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Giardia lamblia is an important protozoan cause of diarrheal disease worldwide, delayed development and cognitive impairment in children in low- and middle-income countries, and protracted post-infectious syndromes in developed regions. G. lamblia resides in the lumen and at the epithelial surface of the proximal small intestine but is not mucosa invasive. The protozoan parasite is genetically diverse with significant genome differences across strains and assemblages. Animal models, particularly murine models, have been instrumental in defining mechanisms of host defense against G. lamblia, but mice cannot be readily infected with most human pathogenic strains. Antibiotic pretreatment can increase susceptibility, suggesting that the normal microbiota plays a role in controlling G. lamblia infection in mice, but the broader implications on susceptibility to diverse strains are not known. Here, we have used gnotobiotic mice to demonstrate that robust intestinal infection can be achieved for a broad set of human-pathogenic strains of the genetic assemblages A and B. Furthermore, gnotobiotic mice were able to eradicate infection with a similar kinetics to conventional mice after trophozoite challenge. Germ-free mice could also be effectively immunized by the mucosal route with a protective antigen, α1-giardin, in a manner dependent on CD4 T cells. These results indicate that the gnotobiotic mouse model is powerful for investigating acquired host defenses in giardiasis, as the mice are broadly susceptible to diverse G. lamblia strains yet display no apparent defects in mucosal immunity needed for controlling and eradicating this lumen-dwelling pathogen.

Far ultraviolet-C irradiation at 222 nm has potent bactericidal effects against severe infections such as peritonitis, with minimal cytotoxicity. Bacterial peritonitis due to bowel perforation is a serious condition with high mortality despite current treatments. This study investigated the safety and efficacy of intraperitoneal far ultraviolet-C irradiation at 222 nm. In vitro experiments optimized the fluid conditions for bacterial or protein concentrations prior to in vivo evaluation. In vivo efficacy was assessed in a rat peritonitis model induced by Escherichia coli, measuring intra-abdominal bacterial concentration, blood cytokine levels, and mortality rates. Safety was evaluated by analyzing cyclobutane pyrimidine dimers as markers of DNA damage in five abdominal organs: stomach, small intestine, colon, liver, and spleen. Statistical analyses employed parametric methods for normally distributed data and non-parametric methods for data without normality. Optimal in vitro conditions included 106 CFU/mL bacteria, 0.5 mW/cm2 irradiation, and 10−3 mg/mL protein. In the rat model, far ultraviolet-C irradiation at 222 nm significantly decreased intra-abdominal bacteria, reduced blood cytokines (interleukin-1β and interleukin-6), and elevated survival rates from 20% to 60%, compared to lavage alone. The formation of cyclobutane pyrimidine dimers was significantly lower with 222 nm irradiation than with 254 nm, suggesting reduced DNA damage. These findings indicate that far ultraviolet-C irradiation at 222 nm, when combined with lavage, represents a promising therapeutic strategy for bacterial peritonitis, providing effective bacterial reduction and a favorable safety profile. Further research is needed to verify these findings and investigate long-term safety and potential clinical applications. [ABSTRACT FROM AUTHOR]

Qiwei Baizhu Powder (QWBZP) has been proven effective in treating antibiotic-associated diarrhea (AAD), and the mechanism is associated with regulating the gut microbiota. However, the role of the bioactive compounds of QWBZP in regulating the gut microbiota is still unclear. In this study, 24 mice were divided into a normal control group (N), a model group (R), a QWBZP decoction group (TW), and a QWBZP-TG group (TG). AAD mouse models were established by mixed antibiotic administration. After modeling, mice in the TW group and TG group were treated with QWBZP decoction and QWBZP-TG, respectively. Mice in the N group and R group were gavaged with sterile water. 16S rRNA gene sequencing was used to investigate the changes of mucosa-associated microbiota (MAM) in the small intestine of mice. Moreover, the levels of diamine oxidase (DAO), D-Lactate, secretory immunoglobulin A (sIgA), interleukin 6 (IL-6), IL-10, and tumor necrosis factor-α (TNF-α) were detected using enzyme-linked immunosorbent assay (ELISA) kits. The results showed that QWBZP-TG significantly altered the diversity, structure, and abundance of MAM in the AAD mice. QWBZP-TG exerted a stronger suppression effect on Escherichia and Clostridium compared with QWBZP decoction. Meanwhile, QWBZP-TG downregulated the abundance of Lactobacillus , which elicited an opposite effect to QWBZP decoction. Prevotella was the signature bacteria that responded to the QWBZP-TG intervention. Furthermore, both QWBZP decoction and QWBZP-TG decreased the levels of DAO, D-Lactate, sIgA, IL-6, and TNF-α in the AAD mice. The role of glycosides is to help QWBZP ameliorate diarrhea symptoms by inhibiting the proliferation of diarrhea-associated bacteria, reducing inflammation and regulating immunity. [ABSTRACT FROM AUTHOR]

Background: To study the effect of laparoscopic ileopexy in patients with afferent-loop syndrome (ALS) after restorative proctocolectomy (RP). Method: Ileopexy has been the treatment of choice in patients with ALS for the last 5 years at our department. All patients who had undergone ileopexy for ALS between January 2019 and August 2023 were identified. Data were extracted from the medical records. All patients were contacted and asked standardized questions regarding symptoms of ALS. A symptom score was calculated and compared before surgery and at the last follow-up. Results: Ten patients, who had undergone ileopexy for ALS, were identified. Eight of these (80%) had been admitted with small bowel obstruction due to ALS. The remaining 2 patients had other symptoms indicative of ALS. In all patients, ileopexy was immediately effective in reducing symptoms. Symptoms recurred after 16.5 weeks (2–80) in 8 patients. Repeat laparoscopy showed that the ileopexy had slipped in 6 of these. Six had a new ileopexy with mesh. Later, one of these developed recurrent symptoms and had a new mesh ileopexy performed. No mesh complications were seen. Symptom score was reduced from 6.5 (1–9) to 2 (0–7) (p = 0.02) at the last follow-up. Conclusions: In this study, ileopexy is effective in reducing symptoms of ALS after RP. In a high proportion of patients, it is necessary to use mesh to ensure long-term fixation of the ileum. [ABSTRACT FROM AUTHOR]

Background: Weaning stress-induced diarrhea is widely recognized as being associated with gut microbiota dysbiosis. However, it has been challenging to clarify which specific intestinal microbiota and their metabolites play a crucial role in the antidiarrhea process of weaned piglets. Results: In this study, we first observed that piglets with diarrhea exhibited a lower average daily gain and higher diarrhea score, and elevated levels of lipopolysaccharide (LPS) and D-lactate (D-LA) compared to healthy piglets. Subsequently, we analyzed the differences in intestinal microbial composition and metabolite levels between healthy and diarrheal weaned piglets. Diarrheal piglets demonstrated intestinal microbiota dysbiosis, characterized primarily by a higher Firmicutes to Bacteroidota ratio, a deficiency of Lactobacillus amylovorus and Lactobacillus reuteri, and an increased abundance of Bacteroides sp.HF-5287 and Bacteroides thetaiotaomicron. Functional profiling of the gut microbiota based on Kyoto Encyclopedia of Genes and Genomes (KEGG) data was performed, and the results showed that tryptophan metabolism was the most significantly inhibited pathway in piglets with diarrhea. Most tryptophan metabolites were detected at lower concentrations in diarrheal piglets than in healthy piglets. Furthermore, we explored the effects of dietary indole-3-aldehyde (IAld), a key tryptophan metabolite, on intestinal development and gut barrier function in weaned piglets. Supplementation with 100 mg/kg IAld in the diet increased the small intestine index and improved intestinal barrier function by promoting intestinal stem cell (ISC) expansion in piglets. The promotion of ISC expansion by IAld was also confirmed in porcine intestinal organoids. Conclusions: These findings revealed that intestinal microbial tryptophan metabolite IAld alleviates impaired intestinal development by promoting ISC expansion in weaned piglets. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion Despite advancements in therapeutic options for Crohn's disease (CD), strictureplasty is a mainstay bowel‐preserving technique for small bowel CD. We sought to audit international practice across three high‐volume centres since the widespread use of biologic medication.A retrospective audit was performed for all strictureplasties undertaken for small bowel CD, over a 15‐year period (2006–2021), in three high‐volume centres in the United Kingdom and Italy. Primary endpoints were clinical recurrence and reoperation for recurrence.In all, 123 patients were included; 58% were men, 25% smoked and 60% had previous abdominal surgery for CD. Median age was 40 years (interquartile range 30–52 years), mean body mass index 22 (15–31) and median disease duration 138 months (81–255 months). 42% had been treated with biologics preoperatively. In total 338 strictureplasties were performed in 123 patients, with a median of two per patient (interquartile range 1–3). Complications occurred in 35%, with 8% scoring Clavien–Dindo Grade 3. There were no Grade 4/5 complications. Postoperative biologic treatment was administered to 84/123 patients (68.3%). Median follow‐up was 54 months. 41/123 patients (33.3%) developed clinical recurrence. Reoperation for recurrent stricturing was performed in 26/123 patients (21%). Clinical recurrence and reoperation rates were significantly higher in patients who continued to smoke after their index surgery.Strictureplasty remains a safe and effective surgical treatment for small bowel CD. Recurrence and reoperation rates remain high, regardless of postoperative biologic therapy. Smoking significantly increases the risk of recurrence. [ABSTRACT FROM AUTHOR]

