Fibrosing colonopathy associated with cysteamine bitartrate delayed-release capsules in cystinosis patients.

BACKGROUND: The objective of this report is to identify and characterize cases of fibrosing colonopathy, a rare and underrecognized adverse event, associated with cysteamine delayed-release (DR) in patients with nephropathic cystinosis. METHODS: We searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the medical literature for postmarketing reports of fibrosing colonopathy associated with cysteamine through August 2, 2023. RESULTS: We identified four cases of fibrosing colonopathy reported with the use of cysteamine DR. The time to onset ranged from 12 to 31 months. In one case, the patient required surgery to have a resection of a section of the strictured colon and a diverting ileostomy. Fibrosing colonopathy was diagnosed by histopathology in two of the cases. CONCLUSIONS: Our case series identified the risk of fibrosing colonopathy in patients taking cysteamine DR and prompted regulatory action by the FDA. As outlined in changes to the U.S. prescribing information for cysteamine DR, healthcare professionals should be aware of the potential risk of fibrosing colonopathy with cysteamine DR, especially as symptoms can be non-specific leading to misdiagnosis or delayed diagnosis. If the diagnosis of fibrosing colonopathy is confirmed, consideration should be given to permanently discontinuing cysteamine DR and switching to cysteamine immediate-release treatment.

Colitis cystica profunda of the rectum diagnosed by endoscopic submucosal dissection.

Colitis cystica profunda is a rare and benign lesion characterized by mucus-containing cysts under the mucosa of the colon and rectum. We report a patient with localized colitis cystica profunda of the rectum diagnosed by endoscopic submucosal dissection. Although colitis cystica profunda is benign, it is sometimes indistinguishable from other malignant lesions. So early excision and biopsy make sense.

Unraveling the role of Epac1-SOCS3 signaling in the development of neonatal-CRD-induced visceral hypersensitivity in rats.

AIMS: Visceral hypersensitivity in irritable bowel syndrome (IBS) is widespread, but effective therapies for it remain elusive. As a canonical anti-inflammatory protein, suppressor of cytokine signaling 3 (SOCS3) reportedly relays exchange protein 1 directly activated by cAMP (Epac1) signaling and inhibits the intracellular response to inflammatory cytokines. Despite the inhibitory effect of SOCS3 on the pro-inflammatory response and neuroinflammation in PVN, the systematic investigation of Epac1-SOCS3 signaling involved in visceral hypersensitivity remains unknown. This study aimed to explore Epac1-SOCS3 signaling in the activity of hypothalamic paraventricular nucleus (PVN) corticotropin-releasing factor (CRF) neurons and visceral hypersensitivity in adult rats experiencing neonatal colorectal distension (CRD). METHODS: Rats were subjected to neonatal CRD to simulate visceral hypersensitivity to investigate the effect of Epac1-SOCS3 signaling on PVN CRF neurons. The expression and activity of Epac1 and SOCS3 in nociceptive hypersensitivity were determined by western blot, RT-PCR, immunofluorescence, radioimmunoassay, electrophysiology, and pharmacology. RESULTS: In neonatal-CRD-induced visceral hypersensitivity model, Epac1 and SOCS3 expressions were downregulated and IL-6 levels elevated in PVN. However, infusion of Epac agonist 8-pCPT in PVN reduced CRF neuronal firing rates, and overexpression of SOCS3 in PVN by AAV-SOCS3 inhibited the activation of PVN neurons, reduced visceral hypersensitivity, and precluded pain precipitation. Intervention with IL-6 neutralizing antibody also alleviated the visceral hypersensitivity. In naïve rats, Epac antagonist ESI-09 in PVN increased CRF neuronal firing. Consistently, genetic knockdown of Epac1 or SOCS3 in PVN potentiated the firing rate of CRF neurons, functionality of HPA axis, and sensitivity of visceral nociception. Moreover, pharmacological intervention with exogenous IL-6 into PVN simulated the visceral hypersensitivity. CONCLUSIONS: Inactivation of Epac1-SOCS3 pathway contributed to the neuroinflammation accompanied by the sensitization of CRF neurons in PVN, precipitating visceral hypersensitivity and pain in rats experiencing neonatal CRD.

