Introduction

Alcohol-induced acute gastric injury results from disruption of the mucosal barrier and the induction of inflammatory responses. IL-33, an epithelial-derived alarmin, and its receptor ST2, are increasingly recognized as regulators of mucosal immunity and inflammation. However, the specific role of IL-33/ST2 signaling in the immunopathogenesis of ethanol-induced gastric damage remains insufficiently defined.

Aims & Methods

This study aimed to investigate the contribution of IL-33/ST2 signaling to the development of ethanol-induced acute gastric injury. Acute gastric injury was induced in WT and ST2⁻/⁻ mice by oral administration of 80% ethanol. Gastric damage was assessed macroscopically and histologically. Immune cell profiles, cytokine levels, and markers of inflammasome activity and pyroptosis were analyzed using flow cytometry, ELISA, and qPCR.

Results

Ethanol exposure induced severe gastric injury in WT mice, characterized by extensive ulceration and epithelial disruption, whereas ST2⁻/⁻ mice exhibited markedly reduced damage and preserved mucosal architecture. Flow cytometric analysis of gastric tissue revealed significantly higher number of Ly6G⁺ neutrophils and F4/80⁺ macrophages in ethanol-treated WT mice compared to their ST2⁻/⁻ counterparts. Moreover, ethanol-treated WT mice exhibited a significantly higher number of CXCR4-expressing neutrophils, accompanied by an increased number of neutrophils producing TNF-α, IFN-γ, and IL-1β. Similarly, the number of IL-1β–producing macrophages was markedly elevated in WT mice compared to ST2⁻/⁻ mice. Notably, ethanol-treated WT mice also displayed a higher number of NLRP3⁺ neutrophils and macrophages, indicating enhanced inflammasome engagement. Consistent with these findings, gastric tissue from ethanol-treated WT mice demonstrated increased expression of molecular markers associated with inflammasome activation and pyroptotic cell death. Systemically, WT mice exhibited elevated serum concentrations of Th1/Th17 cytokines (IFN-γ, TNF-α, IL-1β, IL-17), while IL-10 levels remained similarly increased across genotypes, suggesting a preserved anti-inflammatory feedback despite pronounced immune activation.

Conclusion

IL-33/ST2 signaling aggravates ethanol-induced gastric injury by intensifying mucosal inflammation, promoting inflammasome-driven pyroptosis, and enhancing recruitment and activation of inflammatory immune cells. The relative protection observed in ST2⁻/⁻ mice underscores the pathological role of this axis and its potential as a therapeutic target in acute gastric damage.

Clinical Case Summary

Radiation proctitis is a common complication of radiotherapy and up to 80% of patients with chronic radiation proctitis experience rectal bleeding. Here we report the case of a 56-year-old man with type 3 von Willebrand disease (VWD) and high-titer VWF inhibitors who developed life-threatening rectorrhagia following prostate cancer radiotherapy, requiring urgent hospitalization and almost daily blood transfusions. Endoscopy revealed rectal angiodysplasia secondary to radiation proctitis as the bleeding source. Initial management included administration of recombinant FVIIa and tranexamic acid, paired with endoscopic hydrogel application and argon plasma coagulation (APC). Despite this, bleeding persisted with formation of rectal ulcers, prompting administration of prothrombin complex concentrate, extended half-life recombinant FVIII, plasma-derived VWF/FVIII concentrate, factor XIII, fibrinogen, octreotide, and bevacizumab. All interventions were ineffective and thus, after four weeks, off-label emicizumab in combination with rFVIIa was initiated, resulting in temporary improvement and subsequent discharge.
Four days later, the patient developed rectorrhagia and hemorrhagic shock. Repeated APCs and tamponade were unsuccessful, prompting a bipolar sigmoidostomy placement. Still, bleeding persisted, warranting an innovative and unconventional approach which included endoscopic application of autologous platelet-rich fibrin (PRF) and regular platelet transfusions despite normal platelet counts. Only after PRF applications were started hemostasis was gradually achieved. The patient continued emicizumab prophylaxis with biweekly outpatient PRF applications. At 10-month follow-up, he remained free of anemia and recurrence of gastrointestinal bleeding.
This case demonstrates successful management of refractory bleeding in inhibitor-complicated type 3 VWD using a combination of emicizumab and local PRF application when conventional approaches failed.

References

Figure 1. Endoscopic view of a large rectal ulceration with active bleeding, adherent clots, and visible blood vessels.
Figure 2. Endoscopic view of a healing rectal ulceration covered with fibrin.

Introduction

Gut metabolites are suggested to be potential etiological factors of irritable bowel syndrome (IBS). However, the potential mechanisms remain unclear.