A comprehensive endoscopic small and large intestinal untargeted step biopsy procedure was conducted to compare gene expression between the normal intestinal mucosa of healthy individuals and that of patients with colorectal tumors. From 78 participants (healthy individuals [n = 17], patients with colorectal conventional adenomas [n = 6], patients with Tis–T1 colorectal cancer [n = 41], patients with T2–4 colorectal cancer [n = 14]), biopsies of normal mucosa of the terminal ileum, right-sided colon (cecum and ascending colon), and left-sided colorectum (descending colon, sigmoid colon, and rectum) were obtained using a lower gastrointestinal endoscope. RNA was extracted from all samples, and total transcriptome sequencing was performed. Transcriptome data from 388 samples was analyzed. DNA was also extracted from tumor biopsy tissues and analyzed for whole-exome sequencing. In healthy individuals, gene expression differed significantly among the terminal ileum, right-sided colon, and left-sided colorectum, presumably linked to embryological factors. There were differences in gene expression in the normal mucosa in colorectal cancer patients, compared to healthy controls. Patients with tumors, especially T2–4 colorectal cancer, showed considerable variation in gene expression in non-tumor tissues, even in the terminal ileum distant from the tumor site. Based on endoscopic biopsies, the results imply cancer-predisposing conditions in seemingly normal tissues. The present study points to the importance of small intestine and cancer-predisposing conditions in the colon of colorectal cancer patients, with possible implications for developing novel immunotherapy and other therapeutic modalities. [ABSTRACT FROM AUTHOR]

Background: Although capsule endoscopy (CE) is a crucial tool for diagnosing small bowel diseases, the need to process a vast number of images imposes a significant workload on physicians, leading to a high risk of missed diagnoses. This study aims to develop an artificial intelligence (AI) model and application based on convolutional neural networks that can automatically recognize various lesions in small bowel capsule endoscopy. Methods: Three small bowel capsule endoscopy datasets were used for AI model training, validation, and testing, encompassing 12 categories of images. The model's performance was evaluated using metrics such as AUC, sensitivity, specificity, precision, accuracy, and F1 score to select the best model. A human-machine comparison experiment was conducted using the best model and endoscopists with varying levels of experience. Model interpretability was analyzed using Grad-CAM and SHAP techniques. Finally, a clinical application was developed based on the best model using PyQt5 technology. Results: A total of 34,303 images were included in this study. The best model, MobileNetv3-large, achieved a weighted average sensitivity of 87.17%, specificity of 98.77%, and an AUC of 0.9897 across all categories. The application developed based on this model performed exceptionally well in comparison with endoscopists, achieving an accuracy of 87.17% and a processing speed of 75.04 frames per second, surpassing endoscopists of varying experience levels. Conclusion: The AI model and application developed based on convolutional neural networks can quickly and accurately identify 12 types of small bowel lesions. With its high sensitivity, this system can effectively assist physicians in interpreting small bowel capsule endoscopy images.Future studies will validate the AI system for video evaluations and real-world clinical integration. [ABSTRACT FROM AUTHOR]

Radiotherapy plays an important role in the treatment of tumors, and enteritis is a common side effect of this therapy. The aim of present study was to evaluate the protective effect of melatonin and probiotics on radiation-induced intestinal tissue damage in rats. Histopathological, biochemical and microbiological samples were examined.Thirty-two Wistar Albino rats were randomly distributed into four groups: the control group, only radiotherapy (RT) group, radiotherapy plus melatonin (RT + MEL) groups and radiotherapy plus probiotics (RT + PROB) groups. The abdominal-pelvic region of the experimental rat was irradiated with in a single dose of 16 Gy. The melatonin was administered at a single dose of 50 mg/kg through intraperitoneal injection, 15 min before radiation exposure. The probiotic was administered orally every day to the rats for 5 days starting before radiotherapy.There was a statistically significant changes in histopathological (villus atrophy, mitotic activity, apoptotic index, goblet cell swelling, degenerative changes, atypia) and biochemical (oxidant and antioxidant status, IL-1β, IL-6 and TNF- α levels) parameters in the small intestine in the radiotherapy group G2 compared to the G1 control group (p < 0.05). However, a significant decrease was observed with the administration of probiotics and melatonin (p < 0.05). In addition, although positive bacterial growth was detected in the mesenteric lymph node of all rats in the radiotherapy group, there was no statistically significant difference between all groups (p > 0.05).Melatonin and probiotics were found to have a potent radioprotective effect against radiotherapy-induced acute small intestinal tissue damage. However, their superiority over each other was not observed. [ABSTRACT FROM AUTHOR]

Small intestinal bacterial overgrowth (SIBO) is a gastrointestinal condition characterized by abnormal colonization of bacteria in the small intestine, leading to overgrowth and alteration, which is linked to gastrointestinal issues, potentially affecting neurological and mental health. Despite existing research, we still do not understand how SIBO affects tryptophan metabolism and psychiatric diseases. We investigated the literature for connections between SIBO, tryptophan metabolism disruptions, and psychiatric disorders like autism, schizophrenia, Alzheimer's, and Parkinson's diseases. We also explored the interaction between thyroid disorders and their influence on SIBO and psychiatric illnesses. PubMed and Google Scholar databases were searched using keywords and phrases, individual and in combinations, like "SIBO," "gut microbiota," "neurologic disorders," "mental disorders," "tryptophan," "dopamine," and "thyroid disease." We focused on original research and review papers that presented empirical studies conducted on animal models and human subjects published in English between February 1992 to February 2023. The initial 2 634 534 records were preliminary screened based on title and abstract and then subjected to full-text review to exclude publications with insufficient data on SIBO, lack of a psychiatric disorder component, or methodological limitations compromising the integrity of the findings. The analysis highlights the significance of the association between psychiatric disorders and SIBO, emphasizing the role of gut-microbial diversity in mental health. We advocate for more detailed studies, including longitudinal research, to clarify the causal relationships between SIBO, gut dysbiosis, and psychiatric disorders and for an integrated approach while treating complex psychiatric conditions. [ABSTRACT FROM AUTHOR]

Objective: Endothelial dysfunction plays an important role in the pathogenesis of chronic kidney disease. Prostacyclin (PGI2), an endothelial cell‐produced endogenous prostaglandin, plays a crucial role in maintaining endothelial function. However, its effects on intestinal microcirculation and barrier function are not fully understood. We hypothesized that PGI2 improves intestinal microcirculation and barrier function via endothelial protective effects. Methods: ICR and ICGN (a spontaneous nephrotic model) mice were used in this study. Intestinal microcirculation was visualized in vivo to investigate PGI2 effects. Beraprost served as PGI2. PGI2 administration spanned 4 weeks, following which we assessed its influence on intestinal endothelial, intestinal barrier, and renal functions. Results: We visualized intestinal microcirculation and endothelial glycocalyx in the intestinal blood vessels. Beraprost administration induced a 1.2‐fold dilatation of the vascular diameter of the small intestine. Intestinal blood flow in ICGN mice was significantly reduced compared that in ICR mice but improved with beraprost administration. ICGN mice exhibited reduced serum albumin levels, decreased ambulation, an imbalance in intestinal reactive oxygen species (ROS)/nitric oxide (NO), and impaired tight junctions; all were ameliorated by beraprost administration. Conclusions: Beraprost improves intestinal microcirculation and barrier function by ameliorating ROS/NO imbalances, thereby reducing physical inactivity during renal failure. [ABSTRACT FROM AUTHOR]

Toxoplasmosis, a zoonotic infection caused by Toxoplasma gondii (T. gondii), poses a significant risk to human health and public safety. Despite the availability of clinical treatments, none effectively mitigate the intestinal barrier damage, which is the primary defense against T. gondii invasion. This study introduced aldehyde groups into the indole scaffold of a peptide-like structure to investigate the protective effects of these indole aldehyde derivatives on the intestinal barrier in mice with acute T. gondii infection. This approach leveraged the propensity of peptides and aldehyde groups to form hydrogen bonds. We synthesized a range of indole derivatives using the Vilsmeier–Haack reaction and evaluated their intestinal barrier protective effects both in vitro and in vivo. Our findings revealed that indole derivatives A1 (1-Formyl-1H-indole-3-acetonitrile), A3 (Indole-3-carboxaldehyde), A5 (2-Chloro-1H-indole-3-carboxaldehyde), A8 (1-Methyl-indole-3-carboxaldehyde), and A9 (1-Methyl-2-phenyl-1H-indole-3-carboxaldehyde) demonstrated a higher selectivity index compared to the positive control, spiramycin. These derivatives enhanced gastrointestinal motility, increased glutathione (GSH) levels in the small intestine, and reduced malondialdehyde (MDA) and nitric oxide (NO) levels in the small intestine tissue and diamine oxidase (DAO) and NO levels in the serum of infected mice. Notably, A3 exhibited comparable anti-T. gondii tachyzoites activity in the peritoneal cavity. Molecular docking studies indicated that the aldehyde group on the indole scaffold not only formed a hydrogen bond with NTPase-II but also interacted with TgCDPK1 through hydrogen bonding. Among the derivatives, A3 showed promising intestinal barrier protective effects in mice with acute T. gondii infection. This research suggests that indole derivatives could serve as a potential therapeutic strategy for intestinal diseases induced by T. gondii, offering a novel direction for treating intestinal barrier damage and providing valuable insights for the chemical modification of drugs targeting T. gondii. Furthermore, it contributes to the advancement of therapeutic approaches for toxoplasmosis. [ABSTRACT FROM AUTHOR]

