Is annual screening by fecal immunochemical test necessary after a recent colonoscopy?

Objective: The population-based colorectal cancer screening guidelines in Japan recommend an annual fecal immunochemical test (FIT). However, there is no consensus on the need for annual FIT screening for patients who recently performed a total colonoscopy (TCS). Therefore, we evaluated the repeated TCS results for patients with positive FIT after a recent TCS to assess the necessity of an annual FIT. Methods: We reviewed patients with positive FIT in opportunistic screening from April 2017 to March 2022. The patients were divided into two groups: those who had undergone TCS within the previous 5 years (previous TCS group) and those who had not (non-previous TCS group). We compared the detection rates of advanced neoplasia and colorectal cancer between the two groups. Results: Of 671 patients, 151 had received TCS within 5 years and 520 had not. The detection rates of advanced neoplasia in the previous TCS and non-previous TCS groups were 4.6% and 12.1%, respectively (p < 0.01), and the colorectal cancer detection rates were 0.7% and 1.5%, respectively (no significant difference). The adenoma detection rates were 33.8% in the previous TCS group and 40.0% in the non-previous TCS group (no significant difference). Conclusions: Only a few patients were diagnosed with advanced neoplasia among the patients with FIT positive after a recent TCS. For patients with adenomatous lesions on previous TCS, repeated TCS should be performed according to the surveillance program without an annual FIT. The need for an annual FIT for patients without adenomatous lesions on previous TCS should be prospectively assessed in the future.

A diminutive perivascular epithelioid cell tumor in the colon.

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor. Some papers have reported that colonoscopy could be used to treat PEComa with a predominantly pedunculated polyp, whereas surgical intervention is often required for cases with submucosal-type tumors. These findings suggest that the morphology of PEComa changes dramatically with disease progression. Because of the rapid progression of PEComa, endoscopic treatment remains challenging, and early-stage PEComa morphology is not well understood. A 64-year-old man presented to our hospital for a follow-up colonoscopy after undergoing multiple polypectomies. He had a medical history of colorectal adenoma and prostate cancer. A 4-mm pale blue elevated but not pedunculated lesion was observed in the transverse colon, an area where he had not had polyps previously. Since no epithelial change was observed, the presence of a submucosal tumor, such as a gastrointestinal stromal tumor, was suspected. Cold snare polypectomy was performed, and the lesion was completely resected. Histological evaluation using hematoxylin and eosin staining identified that the submucosal tumor included thickened vascular walls and adipose tissue. Although fragmented due to significant degeneration, spindle-shaped cells staining positive for smooth muscle actin were observed within and surrounding the unstructured hyalinized tissue with calcifications. Based on these findings, the lesion was diagnosed as angiomyolipoma, a subtype of PEComa. Complete resection was confirmed by histopathology. To our knowledge, this PEComa is the smallest of any PEComa reported in the literature. Our finding provides valuable insights into the very early stage of colorectal PEComas.

USP18 promotes colon adenocarcinoma progression via targeting the ERK-MNK signaling pathway.

BACKGROUND: Colorectal cancer is the third most common malignancy worldwide and is one of the leading causes of cancer-related mortality. Ubiquitin-specific peptidase 18 (USP18) protein has been reported to exert different tumor-related effects in distinct tumor types. Here, we initially investigated the expression and signaling pathways of USP18 in colon adenocarcinoma (COAD). METHODS: A quantitative real-time PCR was conducted to evaluate the mRNA level of USP18 in cultured cells. Immunohistochemical staining was used to explore the protein expression of USP18 in clinical COAD samples. Specific knockdown was achieved by transient transfection of small interfering RNAs into SW480 and HT29 cells using Lipo3000. Cell conting kit-8 assay, transwell assay and matrigel-transwell assays were conducted to evaluate proliferation, migration and invasion capacities, respectively. Western blotting was performed to analyze downstream signaling pathways. A chi-squared test and univariate and multivariate analyses were used to evaluate the clinical data. Xenografts from mice model were assessed to validate the in vitro findings. RESULTS: Higher USP18 level was identified in COAD tissues and was positively correlated with advanced tumor stage. High USP18 protein expression indicated poorer prognosis of COAD patients. Silencing USP18 suppressed COAD cell proliferation and invasion via destabilizing extracellular signal-regulated kinase (ERK) protein and suppressing ERK downstream pathways. Simultaneously silencing interferon-stimulated gene 15 (ISG15) with USP18 can partially rescue the tumor cell viability, indicating its involvement in USP18 signaling. The oncogenic effects of USP18 were also confirmed in mice models. CONCLUSIONS: USP18 plays oncogenic effects in colon adenocarcinoma via ISG15-ERK pathways. High USP18 expression indicates poor clinical outcomes for colon adenocarcinoma patients.

