. 175mmHg, P=0.03), indicating preserved contraction of the external sphincter muscle despite the lower anastomosis. Ro Stapled-IPAA for patients with UC led to better short-term outcomes and preservation of defecatory function with lower anastomosis than Lap, suggesting the clinical advantages of the robotic approach in this field.

Aloe-emodin alleviates inflammatory bowel disease in mice by modulating intestinal microbiome homeostasis via the IL-4/IL-13 axis

IntroductionInflammatory bowel disease (IBD) is a global health concern. Aloe-emodin (AE) has diverse pharmacological benefits, including anti-inflammatory effects. However, its role in IBD remains unclear, prompting our investigation of its regulatory effects and mechanisms in an IBD mouse model. MethodsWe studied the therapeutic efficacy of AE in alleviating symptoms and modulating cytokine secretion in a murine model of dextran sulfate sodium (DSS)-induced colitis. BALB/c mice were administered DSS to induce colitis and were subsequently treated with varying doses of AE. Changes in body weight, fecal lipocalin-2 (LCN2) levels, colon tissue histology, and serum cytokine concentrations were evaluated to assess the effects of AE treatment. Additionally, 16 S rRNA sequencing was used to analyze alterations in the composition of the gut microbiota following AE intervention. Finally, the database was used to analyze the signaling pathways associated with IBD in AE and to detect the expression levels of interleukin (IL)-4 pathway using real-time quantitative reverse transcription PCR. Exogenous IL-4 was used in rescue experiments to observe its effects on the disease process of IBD under AE regulation. ResultsAE treatment resulted in a dose-dependent mitigation of weight loss, reduction in fecal LCN2 levels, and amelioration of histological damage in DSS-induced colitis in mice. The levels of superoxide dismutase and catalase increased, whereas malondialdehyde decreased following AE treatment, indicating a dose-dependent alleviation of colitis symptoms. Furthermore, AE administration attenuated the secretion of pro-inflammatory cytokines, including IL-17, tumor necrosis factor-alpha (TNF-α), and chemokine ligand 1, while promoting the expression of anti-inflammatory cytokines IL-4 and IL-13. Analysis of the gut microbiota revealed that AE effectively suppressed the overgrowth of colitis-associated bacterial species and restored microbial homeostasis. Finally, we found that overexpression of IL-4 was able to reverse the therapeutic effect of AE for DSS-induced IBD. ConclusionAE shows promise in alleviating colitis severity, influencing inflammatory cytokines, and modulating the gut microbiota in an IBD mouse model via the IL-4/IL-13 pathway, suggesting its potential as a natural IBD remedy.

The Severity of DSS-Induced Colitis Is Independent of the SCFA-FFAR2/3-GLP-1 Pathway Despite SCFAs Inducing GLP-1 Secretion via FFAR2/3.

Short-chain fatty acids (SCFAs) are the major microbial metabolites produced from the fermentation of dietary fiber in the gut. They are recognised as secretagogues of the glucagon-like peptides, GLP-1 and GLP-2, likely mediated by the activation of free fatty acid receptors 2 and 3 (FFAR2 and 3) expressed on enteroendocrine L-cells. Fiber-deficient diets are associated with decreased intestinal function and decreased colonic GLP-1 and GLP-2 content. Here, we speculated that the lowered colonic GLP-1 observed following a fiber-free diet was a consequence of decreased SCFA production and a subsequent decrease in FFAR2/3 activation. Furthermore, we explored the consequences of a fiber-free diet followed by intestinal injury, and we mechanistically explored the SCFA-FFAR2/3-GLP-1 pathway to explain the increased severity. Colonic luminal content from mice fed either a fiber-free or chow diet were analysed for SCFA content by LC-MS. FFAR2/3 receptor contributions to SCFA-mediated colonic GLP-1 secretion were assessed in isolated perfused preparations of the colon from FFAR2/3 double knockout (KO) and wild-type (WT) mice. Colitis was induced by the delivery of 3% dextran sulfate sodium (DSS) for 4 days in the drinking water of mice exposed to a fiber-free diet for 21 days. Colitis was induced by the delivery of 3% DSS for 7 days in FFAR2/3 KO mice. The removal of dietary fiber significantly decreased SCFA concentrations in the luminal contents of fiber-free fed mice compared to chow-fed mice. In the perfused colon, luminal SCFAs significantly increased colonic GLP-1 secretion in WT mice but not in FFAR2/3 KO mice. In the DSS-induced colitis model, the removal of dietary fiber increased the severity and prevented the recovery from intestinal injury. Additionally, colitis severity was similar in FFAR2/3 KO and WT mice after DSS application. In conclusion, the results confirm that the removal of dietary fiber is sufficient to decrease the colonic concentrations of SCFAs. Additionally, we show that a fiber-free diet predisposes the colon to increased intestinal injury, but this effect is independent of FFAR2 and FFAR3 signalling; therefore, it is unlikely that a fiber-free diet induces a decrease in luminal SCFAs and sensitivity to intestinal disease involves the SCFA-FFAR2/3-GLP-1 pathway.