Background: Small bowel capsule endoscopy (SBCE) is an established non-invasive diagnostic modality for a variety of small bowel pathologies and has a significant role in altering the treatment course. The diagnostic yield of SBCE in the published literature varies widely between 45 and 75%. Furthermore, it is unclear if any patient-related factors predict higher diagnostic yield. The aim of this study is to report the diagnostic yield of SBCE for suspected small bowel disease and identify any predictive factors for identifying significant pathology on SBCE. Method: A retrospective study was conducted at Mubarak Al-Kabeer Hospital in Kuwait for patients who underwent SBCE between October 2013 and February 2022. All patients underwent upper and lower endoscopy prior to referral for SBCE. Patients' medical records were reviewed to determine SBCE indications, results, and complications. The significance of the SBCE finding was classified according to the Saurin system. A logistic regression was performed to characterize baseline predictors for identifying significant pathology on SBCE. Results: Overall, 210 patients underwent SBCE and were included in the analysis. The mean age was 57.9 years (SD 18.5), and 129 (61.4%) were males. The most common indication for SBCE was obscure occult gastrointestinal bleed (75.7%), obscure overt gastrointestinal bleed (28.6%), and investigating gastrointestinal symptoms (7.6%). Adequate bowel preparation was achieved in most patients (88.1%), imaging of the entire small bowel was achieved in 194 patients (92.4%), and no adverse events were recorded. The overall diagnostic yield of SBCE for small bowel disease was 68.1%. The most common findings were vascular lesions in the small bowel (40.0%), small bowel ulcers (22.9%), and erosions (22.9%). On multivariate regression analysis, melena at baseline was significantly associated with increased odds of identifying high-risk lesions (Saurin class P2) (OR 2.1, 95%CI 1.03–4.30, p = 0.04). Conclusions: SBCE is an effective and safe tool for investigating small bowel pathology with a diagnostic yield of 68.1% in carefully selected patients undergoing such a test. Melena at baseline is the strongest predictor of identifying high-risk lesions, and patients with which should be prioritized for SBCE. [ABSTRACT FROM AUTHOR]

Objective: Rare disease Background: A congenital defect known as intestinal malrotation, which has only rarely been described in adults, is most frequently identified in children. For life-threatening consequences, such as intestinal ischemia and death, to be avoided, prompt detection is essential. We report a rare case of adult intestinal malrotation to emphasize the difficulty in diagnosis and surgical treatment. Case Report: An 18-year-old Saudi woman presented with generalized, gradually intermittent abdominal pain accompanied by nausea, and non-bilious vomiting. An abdominal computed tomography (CT) scan showed that the smallbowel loops were identified at the right side of the abdomen with the duodenojejunal junction at the right side or just right paramedian level as well, the superior mesenteric artery and vein had an inverted relationship, and the cecum was observed in the left lumber region. She was treated by open exploratory laparotomy adhesiolysis, the cecum was mobilized, the small-bowel adhesion under the liver was released, and an appendectomy was carried out. Postoperatively, she was managed with a double antibiotic regimen of ceftriaxone and metronidazole for 7 days. Conclusions: Although intestinal malrotation is uncommon in adults and very difficult to identify, it is frequently encountered in young populations. Adults with long history of vague or unexplained abdominal pain should undergo radiological studies to assess findings of intestinal malrotation. In our case, the result of a CT scan helped to make the diagnosis preoperatively. [ABSTRACT FROM AUTHOR]

The weaning phase in piglets causes significant physiological stress, disrupts intestinal integrity and reduces productivity, necessitating strategies to improve intestinal health and nutrient absorption. While current research highlights the role of diet in mitigating these adverse effects, identifying effective dietary supplements remains a challenge. This study evaluated the effects of Hermetia illucens (HI) larvae meal and astaxanthin (AST) on the intestinal histology of weaned piglets. In a controlled experiment, 48 weaned piglets were divided into six groups and received varying levels of HI larval meal (2.5% and 5%) and AST in their diets. The methodology involved comprehensive histological examinations of the small intestine, assessing absorption area, villi elongation, crypt depth, goblet cells, enterocytes and expression of ileal tight junction (TJ) proteins. The study found that HI larval meal significantly improved nutrient absorption in the jejunum and ileum (p < 0.001), thereby enhancing feed conversion. AST supplementation increased the number of enterocytes (p < 0.001). Both HI larval meal and AST positively affected intestinal morphology and function, increasing muscularis muscle mass and villi elongation (p < 0.001 and p < 0.05, respectively). The 2.5% HI meal improved the villi length to crypt depth ratio and slightly increased the goblet cell count (both p < 0.05). Ki‐67 antibody analysis showed increased cell proliferation in the duodenal and jejunal crypts, particularly with the 2.5% HI meal (p < 0.001). Insect meal did not affect TJ protein expression, indicating that it had no effect on intestinal permeability. These findings suggest that HI larval meal and AST can enhance the intestinal wellness and productivity of weaned piglets. [ABSTRACT FROM AUTHOR]

Nine cyclists (age: 26 ± 5 years, height: 168 ± 5 cm and mass 58.5 ± 4.5 kg) were observed using continuous glucose monitoring devices throughout a training camp. Interstitial glucose [iG] data were captured via the Abbott libre sense biosensor (Abbott Laboratories) and paired with the Supersapiens software (TT1 Products Inc.). [iG] data were split into time ranges, that is, overall (24‐hourly), day‐time (06:00–23:59), night‐time (00:00–05:59) and exercise. [iG] data were stratified into percentage of time, below range ([TBR] < 70 mg/dl), in range ([TIR] 70–140 mg/dl) and above range ([TAR] ≥ 141 mg/dl). Differences in diurnal and nocturnal data were analysed via repeated measures analysis of variance and paired t‐tests where appropriate. p‐value of ≤0.05 was accepted as significant. Riders spent an average of 3 ± 1% TAR, 93 ± 2% TIR and 8 ± 3% TBR. Mean 24 h [iG] was 93 ± 2 mg/dl with a coefficient of variation (CV) of 18 ± 1%. Mean (day: 95 ± 3 vs. night: 86 ± 3 mg/dl and p < 0.001) and CV (day: 18 ± 1 vs. night: 9 ± 1% and p < 0.001) in [iG] were higher during the day‐time hours. TAR was greater during the day (day: 3 ± 1 vs. night: 0 ± 0% and p < 0.001) but TBR and TIR were similar. Glucose levels below the clinical range may have implications for those without diabetes and warrants further investigation. Highlights: The data provided in this study offer novel insight into the daily glycaemic responses of female cyclists engaged in consecutive days' worth of heavy exercise training as part of a performance camp.% Time above range was greatest during exercise whereas, the % time below range was at its lowest. This may offer some insight into the demands of exercise and glucose variability.Riders maintained a high percentage of time spent in range, yet displayed some time <70 mg/dl, that is, hypoglycaemia. A proportionate amount of time was spent with glucose levels below the clinical range, the potential health and/or sports performance implications of this in athletic individuals without diabetes warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Metabolic and bariatric surgery (MBS) is gaining traction as a treatment option for adolescents with severe obesity. Since our weight center last published results in 2014, trends have shown increasingly diverse patient populations undergoing MBS and a shift from laparoscopic Roux-en-Y gastric bypass (LRYGB) to sleeve gastrectomy (LSG). We assessed outcomes including follow-up, weight loss, comorbidity resolution, and complications among our recent adolescent and young adult MBS patients. Methods: This is a retrospective cohort analysis of patients under 21 years of age with severe obesity who underwent MBS at a single institution between 2014 and 2020. Data on demographics, comorbidities, body mass index (BMI), percent of total body weight loss (%TBWL) at various timepoints, and subsequent complications were collected via chart review. Regression examined associations between preoperative factors, follow-up, and %TBWL. Results: There were 79 patients of whom 73% were female; overall, 53% were White, 24% Hispanic, and 15% non-Hispanic Black. The majority (80%) of patients underwent LSG. Three-fourths of patients had follow-up data beyond 1 year, and half beyond 3 years. The median %TBWL of LSG patients was 23% at a median follow-up of 3.0 years, and LRYGB patients 28% at 2.4 years. No preoperative factors were associated with follow-up or final %TBWL, but 6-month %TBWL predicted final %TBWL. Preoperatively, 73% of patients had at least one weight-related comorbidity, and 57% had documented improvements in at least one after surgery. There were three 30-day readmissions and no mortalities. Conclusions: This study, which is an update to a previous series from our center, reflects recent national trends with nearly half non-White patients and predominance of LSG over LRYGB. It adds to a growing body of evidence indicating that MBS is a safe and effective method of achieving weight loss and comorbidity resolution in adolescents with severe obesity. [ABSTRACT FROM AUTHOR]

Background: We previously showed worse outcomes among lower socioeconomic status (SES) groups following metabolic/bariatric surgery (MBS). In light of healthcare changes in response to COVID-19, this study aims to evaluate post-pandemic MBS outcomes and determine if prior socioeconomic disparities persisted in the post-COVID era. Methods: A retrospective chart review of patients undergoing primary Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) between 2015 and 2022 was performed. Patients were stratified into pre- and post-COVID groups. Post-COVID cohort was further stratified into high (HT) and low (LT) tier status based on Distressed Communities Index, a geocoded composite measure of SES. Preoperative characteristics and postoperative outcomes were compared between pre- and post-COVID cohorts, as well as between post-COVID HT and LT groups. Results: Of 709 patients, 82.9% were pre-COVID and 17.1% were post-COVID. Post-COVID cohort had greater rate of public insurance (46% vs. 37%, p < 0.001), longer wait time to surgery (mean 358 ± 609.8 days vs 241.9 ± 368.5 days, p = 0.045), and were more likely to undergo RYGB (69% vs. 56%, p = 0.010). Post-COVID patients also had lower risk of any complications on multivariable analysis (OR 0.599, 95% CI 0.372–0.963), had higher follow-up rates at post-discharge (95.8% vs 79.7%, p < 0.005), 6-month (93% vs. 82%, p < 0.001) and 12-month visits (75% vs. 63%, p = 0.005), and lost more weight at 12 months (67% excess weight loss (%EWL) vs. 58%EWL, p = 0.002). Among post-COVID HT and LT cohorts, previously seen disparities in complications were no longer seen. Finally, there were no differences in weight or follow-up rates between post-COVID HT and LT. Conclusions: Post-COVID changes to MBS care have resulted in improved short-term outcomes and reduced disparities for patients of lower SES. Further studies are needed to identify these positive factors to perpetuate practice patterns that optimize care for patients of all socioeconomic status. [ABSTRACT FROM AUTHOR]