Design of chitosan colon delivery micro/nano particles for an Achillea millefolium extract with antiproliferative activity against colorectal cancer cells.

In this study, chitosan low molecular weight (LCH) and chitosan medium molecular weight (MCH) were employed to encapsulate a yarrow extract rich in chlorogenic acid and dicaffeoylquinic acids (DCQAs) that showed antiproliferative activity against colon adenocarcinoma cells. The design of CH micro/nanoparticles to increase the extract colon delivery was carried out by using two different techniques: ionic gelation and spray drying. Ionic gelation nanoparticles obtained were smaller and presented higher yields values than spray-drying microparticles, but spray-drying microparticles showed the best performance in terms of encapsulation efficiency (EE) (> 94%), also allowing the inclusion of a higher quantity of extract. Spray-drying microparticles designed using LCH with an LCH:extract ratio of 6:1 (1.25 mg/mL) showed a mean diameter of 1.31 ± 0.21 µm and EE values > 93%, for all phenolic compounds studied. The release profile of phenolic compounds included in this formulation, at gastrointestinal pHs (2 and 7.4), showed for most of them a small initial release, followed by an increase at 1 h, with a constant release up to 3 h. Chlorogenic acid presented the higher release values at 3 h (56.91% at pH 2; 44.45% at pH 7.4). DCQAs release at 3 h ranged between 9.01- 40.73%, being higher for 1,5- and 3,4-DCQAs. After gastrointestinal digestion, 67.65% of chlorogenic and most DCQAs remained encapsulated. Therefore, spray-drying microparticles can be proposed as a promising vehicle to increase the colon delivery of yarrow phenolics compounds (mainly chlorogenic acid and DCQAs) previously described as potential agents against colorectal cancer.

Paclitaxel in colon cancer management: from conventional chemotherapy to advanced nanocarrier delivery systems.

Paclitaxel, a potent chemotherapeutic agent derived from the bark of the Pacific yew tree, has demonstrated significant efficacy in the treatment of various cancers, including colon cancer. This comprehensive review delves into the conventional treatments for colon cancer, emphasizing the crucial role of paclitaxel in contemporary management strategies. It explores the intricate process of sourcing and synthesizing paclitaxel, highlighting the importance of its structural properties in its anticancer activity. The review further elucidates the mechanism of action of paclitaxel, its pharmacological effects, and its integration into chemotherapy regimens for colon cancer. Additionally, novel drug delivery systems, such as nanocarriers, liposomes, nanoparticles, microspheres, micelles, microemulsions, and niosomes, are examined for their potential to enhance the therapeutic efficacy of paclitaxel. The discussion extends to recent clinical trials and patents, showcasing advancements in paclitaxel formulations aimed at improving treatment outcomes. The review concludes with prospects in the field underscoring the ongoing innovation and potential breakthroughs in colon cancer therapy.

Codelivery of methotrexate and silibinin by niosome nanoparticles for enhanced chemotherapy of CT26 colon cancer cells.

Colon cancer (CC) is one of the most prevalent cancers in the world, and chemotherapy is widely applied to combat it. However, chemotherapy drugs have severe side effects and emergence of multi drug resistance (MDR) is common. This bottleneck can be overcome by niosome nanocarriers that minimize drug dose/toxicity meanwhile allow co-loading of incompatible drugs for combination therapy. In this research, silibinin (Sil) as a hydrophobic drug was loaded into the lipophilic part, and methotrexate (MTX) into the hydrophilic part of niosome by the thin film hydration (TFH) method to form Nio@MS NPs for CT26 colon cancer therapyin vitro. Our results indicated synthesis of ideal niosome nanoparticles (NPs) with spherical morphology, size of ∼100 nm, and a zeta potential of -10 mV. The IC50value for Nio@MS was determined ∼2.6 µg ml-1, which was significantly lower than MTX-Sil (∼6.86 µg ml-1), Sil (18.46 µg ml-1), and MTX (9.8 µg ml-1). Further, Nio@MS significantly reduced cell adhesion density, promoted apoptosis and increased gene expression level of caspase 3 and BAX while promoted significant downregulation of BCL2. In conclusion, the design and application of niosome to co-administer Sil and MTX can increase the drugs cytotoxicity, reduce their dose and improve anti-cancer potential by combating MDR.