Aims & Methods

This study aimed to elucidated the effect and mechanism of gut metabolite homocysteine(Hcy) in IBS development. A stress-induced IBS model was established using neonatal maternal separation (NMS), while a post-inflammatory IBS (PI-IBS) model was constructed by intracolonic administration of trinitrobenzene sulfonic acid (TNBS). A high-methionine diet was applied to elevate homocysteine levels in both blood and feces of mice or rats. Visceral hypersensitivity was assessed by measuring abdominal withdrawal reflex (AWR) and visceral motor responses (VMR). Carmine red was used to determine whole intestinal transit time. The composition of the gut microbiota in rats fecal samples was analyzed by using 16S rRNA sequencing. A series of cell and molecular experiments, including immunostaining, western blot and ELISA was conducted to illustrate the mechanism.

Results

We found that fecal Hcy levels were significantly elevated in both patients with IBS and rats with IBS induced by water avoidance stress (WAS). Moreover, fecal Hcy levels were positively correlated with the severity of IBS symptoms in patients. Next, we investigated the effects of Hcy on the gut-brain axis in NMS rat model and TNBS mice model. Our study showed that elevated Hcy in stool exacerbated visceral hypersensitivity, increased intestinal permeability and disrupted the mucus barrier of IBS rats/mice. Interestingly, folic acid supplementation lowered the Hcy levels and alleviated the effect of Hcy in exacerbating IBS phenotype. Mechanistically, treatment of Hcy inhibited the expression of NLR family pyrin domain containing 6 (NLRP6) and downregulated mucin MUC2 expression in LS174T and intestinal organoids, and impaired the expression of tight junction proteins ZO1 and Occludin in Caco2. Genetic overexpression of NLRP6 and PPARγ agonist Rosiglitazone rescued the inhibitory effect of Hcy on MUC2 expression. In addition, by using 16S rRNA sequencing, we found that Hcy reduced gut bacterial diversity and lowered the abundances of Coprococcus, Roseburia and Acetitomaculum in NMS rats.

Conclusion

Our study showed that gut metabolite Hcy was involved in the pathogenesis of IBS by disrupting mucus barrier and disturbing gut microbiota, indicating Hcy as a therapeutic target and folic acid administration as a potential strategy for IBS management.

Clinical Case Summary

A 66-year-old presented with a one-day history of abdominal pain and fevers. Computer tomography imaging (CT) revealed a foreign body in a sigmoid colon diverticulum with perforation and collection. A sigmoidoscopy failed to identify the foreign body. Ultrasound-guided foreign body extraction was unsuccessful. Surgical treatment was deemed high risk due to comorbidities and he was treated conservatively. Twelve days following a second sigmoidoscopy was performed due to persisting collection. A fish bone was found puncturing a sigmoid diverticulum. A through-the-scope (TTS) clip and methylene blue dye were applied. Removal was achieved with a snare. An over-the-scope clip (OTSC) successfully sealed the perforation.
Endoscopy is proving to be an increasingly viable minimally-invasive option for the treatment of foreign body colonic perforations when used early and in the absence of peritonitis or clinical instability¹. Unique to this case is that endoscopic closure was performed one week following perforation with associated collection, factors considered to influence procedure success due to inflammatory change^1,2. A standard TTS clip was unlikely to achieve closure strength. We used the OTSC system, designed to achieve full-thickness closure³. The technical complexity of using the OTSC system was visualisation which requires colonoscope withdrawal and mounting of a cap reducing endoscopic visibility. TTS clip and dye application prior to OTSC application proved beneficial in achieving definitive endoscopic perforation management. This is a technical aspect that to our knowledge has not been documented elsewhere in the literature.
Lessons:
1. Endoscopy can be effective in delayed colonic perforation management avoiding the need for surgery.
2. A three-step technique is proposed: 1) application of a locator (TTS clip and dye) 2) foreign body removal 3) OTSC application of the perforation site.
Fig1 CT image of fish bone and collection
Fig2 Endoscopic image OTSC

References

1) Morais R, Marques M, Macedo G. Endoscopic treatment of a foreign body–associated colonic perforation. Int. J. Colorectal Dis. 2020; 35: 165-167.
2) Rogalski P, Daniluk J, Baniukiewicz A et al. Endoscopic management of gastrointestinal perforations, leaks and fistulas. World J Gastroenterol. 2015; 21: 10542-10552.
3) Kobara H, Mori H, Nishiyama N et al. Over‐the‐scope clip system: A review of 1517 cases over 9 years. JGH. 2019; 34:22-30.