Aim: The study objective was to evaluate the primary feasibility of endoscopic submucosal resection (ESD) and endoscopic full-thickness resection (EFTR) via balloon-assisted enteroscopy (BAE) to treat small bowel subepithelial lesions (SELs). Method: A retrospective case series study was performed. The first fifteen consecutive patients who underwent ESD (n = 10) and EFTR (n = 5) via BAE to remove small bowel SELs from November 2016 to December 2023 were included. The main outcome measures were the technique success rate, operative time and complication rate. Results: This research focused on 15 cases of jejunoileal SELs, four cases of lipomyoma, three cases of ectopic pancreas, two cases of NETs, three cases of benign fibrous tumours and three cases of angioma. The overall technique success rate was 86.7%, with 100% (10/10) and 60% (3/5) for BAE-ESD and BAE-EFTR, respectively, in removing small bowel SELs. Two cases of EFTR failed, as the BAE operation was unsuitable for tumour resection and suture repair of a perforated wound. No serious bleeding or any postoperative complications occurred. The median time of endoscopic resection via BAE for SELs was 44 min (range 22–68 min). Conclusion: ESD and EFTR via BAE might be alternative choices for treating small SELs in the small bowel, with the advantages of clear and accurate positioning and minimal invasiveness. However, its superiority over surgery still needs to be further investigated. [ABSTRACT FROM AUTHOR]

Introduction: Robotic-assisted metabolic and bariatric surgery (MBS) is gaining popularity. Revisional MBS is associated with higher perioperative morbidity compared to primary MBS. The optimal surgical approach to minimize complications in these complex cases is unclear. The goal of this study was to assess robot utilization in revisional MBS and compare laparoscopic and robotic revisional MBS outcomes in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database. Methods: A retrospective review of the MBSAQIP database was performed identifying revisional sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) cases from 2015 to 2022. Primary MBS, open/emergent cases, cases converted to another approach, and combined cases other than esophagogastroduodenoscopy were excluded. 30-Day outcomes for laparoscopic and robotic cases were compared using multivariate logistic regression adjusting for patient demographics, comorbidities, and operative variables. Results: 41,404 Cases (14,474 SG; 26,930 RYGB) were identified. From 2015 to 2022, the percentage of revisional SG and RYGB cases performed robotically increased from 6.1% and 7.3% to 24.2% and 32.0% respectively. Laparoscopic SG had similar rates of overall morbidity, leak, bleeding, readmission, reoperation, and length of stay compared to robotic. Laparoscopic RYGB had significantly higher rates of overall morbidity (6.2% vs. 4.8%, p < 0.001, AOR 0.80 [0.70–0.93]), blood transfusion (1.5% vs. 1.0%, p < 0.05, AOR 0.74 [0.55–0.99]), superficial incisional SSI (1.2% vs. 0.4%, p < 0.001, AOR 0.30 [0.19–0.47]), and longer length of stay (1.87 vs. 1.76 days, p < 0.001) compared to robotic. Laparoscopic operative times were significantly shorter than robotic (SG: 86.4 ± 45.8 vs. 113.5 ± 51.7 min; RYGB: 130.7 ± 64.7 vs. 165.5 ± 66.8 min, p < 0.001). Conclusion: Robot utilization in revisional bariatric surgery is increasing. Robotic surgery has lower postoperative morbidity and shorter length of stay in revisional RYGB when compared to laparoscopic. Robotic platforms may have the capacity to improve the delivery of care for patients undergoing revisional bariatric surgery. [ABSTRACT FROM AUTHOR]

Background: With the prevalence of obesity rising in the US, medical management is of increasing importance. Two popular options for the treatment of obesity are bariatric surgery (e.g. sleeve gastrectomy and Roux-en-Y gastric bypass) and the increasingly popular GLP-1 Receptor Agonists (GLP-1 s). This study examines the initial and long-term costs of GLP-1 s compared to bariatric surgery. Study design: We compared average 2023 national retail prices for GLP-1 s to surgical cost estimates from 2015 adjusted for inflation. We then plotted the cumulative medication cost over time against the flat cost of each surgery, thus calculating "break-even points" (when medication costs equal surgery costs). The findings revealed a crucial insight, for some GLP-1 s like Saxenda and Wegovy, the high cost of ongoing use surpasses the cost of RYGB in less than a year and sleeve gastrectomy within nine months. Even the most affordable option, Byetta, becomes costlier than surgery after around 1.5 years. Results: This highlights the importance of looking beyond the initial financial investment when considering cost-effectiveness. Additionally, while not directly assessed, this study acknowledges that GLP-1 s take time to reach full effectiveness, potentially delaying weight loss while accumulating costs. Concerns also exist about weight regain after discontinuing the medication. Conclusion: This study is limited by the real-world variation for individual treatment costs (e.g. insurance), a limited evaluation of long-term costs associated with either treatment modality and their co-morbidities, and the reality of patient preference providing subjective value to either modality. Overall, the study offers insights into the financial trade-offs between GLP-1 s and bariatric surgery. [ABSTRACT FROM AUTHOR]

Background: Food insecurity has been linked to higher rates of obesity. It has also been shown to diminish the effectiveness of weight loss strategies, including intensive lifestyle interventions. One essential component of food insecurity is having a geospatial disadvantage in access to healthy, affordable food, such as living within a food desert. This study aims to determine if food insecurity also impacts weight loss and nutritional outcomes in patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Methods: Clinical outcomes of patients who underwent RYGB or SG at Cleveland Clinic or affiliate regional hospitals in the United States from 2010 to 2018 were collected. Modified Retail Food Environmental Index (mRFEI) data was collected from the Center for Disease Control and merged with patient census tract data, allowing the patient cohort to be divided into those living in areas identified as food secure (mRFEI > 10%), food swamps (mRFEI = 1–10%), or food deserts (mRFEI = 0). Postoperative weight change was evaluated with quadratic growth mixture models and stratified by surgery type. Results: A total of 5097 patients were included in this study cohort, including 3424 patients who underwent RYGB and 1673 who underwent SG. The median duration of follow-up was 2.3 years (IQR 0.89–3.6 years). Food security status was not associated with postoperative weight change (RYGB p = 0.73, SG p = 0.60), weight loss nadir (RYGB p = 0.60, SG p = 0.79), or weight regain (RYGB p = 0.93, SG p = 0.85). Deficiencies in nutritional markers at 1–2 years after surgery were also not significantly different between food security groups. Conclusion: Despite the established relationship between food insecurity and obesity, food insecurity does not negatively impact weight loss or nutritional outcomes following RYGB or SG, demonstrating metabolic surgery as a powerful and equitable tool for treating obesity. Level of Evidence: IV. [ABSTRACT FROM AUTHOR]

Background: Roux-en-Y (RYGB) and one anastomosis gastric bypass (OAGB) represent two of the most used bariatric/metabolic surgery (BMS) procedures. Gut microbiota (GM) shift after bypass surgeries, currently understated, may be a possible key driver for the short- and long-term outcomes. Methods: Prospective, multicenter study enrolling patients with severe obesity, randomized between OAGB or RYGB. Fecal and blood samples were collected, pre- (T0) and 24 months postoperatively (T1). GM was determined by V3-V4 16S rRNA regions sequencing and home-made bioinformatic pipeline based on Qiime2 plugin and R packages. Objects: To compare OAGB vs RYGB microbiota profile at T1 and its impact on metabolic and nutritional status. Results: 54 patients completed the study, 27 for each procedure. An overall significant variation was detected in anthropometric and serum nutritional parameters at T1, with a significant, similar decrease in overall microbial alpha and beta diversity observed in both groups. An increase in relative abundances of Actinobacteria and Proteobacteria and a reduction of Bacteroidetes, no significant changes in Firmicutes and Verrucomicrobia, with an increase of the Firmicutes/Bacteroidetes ratio were observed. Conclusions: BMS promotes a dramatic change in GM composition. This is the first multicenter, RCT evaluating the impact of OAGB vs Roux-en-Y bypass on GM profile. The bypass technique per se did not impact differently on GM or other examined metabolic parameters. The emergence of slightly different GM profile postoperatively may be related to clinical conditions or may influence medium or long-term outcomes and as such GM profile may represent a biomarker for bariatric surgery's outcomes. [ABSTRACT FROM AUTHOR]

Upon entry into mammalian barrier tissues such as the intestine and the lungs, immune cells are metabolically reprogrammed by the local milieu. Increased cholesterol metabolism is a feature of tissue-resident lymphocytes in the intestinal lamina propria. Chemotactic oxysterol gradients position immune cells within microanatomical niches in mucosal tissues and also drive immune cell recruitment into the respiratory tract. Recent work provides increasing evidence of the importance of cholesterol metabolism in regulating homeostatic immune function and barrier defense during infection. Immune cell function is highly regulated by cell-autonomous cholesterol metabolism; in turn, secretion of cholesterol-derived metabolites by stromal and immune cells is crucially involved in controlling mucosal immunity via cell positioning and metabolic reprogramming. An in-depth understanding of the complex crosstalk between sterols and immune cells might facilitate the development of targeted candidate therapeutics to treat both chronic and infectious diseases. Cholesterol metabolites, particularly oxidized forms known as oxysterols, play crucial roles in modulating immune and metabolic processes across various tissues. Concentrations of local cholesterol and its metabolites influence tissue-specific immune responses by shaping the metabolic and spatial organization of immune cells in barrier organs like the small intestine (SI) and lungs. We explore recent molecular and cellular evidence supporting the metabolic adaptation of innate and adaptive immune cells in the SI and lung, driven by cholesterol and cholesterol metabolites. Further research should unravel the detailed molecular mechanisms and spatiotemporal adaptations involving cholesterol metabolites in distinct mucosal tissues in homeostasis or infection. We posit that pharmacological interventions targeting the generation or sensing of cholesterol metabolites might be leveraged to enhance long-term immune protection in mucosal tissues or prevent autoinflammatory states. [ABSTRACT FROM AUTHOR]