Evaluating bacterial contamination and surgical site infection risks in intracorporeal anastomosis: Role of bowel preparation.

We recently read the study by Kayano et al on intracorporeal anastomosis (IA) for colon cancer, which assessed bacterial contamination and medium-term oncological outcomes and affirmed that IA is analogous to extracorporeal anastomosis in reducing intraperitoneal bacterial risk and achieving similar oncological results. Our commentary addresses gaps, particularly concerning bowel preparation and surgical site infections (SSIs), and highlights the need for comprehensive details on the bowel preparation methods that are currently employed, including mechanical bowel preparation, oral antibiotics (OA), their combination, and specific OA types. We emphasize the necessity for further analyses that investigate these methods and their correlation with SSI rates, to enhance clinical protocol guidance and optimize surgical outcomes. Such meticulous analyses are essential for refining strategies to effectively mitigate SSI risk in colorectal surgeries.

Laparoscopic right radical hemicolectomy: Central vascular ligation and complete mesocolon excision vs D3 lymphadenectomy - How I do it?

In colon cancer surgery, ensuring the complete removal of the primary tumor and draining lymph nodes is crucial. Lymphatic drainage in the colon follows the vascular supply, typically progressing from pericolic to paraaortic lymph nodes. While NCCN guidelines recommend the removal of 10-12 lymph nodes for adequate oncological resection, achieving complete oncological resection involves more than just meeting these numerical targets. Various techniques have been developed and studied over time to attain optimal oncological outcomes. A key technique central to this goal is identifying the ileocolic vessels at their origin from the superior mesenteric vessels. Complete excision of the visceral and parietal mesocolon ensures the intact removal of the specimen, while D3 lymphadenectomy targets all draining regional lymph nodes. Although these principles emphasize different aspects, they ultimately converge to achieve the same goal of complete oncological resection. This article aims to simplify the surgical steps that align with the principle of central vascular ligation and mesocolon mobilization while ensuring adequate D3 dissection.

Digestive and breast cancer patients managed during the first wave of COVID-19 pandemic: Short and middle term outcomes.

BACKGROUND: The first wave of coronavirus disease 2019 (COVID-19) pandemic in Spain lasted from middle March to the end of June 2020. Spanish population was subjected to lockdown periods and scheduled surgeries were discontinued or reduced during variable periods. In our centre, we managed patients previously and newly diagnosed with cancer. We established a strategy based on limiting perioperative social contacts, preoperative screening (symptoms and reverse transcription-polymerase chain reaction) and creating separated in-hospital COVID-19-free pathways for non-infected patients. We also adopted some practice modifications (surgery in different facilities, changes in staff and guidelines, using continuously changing personal protective equipment…), that supposed new inconveniences. AIM: To analyse cancer patients with a decision for surgery managed during the first wave, focalizing on outcomes and pandemic-related modifications. METHODS: We prospectively included adults with a confirmed diagnosis of colorectal, oesophago-gastric, liver-pancreatic or breast cancer with a decision for surgery, regardless of whether they ultimately underwent surgery. We analysed short-term outcomes [30-d postoperative morbimortality and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection] and outcomes after 3 years (adjuvant therapies, oncological events, death, SARS-CoV-2 infection and vaccination). We also investigated modifications to usual practice. RESULTS: From 96 included patients, seven didn't receive treatment that period and four never (3 due to COVID-19). Operated patients: 28 colon and 21 rectal cancers; laparoscopy 53.6%/90.0%, mortality 3.57%/0%, major complications 7.04%/25.00%, anastomotic leaks 0%/5.00%, 3-years disease-free survival (DFS) 82.14%/52.4% and overall survival (OS) 78.57%/76.2%. Six liver metastases and six pancreatic cancers: no mortality, one major complication, three grade A/B liver failures, one bile leak; 3-year DFS 0%/33.3% and OS 50.0%/33.3% (liver metastases/pancreatic carcinoma). 5 gastric and 2 oesophageal tumours: mortality 0%/50%, major complications 0%/100%, anastomotic leaks 0%/100%, 3-year DFS and OS 66.67% (gastric carcinoma) and 0% (oesophagus). Twenty breast cancer without deaths/major complications; 3-year OS 100% and DFS 85%. Nobody contracted SARS-CoV-2 postoperatively. COVID-19 pandemic-related changes: 78.2% treated in alternative buildings, 43.8% waited more than 4 weeks, two additional colostomies and fewer laparoscopies. CONCLUSION: Some patients lost curative-intent surgery due to COVID-19 pandemic. Despite practice modifications and 43.8% delays higher than 4 weeks, surgery was resumed with minimal changes without impacting outcomes. Clean pathways are essential to continue surgery safely.