Simplified Magnetic Resonance Index of Activity Is Useful for Terminal Ileal but not Colonic Disease in Pediatric Crohn Disease.

BACKGROUND: Ileocolonoscopy (IC) detects mucosal inflammation and magnetic resonance enterography (MRE) detects transmural inflammation in Crohn disease (CD). We aimed to evaluate the relationship between the simplified magnetic resonance index of activity (MARIAs) and measures of inflammation by IC in children with newly diagnosed CD. METHODS: Retrospective review of 140 patients 6-18 years of age with CD who had baseline IC and MRE within 5 weeks of diagnosis. MARIAs was calculated for each intestinal segment (terminal ileum [TI], ascending colon, transverse colon, descending colon, sigmoid colon, rectum), defined as (1 × thickness > 3 mm) + (1 × edema) + (1 × fat stranding) + (2 × ulcers). Sensitivity and specificity were derived using receiver operating characteristic (ROC) curves to compare MARIAs to IC findings. RESULTS: Using IC as the reference standard, the cutoff MARIAs ≥1 identified TI segments with active inflammation with 84% sensitivity, 73% specificity, 85% positive predictive value (PPV), 70% negative predictive value (NPV), and area under the curve (AUC) 0.782 (95% confidence interval [CI] 0.689-0.876). The cutoff MARIAs ≥2 identified TI segments with severe lesions with 87% sensitivity, 76% specificity, 87% PPV, 76% NPV, and AUC 0.814 (95% CI 0.712-0.916). There was poor sensitivity for all colonic segments. CONCLUSION: The MARIAs is feasible and accurate in reflecting disease activity in the TI, but not in the colon, in children with newly diagnosed CD. Although the MARIAs may be useful for monitoring TI disease activity over time, full assessment continues to require both IC and MRE.

Melanosis Coli Is Not Associated with Colonic Dysmotility Nor Severity of Pediatric Functional Constipation.

BACKGROUND: Sennosides are commonly used for the treatment of constipation and associated with melanosis coli. In the present study, we evaluated the utility of melanosis coli as a marker of severity and its association with colonic motility in children with functional constipation. METHODS: Prospective study includes pediatric patients undergoing colonic manometry and colonic biopsies. Demographic data, medication history, surgical history, colonic manometry results (gastrocolonic response to a meal, high-amplitude propagating contractions, and nonpropagating contractions), colonic manometry catheter position, and pathologic results were collected and analyzed. We compared those variables with outcome (need for surgery) between both patient groups (presence or absence of melanosis coli). RESULTS: A total of 150 patients were included, median age was 9.9 years (range 2.1-18) and 77 (51.3%) were female, 17 had melanosis. Patients who took sennosides had higher rates of melanosis coli compared to those who did not (adjusted OR 13.88; 95% CI 4.05-47.57; P < 0.001), and we did not find an association between melanosis coli and use of other medications (osmotic laxatives, bisacodyl, lubiprostone), age, gender, weight, and height. We found no significant difference in the results colonic manometry between patients with and without melanosis coli. The rates of surgery for constipation between patients with and without melanosis coli were not statistically different. (OR 3.00; 95% CI 0.45-20.07; P = 0.257). CONCLUSIONS: Melanosis coli is associated with sennosides use, but it does not influence colonic motility nor is associated with increased subsequent need for surgery in pediatric functional constipation.

Colonoscopic Ultrasound-Guided Fine-Needle Aspiration Using a Curvilinear Array Transducer: A Single-Center Retrospective Cohort Study.