Background: Anaplastic large-cell lymphoma primarily involving the omentum is an extremely rare entity with variable clinical presentation. Owing to its rarity and nonspecific clinical manifestation, omental T-cell lymphoma is often diagnosed at a later stage, riddled with complications. While imaging modalities such as computed tomography scan can help a physician reach a diagnosis, cases that present with complications may require a multidisciplinary approach that combines surgical exploration along with consultation from Oncology. Case presentation: We hereby report a rare case of a 66-year-old African American male patient who presented to the emergency department with complaints of acute gastrointestinal obstruction. A computed tomography scan of the abdomen and pelvis revealed evidence of an internal hernia and surgical exploration revealed a hemorrhagic and infarcted omentum. Biopsies along with immunophenotypic studies confirmed the diagnosis of anaplastic T-cell lymphoma of the omentum complicated by Massilia timonae infection. Conclusion: The case highlights the significance of considering lymphoma, although rare, as a differential in a patient who presents with small bowel obstruction and the importance of investigating for malignancy for early diagnosis and treatment of primary omental lymphomas, before complications develop. [ABSTRACT FROM AUTHOR]

Internal hernias are herniations of abdominal viscera, usually small bowel, through congenital or acquired openings of the peritoneum or mesentery. Congenital hernias may involve anatomic fossae such as the epiploic foramen as well as those related to abnormal peritoneal or mesenteric defects; these include left and right paraduodenal, transomental, transmesenteric, pericecal and broad ligament hernias. Acquired hernias are due to defects in the mesentery or peritoneum, usually resulting from prior surgeries, and include those associated with Roux-en-Y surgery as well as colorectal cancer resections. Internal hernias account for 5.8% of small obstructions. Obstructed internal hernias are considered surgical emergencies due to the high risk of bowel strangulation. This review summarizes the various types of congenital and acquired internal hernias, their relevant anatomy, embryology, associated surgical history and imaging appearance. We will also discuss a location-based approach to identifying internal hernias on CT, as well as complications and relevant signs, of which abdominal imagers should be vigilant. [ABSTRACT FROM AUTHOR]

Caco-2 cells, a human colorectal adenocarcinoma cell line, are widely used to model small intestinal epithelial cells in the drug development process because they can predict drug absorption with high accuracy. However, Caco-2 cells have several issues. First, Caco-2 cells have little expression of cytochrome P450 3A4 (CYP3A4), which is a major drug-metabolizing enzyme in the human intestine. We previously developed Caco-2 cells whose expression of CYP3A4 can be controlled using doxycycline (Dox) (CYP3A4-Caco-2 cells) (Ichikawa et al., Sci. Rep, 2021). However, since the Tet-On system was used to regulate CYP3A4 expression in these cells, there was concern about drug-drug interactions. The second issue is that in the human small intestine, carboxylesterase 2 (CES2) is more highly expressed than carboxylesterase 1 (CES1), while in Caco-2 cells CES1 is more highly expressed. The third issue is the low level expression of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), a phase II drug-metabolizing enzyme. In this study, we used genome-editing technology to establish CES1 -knockout Caco-2 cells whose CYP3A4 and UGT1A1 expression can be regulated by the Tet-Off system. These cell lines would be useful in pharmaceutical researches, including intestinal toxicological studies, as an in vitro model for orally administered drugs. [Display omitted] • CES1-KO/CYP3A4 Caco-2 cells and CES1-KO/CYP3A4-UGT1A1 Caco-2 cells are established. • CES1-KO/CYP3A4 Caco-2 cells can be used to predict absorption of prodrugs metabolized by CES. • CES1-KO/CYP3A4 Caco-2 cells have the potential to predict the metabolism of orally administered drugs involving in CYP3A4 in the small intestine. • CES1-KO/CYP3A4-UGT1A1 Caco-2 cells have the potential to predict the metabolism of orally administered drugs involving in both CYP3A4 and UGT1A1 in the small intestine. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of small bowel motility disorders is performed by manometric evaluation of the contractile patterns of the small intestine. Conventional intestinal manometry systems include few pressure sensors at relatively long intervals. We have recently shown that high‐resolution jejunal manometry, with multiple closely spaced recording sites, allows the analysis of propagation patterns of intestinal motility in healthy subjects that cannot be detected with conventional manometry. The objective of this pilot study was to explore the feasibility and diagnostic value of high‐resolution intestinal manometry in patients with suspected small bowel dysmotility. Methods: Prospective pilot study evaluating intestinal motility patterns in 16 consecutive patients (16–61 years; 11 women) with severe, chronic digestive symptoms referred for the evaluation of intestinal motility and in 18 healthy controls (21–38 years; 8 women). A 36‐channel high‐resolution manometry catheter was orally placed under radiological guidance in the jejunum. Intestinal motility was continuously recorded for 3 h fasting and 2 h after a 450 kcal meal. The manometric recordings were analyzed in two formats: (a) with the high‐resolution data from 34 channels and (b) showing only the recordings from 5 channels separated by 7 cm intervals, mimicking a conventional manometry recording. Key Results: In the analysis mimicking conventional manometry, abnormal motility criteria were detected in six patients and in no healthy subject [bursts (n = 3), postprandial minute rhythm (n = 1) and myopathic pattern (n = 2)]. These classical dysmotility criteria were also detected by high‐resolution manometry. High‐resolution analysis detected one or more abnormal findings in seven additional patients that were not observed in any healthy subject, specifically: (a) abnormal propagation of Phase III (n = 3); (b) reduced propagated activity during Fasting Phase II (n = 4); (c) increased propagated activity during Fasting Phase II and postprandial phase (n = 1). Conclusions and Inferences: This pilot study suggests that high‐resolution intestinal manometry may improve the sensitivity of conventional manometry in the detection of intestinal motor dysfunction. [ABSTRACT FROM AUTHOR]

Older adults (≥65 yr) account for the majority of emergency laparotomies in the UK and are well characterised with reported outcomes. In contrast, there is limited knowledge on those patients that require emergency laparotomy but do not undergo surgery (NoLaps). A multicentre cohort study (n =64 UK surgical centres) recruited 750 consecutive NoLap patients (February 15th - November 15th 2021, inclusive of a 90-day follow up period). Each patient was admitted to hospital with a surgical condition treatable by an emergency laparotomy (defined by The National Emergency Laparotomy Audit (NELA) criteria), but a decision was made not to undergo surgery (NoLap). NoLap patients were predominately female (452 patients, 60%), of advanced age (median age 83.0 yr, interquartile range 77.0–88.8), frail (523 patients, 70%), and had severe comorbidity (750 patients, 100%); 99% underwent CT scanning. The commonest diagnoses were perforation (26%), small bowel obstruction (17%), and ischaemic bowel (13%). The 90-day mortality was 79% and influencing factors were >80 yr, underweight BMI, elevated serum lactate or creatinine concentration. The majority of patients died in hospital (77%), with those with ischaemic bowel dying early. For the 21% of NoLap patients that survived to 90 days, 77% returned home with increased care requirements. This study reports that the NoLap patient population present significant medical challenges because of their extreme levels of comorbidity, frailty, and physiology. Despite these complexities a fifth remained alive at 90 days. Further work is underway to explore this high-risk decision-making process. ISRCTN14556210. [ABSTRACT FROM AUTHOR]

Summary: Abdominal ultrasonography is an important diagnostic tool in the evaluation of colic, yet primary care equine veterinary practitioners are often limited by availability and access to low‐frequency (2–5 MHz curvilinear array or sector) abdominal transducers. Use of high‐frequency (5–10 MHz linear array) transrectal transducers has not previously been compared with use of abdominal transducers for transcutaneous abdominal ultrasonography. One recent pilot study established that there was no significant difference in organ detection by the two transducers on the right side of the equine abdomen, but the stomach, liver and kidney on the left side were less likely to be detected using the transrectal transducer in healthy horses. A clinical study found that the transrectal transducer can be used successfully using the FLASH protocol in horses presenting with colic, with high‐quality images that detected abnormalities of the peritoneal fluid, small intestine and large intestine. The transrectal transducer had decreased visualisation of the stomach and left kidney and was less likely to detect pathology surrounding these organs. This is the first series of studies to evaluate use of transrectal transducers in abdominal ultrasonography of the horse, a tool that is readily accessible to the field practitioner. [ABSTRACT FROM AUTHOR]

Summary: Background: Colic is the commonest emergency in first opinion equine practice. Early referral is important for horses requiring surgery. Fast localised abdominal ultrasonography of horses (FLASH) is frequently used as a diagnostic tool in the investigation of colic at referral hospitals, but its use in first opinion practice has not been evaluated. Objective: To assess the value of FLASH scanning in the primary assessment of horses with colic in the field, using a portable wireless ultrasound system. Study design: Prospective study (2018–2021). Methods: Any horse examined for colic as an emergency in a first opinion ambulatory practice was eligible for inclusion in the study. A FLASH examination was performed using a wireless handheld ultrasound scanner, with the images displayed on a smartphone or tablet. The findings on FLASH scans and the outcome of the case (recovered, referred for surgery or euthanised without referral) were recorded. Results: In total, 135 equids with acute colic were evaluated. Of the 135 horses, 49 (36%) had an abnormal finding on FLASH scanning, including distended loops of small intestine (n = 34), thickened small intestinal walls (n = 23) and/or distension of the stomach (n = 7). Reduced small intestinal motility was recorded in 52 animals (38%). Follow‐up information was available in all animals: 50 (37%) were euthanised due to clinical deterioration and the owners' decision not to undertake surgery; 85/135 (63%) survived, including 5/85 (6%) that underwent surgery and 80/85 (94%) that resolved with medical management. Main limitations: Small number of cases. Lack of results of post‐mortem examination of horses that were euthanised. Potential selection bias. Conclusion: The FLASH technique can be valuable in the primary assessment of horses with colic in first opinion ambulatory practice. Further evaluation with more cases is required. [ABSTRACT FROM AUTHOR]