A Rare Presentation of Epiploic Appendagitis as Chest Pain: A Case Report.

Epiploic appendagitis (EA) is an ischemic infarction of an epiploic appendage due to torsion or spontaneous thrombosis of the central vein of an epiploic appendage. It is a rare but benign and self-limiting cause of abdominal pain that is often misdiagnosed. The typical presentation of EA is lower abdominal pain, but pain can also occur in other parts of the abdomen. Presentation outside of the abdomen is a rare occurrence. Our patient presented with chest pain, and it was only through physical examination that mild right upper quadrant tenderness led to the suspicion of an intra-abdominal pathology, which was then confirmed with imaging. The patient responded to conservative management. Our possible explanation for this occurrence includes the proximity of the inflamed appendage to organs associated with chest pain and the possibility that patients sometimes describe pain location inaccurately.

Elevated Procalcitonin Levels can Occur in Bacterial Infections and also in Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) is a rare and challenging type of thyroid cancer originating from parafollicular cells (C cells) that produce calcitonin. Diagnosing and monitoring this carcinoma can be complex due to its unique biomarkers. Procalcitonin (PCT), a precursor of calcitonin, and carcinoembryonic antigen (CEA) are important markers for MTC. Elevated PCT levels, particularly when they remain high post-infection treatment, and elevated CEA levels are significant indicators for suspecting MTC. This report emphasises the diagnostic and prognostic importance of these biomarkers in MTC, highlighting their roles in detecting and monitoring disease progression. Integrating PCT and CEA measurements into routine clinical practice can enhance detection, provide understanding of therapeutic responses and aid in the effective management of MTC. LEARNING POINTS: Procalcitonin (PCT) is a more stable and reliable biomarker than calcitonin for diagnosing and monitoring medullary thyroid carcinoma (MTC).Elevated carcinoembryonic antigen (CEA) levels effectively monitor MTC progression, especially when calcitonin levels are inconsistent.Incorporating PCT and CEA measurements into routine practice enhances MTC management, providing reliable biomarkers for diagnosis and monitoring.

Activation of fetal-like molecular programs during regeneration in the intestine and beyond.

Tissue regeneration after damage is generally thought to involve the mobilization of adult stem cells that divide and differentiate into progressively specialized progeny. However, recent studies indicate that tissue regeneration can be accompanied by reversion to a fetal-like state. During this process, cells at the injury site reactivate programs that operate during fetal development but are typically absent in adult homeostasis. Here, we summarize our current understanding of the molecular signals and epigenetic mediators that orchestrate "fetal-like reversion" during intestinal regeneration. We also explore evidence for this phenomenon in other organs and species and highlight open questions that merit future examination.

"Textbook outcome(s)" in colorectal surgery: a systematic review and meta-analysis.

BACKGROUND: Textbook outcome (TO) is a composite measure used in surgery to evaluate post operative outcomes. No review has synthesised the evidence in relation to TO regarding the elements surgeons are utilising to inform their TO composite measure and the rates of TO achieved. METHODS: Our systematic review and meta analysis was conducted in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) recommendations. PubMed, EMBASE, and Cochrane central registry of controlled trials were searched up to 8th November 2023. Pooled proportions of TO, clinical factors considered and risk factors in relation to TO are reported. RESULTS: Fifteen studies with 301,502 patients were included in our systematic review while fourteen studies comprising of 247,843 patients were included in our meta-analysis. Pooled rates of TO achieved were 55% with a 95% confidence interval (95% CI) of 54-55%. When stratified by elective versus mixed case load, rates were 56% (95% CI 49-62) and 54% (95% CI 50-58), respectively. Studies reported differing definitions of TO. Reported predictors of achieving TO include age, left sided surgery and elective nature. CONCLUSIONS: TO is achieved, on average in 55% of reported cases and it may predict short and long term post operative patient outcomes. This study did not detect a difference in rates between elective versus mixed case load TO proportions. There is no standardised definition in use of TO. Standardisation of the composite is likely required to enable meaning comparison using TO in the future and a Delphi consensus is warranted.