BACKGROUND: Curvilinear array ultrasound transducers enable tissue sampling and have therapeutic capabilities. Nevertheless, colonic intubation and maneuvering with these transducers is technically challenging and is therefore typically limited to the rectosigmoid area. This retrospective cohort study aimed to evaluate the safety, feasibility, and diagnostic yield of colonoscopic ultrasound-guided fine-needle aspiration in deep colonic intubation. IMPACT OF INNOVATION: The impact of this innovation is to enable tissue sampling of colonic and extracolonic lesions guided by endoscopic ultrasound. TECHNOLOGY, MATERIALS, AND METHODS: Curvilinear array ultrasound is used in the evaluation of luminal and extraluminal colonic diseases. Thirteen patients underwent colonoscopic ultrasound with a curvilinear array ultrasound endoscope in a single center for subepithelial lesions, cancer staging, and extracolonic lesions from July 2015 to February 2021. Endosonography was performed using an Olympus EU-ME1 and GF-UCT 180 with a 5-12MHz curvilinear array transducer. The primary outcome was the percentage of patients who were successfully scanned with the endoscopic ultrasound. The secondary outcomes included the success rate of fine-needle aspiration, the diagnostic yield of the tissue samples, and the adverse events related to the procedure. PRELIMINARY RESULTS: A total of 13 female patients underwent colonoscopic ultrasound. All patients (100%, 13/13) were successfully scanned. Fine-needle aspiration was deemed necessary and successfully performed in 100% (5/5) of the patients. Tissue samples collected by fine-needle aspiration resulted in a diagnostic yield of 60%, and no adverse events resulted from this intervention. CONCLUSIONS: This study demonstrates the feasibility of performing colonoscopic ultrasound with a curvilinear array transducer. Fine-needle aspiration for subepithelial, colonic, and extracolonic lesions is feasible and safe in this setting with no adverse events reported in our study. FUTURE DIRECTIONS: Future research should be directed toward validating colonoscopic ultrasound with a curvilinear array transducer technique in prospective randomized trials. Studies evaluating the feasibility and safety of endoscopic ultrasound-guided interventions in the colon, such as abscess drainage and enteral anastomosis, should be considered.

Evaluating the Validity of the Clavien-Dindo Classification in Colectomy Studies: A 90-Day Cost of Care Analysis.