Somatostatin (SST) is a peptide expressed in the peripheral and central nervous systems, as well as in endocrine and immune cells. The aim of the current study is to determine the percentage of SST immunoreactive (IR) neurons and their colocalization with choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), neuropeptide Y (NPY), and glial fibrillary acidic protein (GFAP) in the myenteric plexus (MP) and submucous plexus (SP) of the small intestine (SI) and large intestine (LI) of rats across different age groups from newborn to senescence using immunohistochemistry. In the MP of the SI and LI, the percentage of SST-IR neurons significantly increased during early postnatal development from 12 ± 2.4 (SI) and 13 ± 3.0 (LI) in newborn rats to 23 ± 1.5 (SI) and 18 ± 1.6 (LI) in 20-day-old animals, remaining stable until 60 days of age. The proportion of SST-IR cells then decreased in aged 2-year-old animals to 14 ± 2.0 (SI) and 10 ± 2.6 (LI). In the SP, the percentage of SST-IR neurons significantly rose from 22 ± 3.2 (SI) and 23 ± 1.7 (LI) in newborn rats to 42 ± 4.0 in 20-day-old animals (SI) and 32 ± 4.9 in 30-day-old animals (LI), before declining in aged 2-year-old animals to 21 ± 2.6 (SI) and 28 ± 7.4 (LI). Between birth and 60 days of age, 97–98% of SST-IR neurons in the MP and SP colocalized with ChAT in both plexuses of the SI and LI. The percentage of SST/ChAT neurons decreased in old rats to 85 ± 5.0 (SI) and 90 ± 3.8 (LI) in the MP and 89 ± 3.2 (SI) and 89 ± 1.6 (LI) in the SP. Conversely, in young rats, only a few SST-IR neurons colocalized with nNOS, but this percentage significantly increased in 2-year-old rats. The percentage of SST/NPY-IR neurons exhibited considerable variation throughout postnatal development, with no significant differences across different age groups in both the MP and SP of both intestines. No colocalization of SST with GFAP was observed in any of the studied animals. In conclusion, the expression of SST in enteric neurons increases in young rats and decreases in senescence, accompanied by changes in SST colocalization with ChAT and nNOS. [ABSTRACT FROM AUTHOR]

The consumption of fructose is increasing day by day. Understanding the impact of increasing fructose consumption on the small intestine is crucial since the small intestine processes fructose into glucose. ∆9-Tetrahydrocannabinol (THC), a key cannabinoid, interacts with CB1 and CB2 receptors in the gastrointestinal tract, potentially mitigating inflammation. Therefore, this study aimed to investigate the effects of the high-fructose diet (HFD) on the jejunum of rats and the role of THC consumption in reversing these effects. Experiments were conducted on Sprague–Dawley rats, with the experimental groups as follows: control (C), HFD, THC, and HFD + THC. The HFD group received a 10% fructose solution in drinking water for 12 weeks. THC groups were administered 1.5 mg/kg/day of THC intraperitoneally for the last four weeks. Following sacrification, the jejunum was evaluated for mucus secretion capacity. IL-6, JNK, CB2 and PCNA expressions were assessed through immunohistochemical analysis and the ultrastructural alterations via transmission electron microscopy. The results showed that fructose consumption did not cause weight gain but triggered inflammation in the jejunum, disrupted the cell proliferation balance, and increased mucus secretion in rats. Conversely, THC treatment displayed suppressed inflammation and improved cell proliferation balance caused by HFD. Ultrastructural examinations showed that the zonula occludens structures deteriorated in the HFD group, along with desmosome shrinkage. Mitochondria were found to be increased due to THC application following HFD. In conclusion, the findings of this research reveal the therapeutic potential of THC in reversing HFD-related alterations and provide valuable insights for clinical application. [ABSTRACT FROM AUTHOR]

[Display omitted] Microbial therapies have promising applications in the treatment of a broad range of diseases. However, effective colonization of the target region by therapeutic microorganisms remains a significant challenge owing to the complexity of the intestinal system. Here, we developed surface nanocoating-based universal platform (SNUP), which enabled the manipulation of controlled release and targeted colonization of therapeutic microbes in the digestive tract without the utilization of any targeting molecules. The system controlled the decomposition time of SNUP in the gut by regulating different modification layers and modification sequences on the microorganism's surface, so that the microorganism was released at a predetermined time and space. With the SNUP nanomodification technology, we could effectively deliver therapeutic microorganisms to specific complex intestinal regions such as the small intestine and colon, and protect the bioactivity of therapeutic microorganisms from destruction by both strong acids and digestive enzymes. In this study, we found that two layers SNUP-encapsulated Liiliilactobacillus salivarius (LS@CCMC) could efficiently colonize the small intestine and significantly improve the symptoms of a mouse model of Parkinson's disease through sustained secretion of γ-aminobutyric acid (GABA). This surface nanocoating-based universal platform system does not require the design of specific targeting molecules, providing a simple and universal method for colonized microbial therapy, target theranostics, precision medicine, and personalized medicine. [ABSTRACT FROM AUTHOR]

Background: Invasive fungal intestinal infections are rare in pediatric patients with limited studies reported to date. Methods: Retrospective study of invasive intestinal fungal infections in pediatric patients. For fungal specification, 18S rRNA gene PCR was performed using formalin-fixed paraffin-embedded tissues. Results: A total of 19 cases from 18 patients were included (13 males, 72%) with a median age of 20 days (8 days–14 years). About 13 patients (72%) presented within 67 days of birth and 11 patients (61%) were premature and 14 patients (78%) had a significant medical history. The most common location was the jejunum/ileum (56%) followed by the right colon and terminal ileum (22%). In 10 patients, the fungal elements were seen in the mucosa with 3 extending into the submucosa, and only 3 patients showed full-thickness involvement. Tissue necrosis and angioinvasion were seen in 13 (72%) and 8 (44%) patients, respectively. Morphologically, organisms consistent with Candida spp. were seen in 17 patients and with a mucoraceous mold in 1 patient. A 18S rRNA gene sequencing performed in 18 cases identified Candida dubliniensis in 16 cases and Candida spp. in 2 cases. During the study follow-up period, 56% of the patients died. Conclusion: In our experience, most cases were due to Candida spp. and predominantly in premature infants and associated with poor outcomes. [ABSTRACT FROM AUTHOR]

Background/Objectives: Western-type diets (WDs) damage the intestinal barrier by disrupting the gut microbiota composition and causing inflammation, leading to the development of obesity, type 2 diabetes, and non-alcoholic fatty liver disease. Short-chain fatty acids (SCFAs) are produced by the gut microbiota and found in fermented foods and can stimulate the anti-inflammatory action of type 3 innate lymphoid cells (ILCS3s) in the intestine. This study hypothesised that supplementing miso, a Japanese fermented food, to a WD could increase the levels of SCFAs and thus stimulate ILC3s, decreasing inflammation in the intestine and protecting intestinal barrier integrity. Methods: Mice with RORγt total (KI/KI) or partial (KI/w) knockout were fed a high-fat high-sugar diet (HFHSD) for eight weeks as a model of WD. Half of the mice received miso supplementation in addition to the HFHSD. Weight gain, glucose tolerance and insulin resistance, intestinal barrier integrity, intestinal immunity, and liver condition were assessed. Results: Miso supplementation increased SCFA levels in the small intestine, which stimulated ILC3 function in KI/w mice. Glucose tolerance was improved, intestinal barrier integrity was ameliorated, and mucus production was increased. The level of IL-22 was increased, while pro-inflammatory ILC1s, M1 macrophages, TNF-α, and IL-1β were decreased. Liver condition was not affected. Conclusions: This study demonstrated that miso supplementation influenced several factors involved in inflammation and intestinal barrier integrity by stimulating ILC3s in RORγt heterozygous mice. Moreover, it showed that the number of ILC3s is not the key factor in immune regulation, but rather the ability of ILC3 to produce IL-22 and employ it to control the immune response in the small intestine. [ABSTRACT FROM AUTHOR]

Oral tolerance is essential for intestinal homeostasis and systemic immune function. However, our understanding of how oral tolerance is maintained is inadequate. Here we report that food-derived nucleic acids promote oral tolerance through innate sensing pathways. We find that dietary nucleic acids, but not microbiota, expand the natural intraepithelial lymphocyte (IEL) pool, specifically in the small intestine. TGF-β1, produced by natural IELs, then promotes activation of gut CD103+ dendritic cells to support the induction of antigen-specific Treg cells in a mouse model of OVA-induced oral tolerance. Mechanistically, MAVS and STING are redundantly required for sensing dietary RNAs and DNAs to activate downstream TBK1 signalling to induce IL-15 production, which results in the accumulation of natural IELs. Thus, our study demonstrates a key role of food-triggered innate sensing pathways in the maintenance of natural IELs and oral tolerance. Oral tolerance is an important feature of gut immune homeostasis but how it is maintained is not fully known. Here authors show in a mouse model that dietary nucleic acids activate the MAVS and STING pathways, which leads to an increased abundance of natural intraepithelial lymphocytes, producing soluble factors that maintain tolerance. [ABSTRACT FROM AUTHOR]