Tips and tricks for transluminal specimen extraction and extra-abdominal sigmoid colon resection.

The purpose of this video is to demonstrate how to achieve adequate length and blood supply of the proximal colon for a perineal pull-through procedure, without splenic flexure mobilization during natural orifice specimen extraction. Key steps of the procedure include lateral mobilization of the colon, D3 lymph node dissection, preservation of the left colic artery, low ligation of the inferior mesenteric vein, ligation and washout of the distal bowel lumen, extra-abdominally proximal resection of sigmoid colon, purse-string sutures on the distal sigmoid colon, and an air leak test. Transluminal specimen extraction with extra-abdominal resection was found to be a cost-effective procedure with good cosmetic effects. Tension-free anastomosis was achieved by preservation of the left colic artery and low ligation of the inferior mesenteric vein. The purse-string sutures were placed on the proximal and distal bowel to avoid crossing the staples line. Transluminal specimen extraction with extra-abdominal resection required minimal manipulation intra-abdominally in comparison with other natural orifice specimen extraction techniques.

Assessment of the piroxicam-incited model of synchronized colitis in T-cell receptor alpha chain-deficient mice.

BACKGROUND: A multitude of mouse models are utilized to emulate and study intestinal inflammation. T-cell receptor alpha chain (TCRα)-deficient mice are used as a model of spontaneous colitis that has similarities with human ulcerative colitis. However, colitis is triggered late in the life of the mouse (age: 4-5 months), and inflammation does not develop at the same time in different mice. A previously conducted study reported that the administration of the drug piroxicam triggered predictable and early colitis in TCRα-deficient mice at the age of 6-8 weeks. However, a detailed characterization of ensuing inflammation was not provided. METHODS: We conducted an in-depth examination of piroxicam-triggered colitis in TCRα-deficient mice, with emphasis on spatial histopathologic changes and analysis of expression of inflammatory markers. Furthermore, we tested amelioration of colitis with dexamethasone. RESULTS: We confirmed that piroxicam induced a time-prescribed colitis and did so in the proximal colon as well as the cecum of TCRα-deficient mice. Piroxicam administration was observed to induce epithelial hyperplasia, goblet cell loss, and leukocyte infiltration with occasional ulceration. A Swiss roll technique was used to examine the colon and cecum in its entirety. Importantly, we observed that inflammation was multifocal segmental, with areas of tissue damage in between healthy tissue. In addition, we observed variability in the severity of inflammation among replicate animals and treatments, and that the administration of dexamethasone only partially ameliorated inflammation in the proximal colon. CONCLUSIONS: Piroxicam consistently induced multifocal segmental colitis in the proximal colon and cecum, although the degree of inflammation was reduced in the latter. Importantly, spatial variability in inflammation in the large intestine and the inter-replicate variation in the severity of inflammation must be taken into consideration when utilizing this murine model of synchronized colitis.

Applications of polysaccharides in enzyme-triggered oral colon-specific drug delivery systems: A review.

Enzyme-triggered oral colon-specific drug delivery system (EtOCDDS1) can withstand the harsh stomach and small intestine environments, releasing encapsulated drugs selectively in the colon in response to colonic microflora, exerting local or systematic therapeutic effects. EtOCDDS boasts high colon targetability, enhanced drug bioavailability, and reduced systemic side effects. Polysaccharides are extensively used in enzyme-triggered oral colon-specific drug delivery systems, and its colon targetability has been widely confirmed, as their properties meet the demand of EtOCDDS. Polysaccharides, known for their high safety and excellent biocompatibility, feature modifiable structures. Some remain undigested in the stomach and small intestine, whether in their natural state or after modifications, and are exclusively broken down by colon-resident microbiota. Such characteristics make them ideal materials for EtOCDDS. This article reviews the design principles of EtOCDDS as well as commonly used polysaccharides and their characteristics, modifications, applications and specific mechanism for colon targeting. The article concludes by summarizing the limitations and potential of ETOCDDS to stimulate the development of innovative design approaches.

Immunohistochemical analysis of tumor budding in stage II colon cancer: exploring zero budding as a prognostic marker.