Introduction

Colonic polypectomy is a widely used endoscopic technique for colorectal cancer prevention. However, post-polypectomy bleeding (PPB) and local recurrence remain notable complications. Snare Tip Coagulation (STC) involves the application of thermal coagulation to the resection margin using the tip of the snare after polyp removal. This study aimed to evaluate the clinical efficacy of STC in reducing immediate and delayed PPB, as well as local recurrence, following polypectomy.

Aims & Methods

We retrospectively reviewed 156 patients who underwent endoscopic resection—either snare polypectomy or endoscopic mucosal resection (EMR)—for pedunculated or sessile colorectal polyps measuring 6–20 mm at a single center between January 2022 and February 2024. Patients were divided into two groups: those who received STC (n=78) and those who did not (control group, n=78). Primary outcomes included the incidence of PPB within 14 days and local recurrence at 12-month follow-up colonoscopy.

Results

The STC group demonstrated significantly lower rates of early (0.4%) and delayed (1.6%) PPB compared to the control group (1.9% and 3.8%, respectively; p<0.05). Local recurrence was also significantly reduced in the STC group (1.3%) versus the control group (4.8%; p=0.01). No significant differences were observed between the groups regarding procedure time or major complications such as perforation.

Conclusion

Snare Tip Coagulation is a safe and effective adjunctive technique in colorectal polypectomy, significantly reducing the risk of both post-procedural bleeding and local recurrence without increasing procedural complications. STC may offer particular benefit in the resection of medium-sized colorectal adenomas and should be considered for integration into routine endoscopic practice.

References

1. ​Snare Tip Soft Coagulation vs Argon Plasma Coagulation vs No Margin Treatment After Large Nonpedunculated Colorectal Polyp Resection: a Randomized Trial. Douglas K Rex, Gregory B Haber, Mouen Khashab, et al. Clin Gastroenterol Hepatol. 2024 Mar;22(3):552-561.e4.
2. Recurrences of advanced sessile and lateral spreading colorectal adenoma after endoscopic mucosal resection (EMR) thermal ablation versus no adjuvant therapy (RESPECT): a protocol of an international randomized controlled trial. Kemper G, Gerges C, Schoon EJ, Schreuder RM, Schrauwen RRW, Epping LSM, Beyna T, Drenth JPH, Gündug U, Siersema PD, van Geenen EJM; ENDOCARE study group.Trials. 2024 Feb 17;25(1):132. doi: 10.1186/s13063-024-07915-2.

Disclosure

Nothing to disclose

Clinical Case Summary

Condyloma acuminatum represents the clinical expression of epidermal infection caused by the human papillomavirus (HPV) one of the most common sexually transmitted diseases. These lesions range from benign papules to potential precursors of anal squamous cell invasive carcinoma.
Conventional treatments include surgical excision, cryotherapy, immunotherapy and CO₂ laser ablation.Endoscopic approaches such as radiofrequency ablation (RFA) and argon plasma coagulation (APC) are emerging as therapeutic alternatives with promising efficacy and safety profiles.
We report the case of a 49-year-old woman with no relevant medical or surgical history presented with rectal bleeding. Colonoscopy revealed a flat, polypoid lesion circumferentially involving approximately 3–4 cm of distal rectum (Fig1). Biopsy confirmed HPV-6–related condyloma. She underwent transanal minimally invasive surgery (TAMIS) in 2023.
One year later, symptoms recurred. Colonoscopy showed a similar lesion now extending over more than 5 cm of the lower rectum (Fig2-3).Given the lesion's recurrence, extensive involvement, and challenging location, endoscopic RFA was selected as the treatment modality. Using a HALO90° catheter (BARRX Medical Inc.) introduced through a flexible colonoscope, high-energy pulses (1000 pulses at 15 Joules per pulse) were applied to the affected mucosa, achieving near-complete ablation. Residual lesions and the anal canal were subsequently treated with APC (AXIAL catheter, 0.8 L/min, 30 W)(Fig4). The procedure was completed on an outpatient basis without immediate complications.
Post-procedurally, the patient reported transient anal pain and mild bleeding. At 3-month follow-up, mucosal healing was adequate (Fig5), with minor residual lesions successfully treated with APC (Fig6).
This case highlights the utility of combined endoscopic RFA and APC in managing extensive, recurrent rectal condyloma refractory to surgery reducing morbidity and preserving anorectal function.