Background: Parenteral nutrition (PN) without enteral nutrition (EN) leads to marked atrophy of gut‐associated lymphoid tissue (GALT), causing mucosal defense failure in both the gut and the extraintestinal mucosal system. We evaluated the effects of beta‐hydroxy‐beta‐methylbutyrate (HMB) on GALT and gut morphology in PN‐fed mice. Methods: Experiment 1: male Institute of Cancer Research mice were assigned to the Chow (n = 12), Control (standard PN: n = 10), or H600 and H2000 (PN containing 600 mg/kg or H2000 mg/kg body weight of Ca‐HMB: n = 12 and 10, respectively) groups. After 5 days of dietary manipulation, all mice were killed and the whole small intestine was harvested. GALT lymphocyte cell numbers and phenotypes of Peyer patch (PP), intraepithelial space, and lamina propria lymphocytes were evaluated. Experiment 2: 47 mice (Chow: n = 12; Control: n = 14; H600: n = 11; and H2000: n = 10) were fed for 5 days as in experiment 1. Proliferation and apoptosis of gut immune cells and mucosa, and protein expressions (mammalian target of rapamycin [mTOR], caspase‐3, and Bcl2) were evaluated in the small intestine. Results: Compared with the Controls, the Chow and HMB groups showed significantly higher PP cell numbers, prevented gut mucosal atrophy, inhibited apoptosis of gut cells, and increased their proliferation in association with increased mTOR activity and Bcl2 expression. Conclusion: HMB‐supplemented PN is a potentially novel method of preserving GALT mass and gut morphology in the absence of EN. [ABSTRACT FROM AUTHOR]

The small intestine contains a two-front nutrient supply environment created by luminal dietary and microbial metabolites (enteral side) and systemic metabolites from the host (serosal side). Yet, it is unknown how each side contributes differentially to the small intestinal physiology. Here, we generated a comprehensive, high-resolution map of the small intestinal two-front nutrient supply environment. Using in vivo tracing of macronutrients and spatial metabolomics, we visualized the spatiotemporal dynamics and cell-type tropism in nutrient absorption and the region-specific metabolic heterogeneity within the villi. Specifically, glutamine from the enteral side fuels goblet cells to support mucus production, and the serosal side loosens the epithelial barrier by calibrating fungal metabolites. Disorganized feeding patterns, akin to the human lifestyle of skipping breakfast, increase the risk of metabolic diseases by inducing epithelial memory of lipid absorption. This study improves our understanding of how the small intestine is spatiotemporally regulated by its unique nutritional environment. [Display omitted] • A comprehensive map of the small intestinal two-front nutrient supply environment • Characterization of spatiotemporal dynamics and cell-type tropism in nutrient absorption • Two nutrient supplies differentially configure the functional zonation of enterocytes • Breakfast skipping exacerbates metabolic diseases by inducing epithelial lipid absorption Spatiotemporal mapping of the environment of the mouse small intestine enables the examination of how circulating metabolites and dietary and gut microbial metabolites contribute to aspects of host metabolism and intestinal physiology. [ABSTRACT FROM AUTHOR]

Introduction: Antibiotic use in broilers is being discouraged globally due to the challenges it poses. This study was conducted to assess the effects of supplementing broilers with a Symbiotic-Enzyme complex (SEC) containing prebiotics (mannose oligosaccharides), probiotics (Clostridium butyricum and Bacillus subtilis), and enzymes (glucose oxidase, and α-galactosidase) as an alternative to antibiotics on growth performance, carcass and meat quality traits, mortality, linear body measurements, intestinal morphology and immune organ indexes. Method: A total of 864 mixed-sex 1-day-old arbor acres (AA+) broilers were allocated to 8 experimental groups replicated 9 times with 12 chickens per replicate. These included 6 treatment groups with SEC inclusion levels of 0.025, 0.04, 0.05, 0.06, 0.08, and 0.10%, respectively, and two control groups: a negative control group containing a basal diet only and the positive control group (Antibiotics group) containing a basal diet and antibiotic oxytetracycline added at 0.2%. Growth performance was measured on day 21 and 42, and the mortality, carcass, meat quality traits, linear body measurements, intestinal morphology, and organ size indexes were measured on day 42. Results: The results indicated that supplementing broilers with 0.1% SEC resulted in insignificant (P > 0.05) increases in average daily feed intake (ADFI), significant (P < 0.05) increases in the average daily gains (ADG), and significant (P < 0.05) reduction in a feed-to-gain ratio (F/G) in all the phases compared to the control and antibiotics groups. Supplementation of broilers with 0.1% SEC inclusion levels also significantly (P<0.05) increased the body slope length, chest width, chest depth, keel length, and shank circumference. Furthermore, broilers on diets containing 0.1% SEC inclusion level also had significantly (P < 0.05) higher dressed, semi-evisceration, evisceration, and breast muscle percentages. Including SEC at 0.1% also significantly (P < 0.05) increased villus height and villus-to-crypt ratio (V/C) but reduced crypt depth in the duodenum, jejunum, and ileum compared to the control groups. SEC inclusion at 0.1% significantly (P < 0.05) increased the spleen, bursal, and thymus indexes, respectively. Conclusion: Supplementation of broilers with 0.1% SEC can be used as an antibiotic alternative because it increases the F/G, improves the carcass and meat quality, increases the body conformation, improves the small intestines' functions, and immune organ size. [ABSTRACT FROM AUTHOR]

Objective: Rare disease. Background: Encapsulating peritoneal sclerosis (EPS) is a life-threatening complication of peritoneal dialysis (PD). It is characterized by a fibrous membrane partially or totally encasing the small bowel and is a rare cause of small bowel obstruction (SBO). Here we present a case of a young woman with a history of PD presenting with SBO due to EPS. Case Report: A 37-year-old woman with end-stage renal disease secondary to uncontrolled hypertension previously on PD presented to the emergency department for evaluation of 1 week of intractable nausea and vomiting associated with diffuse abdominal pain. Computed tomography of the abdomen showed findings consistent with a fibrous membrane encapsulating the small bowel and a small bowel follow-through revealed an SBO. She was diagnosed with secondary stage 3 EPS due to PD. She was started on prednisone and tamoxifen with quick resolution of her symptoms. Unfortunately, due to numerous recurrent SBOs, she is now being evaluated for surgical treatment options. Conclusions: This report has presented a case of EPS, a rare complication of PD, which requires early diagnosis and management to prevent potentially fatal consequences. Management should focus on treating the underlying condition, optimizing nutrition, and using corticosteroids or tamoxifen (alone or in combination) depending on disease state and contraindications, with the aim of reducing recurrent SBOs. Failure of conservative management may require surgical evaluation. [ABSTRACT FROM AUTHOR]

Effective inhibition of intestinal lipid uptake is an efficient strategy for the treatment of disorders related to lipid metabolism. Sterol O‐acyltransferase 2 (SOAT2) is responsible for the esterification of free cholesterol and fatty acids into cholesteryl esters. We found that intestine‐specific SOAT2 knockout (Soat2I‐KO) mice was capable to prevent the development of dietary induced obesity due to reduced intestinal lipid absorption. Soat2 siRNA/CS‐PLGA nanoparticle system was constructed to enable intestinal delivery and inhibition of Soat2. This nanoparticle system was composed of PLGA‐block‐PEG and chitosan specifically delivering Soat2 siRNAs into small intestines in mice, effectively inhibit intestinal lipid uptake and resolving obesity. In revealing the underlying mechanism by which intestinal SOAT2 regulating fatty acid uptake, enhanced CD36 ubiquitination degradation was found in enterocytes upon SOAT2 inhibition. Insufficient free cholesterol esterification promoted endoplasmic reticulum stress and recruitment of E3 ligase RNF5 to activate CD36 ubiquitination in SOAT2 knockdown enterocytes. This work demonstrates a potential modulatory function of intestinal SOAT2 on lipid uptake highlighting the therapeutic effect on obesity by targeting intestinal SOAT2, exhibiting promising translational relevance in the siRNA therapeutic–based treatment for obesity. [ABSTRACT FROM AUTHOR]

Background: Propionic acid (PA) is an intermediate product of metabolism of intestinal bacteria and may protect the intestinal barrier from disruption. The aim of the study was to investigate the apoptotic and proliferative processes in the small intestine (SI) of rats with type 2 diabetes mellitus (T2DM) on the background of metformin monotherapy and its combination with PA. Methods: Male Wistar rats were divided: 1) control; 2) T2DM (3-month high-fat diet followed by streptozotocin injection of 25 mg/kg of body weight); 3) T2DM + metformin (60 mg/kg, 14 days, orally); 4) T2DM + PA (60 mg/kg, 14 days, orally); 5) T2DM + PA + metformin. Western blotting, RT-PCR, and scanning electron microscopy were performed. Results: We observed profound changes in the SI of diabetic rats suggesting the disturbed intestinal homeostasis: impaired mitochondrial ultrastructure, increased cristae volume, and decreased content of proliferative marker Ki67 with almost unchanged proapoptotic caspase-3 and its p17 subunit levels. Metformin and PA monotherapies also led to an increased cristae volume, however, after their combination, a tendency to normalization of ultrastructure of mitochondria was observed. While there was a significant inhibition of proliferation in T2DM and, in greater extent, after metformin and PA monotherapies, differential influence on apoptosis in the SI was observed. While metformin inhibited apoptosis via Bax declining, PA mainly acted via caspase-3-dependent mechanism elevating its active p17 subunit. Conclusion: PA supplementation for the improvement of diabetes-induced gastrointestinal complications concurrently with metformin may be consider as a perspective supportive therapy. Data related to PA action on SI may be valuable during the development of new treatment strategies for diabetes induced intestinal disturbances raised after metformin treatment. [ABSTRACT FROM AUTHOR]