BACKGROUND: The Clavien-Dindo classification is widely used to report postoperative morbidity but may underestimate the severity of colectomy complications. OBJECTIVE: The purpose of this study was to assess how well the Clavien-Dindo classification represents the severity of all grades of complications after colectomy using cost of care modeling. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at a comprehensive cancer center. PATIENTS: Consecutive patients (N = 1807) undergoing elective colon or rectal resections without a stoma performed at Memorial Sloan Kettering Cancer Center between 2009 and 2014 who were followed up for ≥90 days, were not transferred to other hospitals, and did not receive intraperitoneal chemotherapy were included in the study. MAIN OUTCOME MEASURES: Complication severity was measured by the highest-grade complication per patient and attributable outpatient and inpatient costs. Associations were evaluated between patient complication grade and cost during 3 time periods: the 90 days after surgery, index admission, and postdischarge (<90 d). RESULTS: Of the 1807 patients (median age = 62 y), 779 (43%) had a complication; 80% of these patients had only grade 1 or 2 complications. Increasing patient complication grade correlated with 90-day cost, driven by inpatient cost differences (p < 0.001). For grade 1 and 2 patients, most costs were incurred after discharge and were the same between these grade categories. Among patients with a single complication (52%), there was no difference in index hospitalization, postdischarge, or total 90-day costs between grade 1 and 2 categories. LIMITATIONS: The study was limited by its retrospective design and generalizability. CONCLUSIONS: The Clavien-Dindo classification correlates well with 90-day costs, driven largely by inpatient resource use. Clavien-Dindo does not discriminate well among patients with low-grade complications in terms of their substantial postdischarge costs. These patients represent 80% of patients with a complication after colectomy. Examining the long-term burden associated with complications can help refine the Clavien-Dindo classification for use in colectomy studies. See Video Abstract at http://links.lww.com/DCR/B521. EVALUACIN DE LA VALIDEZ DE LA CLASIFICACIN DE CLAVIENDINDO EN ESTUDIOS DE COLECTOMA ANLISIS DEL COSTO DE LA ATENCIN EN DAS: ANTECEDENTES:La clasificación de Clavien-Dindo es utilizada ampliamante para conocer la morbilidad posoperatoria, pero puede subestimar la gravedad de las complicaciones de la colectomía.OBJETIVO:Evaluar que tan bien representa la clasificación de Clavien-Dindo la gravedad de todos los grados de complicaciones después de la colectomía utilizando un modelo de costo de la atención.DISEÑO:Estudio de cohorte retrospectivo.ENTORNO CLÍNICO:Centro oncológico integral.PACIENTES:Pacientes consecutivos (n = 1807) sometidos a resecciones electivas de colon o recto sin estoma realizadas en el Memorial Sloan Kettering Cancer Center entre 2009 y 2014 que fueron seguidos durante ≥ 90 días, no fueron transferidos a otros hospitales y no recibieron quimioterapia intraperitoneal.PRINCIPALES MEDIDAS DE VALORACION:Gravedad de la complicación medida por la complicación de mayor grado por paciente y los costos atribuibles para pacientes ambulatorios y hospitalizados. Se evaluó la asociación entre el grado de complicación del paciente y el costo durante 3 períodos de tiempo: posterior a la cirugía (hasta 90 días), a su ingreso y posterior al egreso (hasta 90 días).RESULTADOS:De los 1807 pacientes (mediana de edad de 62 años), 779 (43%) tuvieron una complicación; El 80% de estos pacientes tuvieron solo complicaciones de grado 1 o 2. El aumento del grado de complicación del paciente se correlacionó con el costo a 90 días, impulsado por las diferencias en el costo de los pacientes hospitalizados (p <0,001). Para los pacientes de grado 1 y 2, la mayoría de los costos se incurrieron después del alta y fueron los mismos entre ambas categorías. Entre los pacientes con una sola complicación (52%), no hubo diferencia en el índice de hospitalización, posterior al alta o en el costo total de 90 días entre las categorías de grado 1 y 2.LIMITACIONES:Diseño retrospectivo, generalizabilidad.CONCLUSIONES:La clasificación de Clavien-Dindo se correlaciona bien con los costos a 90 días, impulsados en gran parte por la utilización de recursos de pacientes hospitalizados. Clavien-Dindo no discrimina entre los pacientes con complicaciones de bajo grado en términos de sus costos sustanciales posterior al alta. Estos pacientes representan el 80% de los pacientes aquellos con una complicación tras la colectomía. Examinar la carga a largo plazo asociada a las complicaciones puede ayudar a mejorar la clasificación de Clavien-Dindo para su uso en estudios de colectomía. Consulte Video Resumen en http://links.lww.com/DCR/B521.

Interstitial cells of Cajal and human colon motility in health and disease.

Our understanding of human colonic motility, and autonomic reflexes that generate motor patterns, has increased markedly through high-resolution manometry. Details of the motor patterns are emerging related to frequency and propagation characteristics that allow linkage to interstitial cells of Cajal (ICC) networks. In studies on colonic motor dysfunction requiring surgery, ICC are almost always abnormal or significantly reduced. However, there are still gaps in our knowledge about the role of ICC in the control of colonic motility and there is little understanding of a mechanistic link between ICC abnormalities and colonic motor dysfunction. This review will outline the various ICC networks in the human colon and their proven and likely associations with the enteric and extrinsic autonomic nervous systems. Based on our extensive knowledge of the role of ICC in the control of gastrointestinal motility of animal models and the human stomach and small intestine, we propose how ICC networks are underlying the motor patterns of the human colon. The role of ICC will be reviewed in the autonomic neural reflexes that evoke essential motor patterns for transit and defecation. Mechanisms underlying ICC injury, maintenance, and repair will be discussed. Hypotheses are formulated as to how ICC dysfunction can lead to motor abnormalities in slow transit constipation, chronic idiopathic pseudo-obstruction, Hirschsprung's disease, fecal incontinence, diverticular disease, and inflammatory conditions. Recent studies on ICC repair after injury hold promise for future therapies.