References

1. Mark Schiffman, Susanne Krüger Kjaer, Chapter 2: Natural History of Anogenital Human Papillomavirus Infection and Neoplasia, JNCI Monographs, Volume 2003, Issue 31, June 2003, Pages 14-19, https://doi.org/10.1093/oxfordjournals.jncimonographs.a003476
2. Ramamoorthy S, Liu YT, Luo L, Miyai K, Lu Q, CarethersJM:Detection of multiple human papillomavirus genotypes in analcarcinoma. Infect Agent Cancer, 2010; 5:17.
3. Wiley DJ, Douglas J, Beutner K, et al.:External genital warts:Diagnosis, treatment, and prevention. Clin Infect Dis, 2002; 35(Suppl 2), S210-24.
4. Goldstone, R.N., Hasan, S.R., Drury, S. et al. A trial of radiofrequency ablation for anal intraepithelial neoplasia. Int J Colorectal Dis 32, 357–365 (2017). https://doi.org/10.1007/s00384-016-2679-2
5. Goldstone, R. N., Hasan, S. R., & Goldstone, S. E. (2017). Brief report: radiofrequency ablation therapy for anal intraepithelial neoplasia: results from a single-center prospective pilot study in HIV+ participants. JAIDS Journal of Acquired Immune Deficiency Syndromes, 76(4), e93-e97.
6. Smulian, A. G., Moore, D. M., Robertson, J. C., & Kralovic, S. M. (2014). Phase I Study Demonstrates Safety and Tolerability of Radiofrequency Ablation (RFA) of the Anal Mucosa. HIV Clinical Trials, 15(1), 36–44. https://doi.org/10.1310/hct1501-36.
7. Bulsiewicz WJ, Shaheen NJ. The role of radiofrequency ablation in the management of Barrett’s esophagus. Gastrointest Endosc Clin N Am 2011; 21: 95-109.

Introduction

Hepatocellular carcinoma (HCC), the sixth most prevalent malignancy and third leading cause of cancer-related mortality globally, accounts for 75-85% of primary liver cancers with a 5-year survival rate below 20%. Early-stage HCC is managed by resection or ablation, while advanced cases rely on transarterial therapies and systemic treatments. However, drug resistance to multi-kinase inhibitors (e.g., sorafenib) significantly limits efficacy. HCC progression is closely linked to an immunosuppressive tumor microenvironment characterized by T-cell co-stimulatory molecule deficiency and checkpoint activation (PD-L1/CTLA-4), driving T-cell exhaustion. Recent evidence highlights intratumoral microbiota dysbiosis as a modulator of immune remodeling, yet the spatial distribution patterns and regulatory mechanisms of bacterial communities within HCC lesions remain poorly defined.

Aims & Methods

This study employed invasion-adhesion-directed expression sequencing (INVADE-seq) integrated with single-cell host transcriptomics to profile intratumoral microbiota and construct microbial-immune interaction networks in five HCC tumors and paired adjacent normal tissues. Peritumoral microbiome analysis was conducted using 2b-Rad-M sequencing. Through systematic bacterial isolation (LB/Columbia/BCSA/Schaedler media) and Sanger sequencing validation, Pseudomonas koreensis (P.K) was identified as a key HCC-associated strain. Spatial localization and ultrastructural characterization were achieved via fluorescence in situ hybridization (FISH), multiplex fluorescence staining, and electron microscopy. Whole-genome sequencing delineated its genomic architecture, while metabolomics uncovered unique metabolic signatures. Functional validation using orthotopic HCC models (MYC/Alb and NSG mice) revealed its pro-tumorigenic role and immunomodulatory effects.

Results

2b-Rad-M sequencing showed significantly higher abundance of Bacillus, Pseudomonas, and Klebsiella in HCC tissues compared to adjacent non-tumor tissues, with reduced bacterial diversity. Circos plots highlighted increased Proteobacteria and Firmicutes in HCC. Through culturing and Sanger sequencing, P.K was identified as a dominant strain in HCC, showing quinolone sensitivity and urease activity. FISH confirmed its widespread presence in HCC tissues, with elevated abundance in T cells from advanced-stage patients. INVADE-seq analysis of five additional HCC tissue pairs also detected P.K Single-cell INVADE-seq revealed that T cells harboring this bacterium exhibited increased exhaustion scores and upregulated TOX expression. In MYC/Alb mice, oral gavage of P.K accelerated hepatocarcinogenesis, but no significant effect was observed in NSG immunodeficient mice, indicating immune system dependency. Whole-genome sequencing linked HCC-derived P.K to the fish pathogen P. koreensis CM-01, with enriched amino acid and carbon metabolism pathways. Metabolomics analysis associated it with purine/pyrimidine metabolism and cGMP-PKG signaling. Reduced spermidine levels impaired fatty acid oxidation, exacerbated T cell exhaustion, and promoted an immunosuppressive microenvironment, enhancing tumor proliferation, invasion, and metastasis.

Conclusion

This study reveals how intratumoral microbiota regulate the tumor microenvironment via the metabolism-immune axis, offering new insights into HCC immunotherapy. Targeting P.K-related metabolic pathways may provide a novel therapeutic strategy.

Disclosure

The authors declare no conflict of interest.