Background: Small mesenteric hiatal hernias (SMHHs) are defined as a small group of internal hernias (IHs) that frequently diagnosed in children. However, SMHHs are relatively rare in adults. Bowel loop herniation via an abnormal mesenteric defect can lead to strangulated intestinal obstruction. Congenital SMHHs are commonly observed in pediatric patients, with some cases involving neonatal death. Case presentation: A 24-year-old healthy male patient visited our hospital with a 2-day history of a sudden onset lower abdominal pain. He was initially diagnosed with enteritis. However, his symptoms worsened, and he was brought to our hospital. Contrast-enhanced computed tomography (CT) scan showed formation of a closed loop in the small intestine within the pelvis and signs of ischemia. As the patient was diagnosed with small bowel obstruction (SBO) caused by IH, emergency laparoscopic surgery was performed to loosen the obstruction. The patient was found to have ascites and small-bowel necrosis. A part of the small intestine that measured 30 cm was strangulated via a large-diameter defect (17 × 11 cm) in the ileal mesentery. Via a small abdominal incision, the necrotic bowel was resected, and the mesenteric defect was repaired. Conclusion: SMHHs are rare in adults, and they should be considered as potential causes of strangulated intestinal obstruction in adults without a history of laparotomy or trauma. [ABSTRACT FROM AUTHOR]

Canonical models of intestinal regeneration emphasize the critical role of the crypt stem cell niche to generate enterocytes that migrate to villus ends. Burmese pythons possess extreme intestinal regenerative capacity yet lack crypts, thus providing opportunities to identify noncanonical but potentially conserved mechanisms that expand our understanding of regenerative capacity in vertebrates, including humans. Here, we leverage single-nucleus RNA sequencing of fasted and postprandial python small intestine to identify the signaling pathways and cell–cell interactions underlying the python’s regenerative response. We find that python intestinal regeneration entails the activation of multiple conserved mechanisms of growth and stress response, including core lipid metabolism pathways and the unfolded protein response in intestinal enterocytes. Our single-cell resolution highlights extensive heterogeneity in mesenchymal cell population signaling and intercellular communication that directs major tissue restructuring and the shift out of a dormant fasted state by activating both embryonic developmental and wound healing pathways. We also identify distinct roles of BEST4+ enterocytes in coordinating key regenerative transitions via NOTCH signaling. Python intestinal regeneration shares key signaling features and molecules with mammalian gastric bypass, indicating that conserved regenerative programs are common to both. Our findings provide different insights into cooperative and conserved regenerative programs and intercellular interactions in vertebrates independent of crypts which have been otherwise obscured in model species where temporal phases of generative growth are limited to embryonic development or recovery from injury. [ABSTRACT FROM AUTHOR]

AbstractPurposeMaterials and methodsResultsConclusionsGastrointestinal (GI) injury is one of the serious problems of total-body irradiation (TBI). However, no fundamental treatment for TBI and other radiation-induced GI injury has yet been established. Valproic acid (VPA) administration reduces mortality in mice subjected to total-body irradiation (TBI) with X-rays. This study aimed to evaluate the effects of VPA on GI injury induced by TBI in mice.Mice were subjected to TBI with X-rays to induce GI injury. Changes in survival and weight were observed after VPA administration. The small intestine was then sampled at 0, 1, 3, 7, and 10 d after irradiation for histological and immunohistological evaluation and measurement of myeloperoxidase (MPO) activity and inflammatory cytokine levels (IL-1β).VPA (200 and 600 mg/kg) increased survival rate and reduced weight loss in model mice. IL-1β expression 1 d after irradiation was significantly lower in the VPA group than that in the vehicle group. Furthermore, the increase in MPO activity at 3 and 7 d after irradiation was significantly suppressed by VPA administration. Histological examination (hematoxylin and eosin staining) revealed that 600 mg/kg VPA inhibited inflammatory cell infiltration. Immunostaining for the proliferating cell nuclear antigen involved in cell proliferation showed that VPA suppressed the irradiation-induced decrease in cell proliferative capacity.Treatment with VPA in mice with GI injury caused by TBI suppressed inflammatory responses in small intestinal mucosal cells. These results suggest that VPA may be a useful therapeutic agent against TBI-induced small intestinal mucositis. [ABSTRACT FROM AUTHOR]

Acute upper gastrointestinal bleeding (UGIB) is a medical emergency with most common cause being peptic ulcer disease (PUD) or variceal bleeding. However, cancers that cause UGIB by invading the small intestine are uncommon, and the invasion of renal cell carcinoma (RCC) into the duodenum is an even rarer occurrence. A 55‐year‐old male presented with melena and right flank pain. Esophagogastroduodenoscopy (EGD) revealed an active bleeding source in the duodenum, later identified on contrast‐enhanced computed tomography (CECT) as a duodenorenal fistula (DRF) caused by direct extension of the RCC. The imaging confirmed the presence of a malignant renal mass infiltrating adjacent organs. This atypical presentation of RCC with DRF manifesting as UGIB underscores the importance of comprehensive evaluations in cases of gastrointestinal bleeding to identify rare underlying causes. [ABSTRACT FROM AUTHOR]

Cryptosporidiosis is a diarrheal disease caused by infection with Cryptosporidium spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population. Additional safe therapeutics are urgently required to tackle this unmet medical need. However, the development of anti-cryptosporidial drugs is hindered by a lack of understanding of the optimal compound properties required to treat this gastrointestinal infection. To address this knowledge gap, a diverse set of potent lysyl-tRNA synthetase inhibitors was profiled to identify optimal physicochemical and pharmacokinetic properties required for efficacy in a chronic mouse model of infection. The results from this comprehensive study illustrated the importance of balancing solubility and permeability to achieve efficacy in vivo. Our results establish in vitro criteria for solubility and permeability that are predictive of compound efficacy in vivo to guide the optimization of anti-cryptosporidial drugs. Two compounds from chemically distinct series (DDD489 and DDD508) were identified as demonstrating superior efficacy and prioritized for further evaluation. Both compounds achieved marked parasite reduction in immunocompromised mouse models and a disease-relevant calf model of infection. On the basis of these promising data, these compounds have been selected for progression to preclinical safety studies, expanding the portfolio of potential treatments for this neglected infectious disease. Editor's summary: Cryptosporidium spp. parasites are a major cause of potentially fatal, severe diarrhea in malnourished children, with no vaccine available and no reliably effective treatment for this at-risk population. Caldwell et al. studied the physiochemical properties required for lysyl-tRNA synthetase targeting anti-cryptosporidial compounds to be effective given the unique intracellular but extracytoplasmic location of infecting protozoa in the small intestine. Testing of two chemically distinct lead compounds in immunocompromised mouse and neonatal calf models showed improvement in infection, suggesting that these leads should be prioritized for further efficacy and safety studies. —Catherine Charneski [ABSTRACT FROM AUTHOR]

The mechanism that triggers the progressive dysregulation of cell functions, inflammation, and breakdown of tissues during aging is currently unknown. We propose here a previously unknown mechanism due to tissue autodigestion by the digestive enzymes. After synthesis in the pancreas, these powerful enzymes are activated and transported inside the lumen of the small intestine to which they are compartmentalized by the mucin/epithelial barrier. We hypothesize that this barrier leaks active digestive enzymes (e.g. during meals) and leads to their accumulation in tissues outside the gastrointestinal tract. Using immune-histochemistry we provide evidence in young (4 months) and old (24 months) rats for significant accumulation of pancreatic trypsin, elastase, lipase, and amylase in peripheral organs, including liver, lung, heart, kidney, brain, and skin. The mucin layer density on the small intestine barrier is attenuated in the old and trypsin leaks across the tip region of intestinal villi with depleted mucin. The accumulation of digestive enzymes is accompanied in the same tissues of the old by damage to collagen, as detected with collagen fragment hybridizing peptides. We provide evidence that the hyperglycemia in the old is accompanied by proteolytic cleavage of the extracellular domain of the insulin receptor. Blockade of pancreatic trypsin in the old by a two-week oral treatment with a serine protease inhibitor (tranexamic acid) serves to significantly reduce trypsin accumulation in organs outside the intestine, collagen damage, as well as hyperglycemia and insulin receptor cleavage. These results support the hypothesis that the breakdown of tissues in aging is due to autodigestion and a side-effect of the fundamental requirement for digestion. [ABSTRACT FROM AUTHOR]

Malabsorption of NaCl is the primary cause of diarrhea in inflammatory bowel disease (IBD). Coupled NaCl absorption occurs via the dual operation of Na:H and Cl:HCO3 exchange in the brush border membrane (BBM) of villus cells. Cl:HCO3 exchange is mediated by BBM transporters DRA (downregulated in adenoma) and PAT1 (putative anion transporter 1) in the mammalian small intestine. DRA/PAT1-mediated Cl:HCO3 exchange was significantly downregulated in the BBM of villus cells in a rabbit model of chronic ileitis, while Na:H exchange was unaffected. The inhibition of Cl:HCO3 exchange was restored in the rabbits when treated with a broad-spectrum immunomodulator, i.e. a glucocorticoid, indicating that the downregulation of DRA/PAT1 is likely to be immune-mediated during chronic enteritis. Mucosal mast cells are one type of key immune cells that are known to proliferate and release immune inflammatory mediators, thus playing a significant role in the pathogenesis of IBD. However, how mast cells may regulate DRA- and PAT1-mediated Cl:HCO3 exchange in a rabbit model of chronic ileitis is unknown. In this study, treatment of rabbits with chronic intestinal inflammation with the mast cell stabilizer ketotifen did not affect the mucosal architecture of the inflamed intestine. However, ketotifen treatment reversed the inhibition of Cl:HCO3 activity in the BBM of villus cells. This restoration of Cl:HCO3 activity to normal levels by ketotifen was found to be secondary to restoring the affinity of the exchangers for its substrate chloride. This observation was consistent with molecular studies, where the mRNA and BBM protein expressions of DRA and PAT1 remained unaffected in the villus cells under all experimental conditions. Thus, this study indicates that mast cells mediated the inhibition of coupled NaCl absorption by inhibiting Cl:HCO3 exchange in a rabbit model of chronic enteritis. [ABSTRACT FROM AUTHOR]