Label-Free Quantitative Phase Imaging Reveals Spatial Heterogeneity of Extracellular Vesicles in Select Colon Disorders.

Three-dimensional (3D) imaging and quantitative analysis of extracellular vesicles (EVs) remain largely unexplored, mainly because of limitations in detection techniques. In this study, EVs from patients diagnosed with colorectal cancer (CRC) and ulcerative colitis were examined. To investigate the spatial heterogeneity and 3D refractive index (RI) distribution of single EVs, a label-free digital holographic tomography technique was used at a submicrometer spatial resolution. The presented image-processing algorithms were used in quantitative analysis with digital staining and 3D visualization, the determination of the EV size distribution and extraction of fractions with different RIs. Reconstructed 3D RI distributions revealed variations in the spatial heterogeneity of EVs related to tissue specificity, such as CRC, normal colonic mucosa, and ulcerative colitis, as well as the isolation procedures used. The RI values of EVs isolated from solid tissues of frozen CRC samples were also dependent on the tumor grade and cancer cell proliferation. The simultaneous examination of cell culture models confirmed the association of the RI of EVs with the tumor grade. 3D-RI data analysis generates new perspectives with the optical, contact-free, label-free examination of the individual EVs. Depending on the specific tissue and isolation method, EVs exhibit significant spatial heterogeneity. The optical parameters of single EVs enabled their classification into two unique subgroups with different RI values.

Preventable Emergency Department Visits After Colorectal Surgery.

BACKGROUND: The emergency department plays a common and critical role in the treatment of postoperative patients. However, many quality improvement databases fail to record these interactions. As such, our understanding of the prevalence and etiology of postoperative emergency department visits in contemporary colorectal surgery is limited. Visits with potentially preventable etiologies represent a significant target for quality improvement, particularly in the current era of rapidly evolving postoperative and ambulatory care patterns. OBJECTIVE: We aimed to characterize postoperative emergency department visits and identify factors associated with these visits for potential intervention. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at an academic medical center. PATIENTS: Consecutive patients undergoing colectomy or proctectomy within the division of colorectal surgery at an academic medical center between 2014 and 2018 were included. MAIN OUTCOME MEASURES: Frequency and indication for emergency department visits, as well as clinical and sociodemographic factors associated with emergency department visits in the postoperative period, were included measures. RESULTS: From the 1763 individual operations, there were 207 emergency department visits from 199 patients (11%) within 30 days of discharge. Two thirds of emergency department visits led to readmission. Median (interquartile range) time to presentation was 8 days (4-16 d). Median time in the emergency department was 7.8 hours (6.0-10.1 h). One third of visits were identified as potentially preventable, most commonly for pain (17%) and stoma complications (excluding dehydration; 13%). A primary language other than English was associated with any postoperative emergency department visit risk ratio of 2.7 (95% CI, 1.3-5.3), as well as a preventable visit risk ratio of 3.6 (95% CI, 1.7-8.0). LIMITATIONS: This was a single-center study and a retrospective review. CONCLUSIONS: One third of emergency department visits after colorectal surgery are potentially preventable. Special attention should be directed toward those patients who do not speak English as a primary language. See Video Abstract at http://links.lww.com/DCR/B648. SE PUEDEN EVITAR LAS VISITAS AL SERVICIO DE URGENCIA DESPUS DE UNA CIRUGA COLORECTAL: ANTECEDENTES:Las unidades de emergencia tienen un rol fundamental en el periodo posterior a una cirugía. Sin embargo muchos de los registros en las bases de datos de estas secciones no son de buena calidad. Por esto analizar la prevalencia y etiología de las visitas postoperatorias en cirugía colorectal resulta ser bastante limitada. Para lograr una mejoría en la calidad es fundamental analizar las causas potencialmente evitables, especialmente al considerer la rapida evolucion de los parametros de medición actuales.OBJETIVO:Nuestro objetivo es caracterizar las visitas postoperatorias al servicio de urgencias e identificar los factores asociados potencialmente evitables.DISEÑO:Estudio de cohorte retrospectivo.AJUSTE:Centro médico académico, 2014-2018.PACIENTES:Pacientes consecutivos sometidos a colectomía o proctectomía dentro de la división de cirugía colorrectal en un centro médico académico entre 2014 y 2018.PRINCIPALES MEDIDAS DE RESULTADO:Frecuencia e indicación de las visitas al servicio de urgencias en el period postoperatorio: factores clínicos y sociodemográficos.RESULTADOS:De 1763 operaciones individuales, hubo 207 visitas al departamento de emergencias de 199 pacientes (11%) en los 30 días posteriores al alta. Dos tercios de las visitas al servicio de urgencias dieron lugar a readmisiones. La mediana [rango intercuartílico] de tiempo hasta la presentación fue de 8 [4-16] días. La mediana de tiempo en el servicio de urgencias fue de 7,8 [6-10,1] horas. Un tercio de las visitas se identificaron como potencialmente evitables, más comúnmente dolor (17%) y complicaciones del estoma (excluida la deshidratación) (13%). En los pacientes con poco manejo del inglés se asoció con una mayor frecuencia razón de visitas al departamento de emergencias posoperatorias [IC del 95%] 2,7 [1,3-5,3], así como opetancialmente evitables con un RR de 3,6 [1,7-8,0].LIMITACIONES:Estudio de un solo centro y revisión retrospectiva.CONCLUSIÓN:Al menos un tercio de las visitas al servicio de urgencias después de una cirugía colorrectal son potencialmente evitables. Se debe prestar especial atención a los pacientes que no hablan inglés como idioma materno. Consulte Video Resumen en http://links.lww.com/DCR/B648.