Tumor budding, a biomarker traditionally evaluated using hematoxylin and eosin (H&E) staining, has gained recognition as a prognostic biomarker for stage II colon cancer. Nevertheless, while H&E staining offers valuable insights, its limitations prompt the utilization of pan-cytokeratin immunohistochemistry (IHC). Consequently, this study seeks to evaluate the prognostic significance of tumor budding using IHC in a contemporary cohort of stage II colon cancer patients, aiming to deepen our understanding of this critical facet in cancer prognosis. We conducted a retrospective, population-based cohort study including 493 patients with stage II colon cancer and evaluated tumor budding using IHC, following the H&E-based guidelines proposed by the International Tumor Budding Consensus Conference Group. Correlation between H&E-based and IHC-based tumor budding was assessed using a four-tiered scoring system that included a zero budding (Bd0) category. Survival analyses explored the prognostic significance of tumor budding assessed by IHC and H&E. As expected, IHC-based tumor budding evaluation yielded significantly higher bud counts compared to H&E (p < 0.01). Interestingly, 21 patients were identified with no tumor budding using IHC. This was associated with significantly improved recurrence-free survival (HR = 5.19, p = 0.02) and overall survival (HR = 4.47, p = 0.04) in a multivariate analysis when compared to tumors with budding. The Bd0 category demonstrated a 100% predictive value for the absence of recurrence. In conclusion, IHC-based tumor budding evaluation in stage II colon cancer provides additional prognostic information. The absence of tumor budding is associated with a favorable prognosis and may serve as a potential marker for identifying patients with no risk of recurrence.

Robotic versus laparoscopic right colectomy for nonmetastatic pT4 colon cancer: A European multicentre propensity score-matched analysis.

AIM: Minimally invasive surgery has been increasingly adopted for locally advanced colon cancer. However, evidence comparing robotic (RRC) versus laparoscopic right colectomy (LRC) for nonmetastatic pT4 cancers is lacking. METHODS: This was a multicentre propensity score-matched (PSM) study of a cohort of consecutive patients with pT4 right colon cancer treated with RRC or LRC. The two surgical approaches were compared in terms of R0, number of lymph nodes harvested, intra- and postoperative complication rates, overall (OS), and disease-free survival (DFS). RESULTS: Among a total of 200 patients, 39 RRC were compared with 78 PS-matched LRC patients. The R0 rate was similar between RRC and LRC (92.3% vs. 96.2%, respectively; p = 0.399), as was the odds of retrieving 12 or more lymph nodes (97.4% vs. 96.2%; p = 1). No significant difference was noted for the mean operating time (192.9 min vs. 198.3 min; p = 0.750). However, RRC was associated with fewer conversions to laparotomy (5.1% vs. 20.5%; p = 0.032), less blood loss (36.9 vs. 95.2 mL; p < 0.0001), fewer postoperative complications (17.9% vs. 41%; p = 0.013), a shorter time to flatus (2 vs. 2.8 days; p = 0.009), and a shorter hospital stay (6.4 vs. 9.5 days; p < 0.0001) compared with LRC. These results were confirmed even when converted procedures were excluded from the analysis. The 1-, 3- and 5-year OS (p = 0.757) and DFS (p = 0.321) did not significantly differ between RRC and LRC. CONCLUSION: Adequate oncological outcomes are observed for RRC and LRC performed for pT4 right colon cancer. However, RRC is associated with lower conversion rates and improved short-term postoperative outcomes.

Sleep Deprivation Induces Gut Damage via Ferroptosis.

Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.

Effects of chronic unpredictable mild stress on gut sensation and function in male mice.

Stress has been linked to the development of irritable bowel syndrome (IBS), and various methods have been explored to model IBS in combination with other stimuli. However, it remains unclear whether stress alone can induce IBS in animals. This study aimed to investigate the impact of chronic unpredictable mild stress (CUMS) on gastrointestinal sensation and function in mice and assess the potential of CUMS as a modeling approach for IBS. To evaluate the mice's behavior, we conducted open field test, sucrose preference test and weighed the mice, revealing that CUMS indeed induced anxiety and depression in the mice and caused weight loss. Further analyses, including fecal analysis, a total gastrointestinal transport test, and a colon propulsion test, demonstrated that CUMS led to abnormal defecation and disruptions in gastrointestinal motility in the mice. Additionally, the abdominal withdrawal reflex test indicated an increase in visceral sensitivity in CUMS-exposed mice. Histological examination using hematoxylin and eosin staining revealed no significant histological alterations in the colons of CUMS-exposed mice, but it did show a minor degree of inflammatory cell infiltration. In summary, the findings suggest that CUMS can replicate IBS-like symptoms in mice, offering a novel top-down approach to modeling IBS.