Colonic mucosal eosinophilia in children without inflammatory bowel disease.

Children undergoing colonoscopy and mucosal biopsies may show increased colonic mucosal eosinophils, which may or may not be associated with inflammatory bowel disease. There is not much clinical data on American children who have isolated increased colonic mucosal eosinophils. We sought to study the clinical correlates of children without inflammatory bowel disease who show increased mucosal eosinophils to understand their clinical presentation, etiological associations, and outcome. A retrospective analysis of children seen at a tertiary-level Children's hospital was performed by reviewing their medical charts and extracting pertinent data. There were 110 children in the study who had increased colonic mucosal eosinophils. Most children presented with abdominal pain, but several of them also had constipation, blood in stools, and diarrhea. Food allergies, irritable bowel syndrome, asthma, and lactase deficiency were the top four conditions present in these patients. Pathology of the colonic distribution revealed involvement of more than two colonic regions in 86% of the subjects, and only two subjects showing epithelial or crypt involvement by eosinophils. All subjects had a good outcome. Children with colonic mucosal eosinophilia (CME) who do not have an inflammatory bowel disease most frequently present with abdominal pain and primarily an increase of lamina propria eosinophils in two or more colonic regions. Based on the etiological associations we noted in the study, a work-up of children with CME may encompass detailed history for functional gastrointestinal disorders and lactose intolerance, testing for food and environmental allergies, stool examination for parasites, and peripheral blood counts. Almost all children had resolution of symptoms in the studied period suggesting that CME in children has a good clinical outcome.

An objective approach to assess colonic pain in mice using colonometry.

The present study presents a non-surgical approach to assess colonic mechanical sensitivity in mice using colonometry, a technique in which colonic stretch-reflex contractions are measured by recording intracolonic pressures during saline infusion into the distal colon in a constant rate. Colonometrical recording has been used to assess colonic function in healthy individuals and patients with neurological disorders. Here we found that colonometry can also be implemented in mice, with an optimal saline infusion rate of 1.2 mL/h. Colonometrograms showed intermittent pressure rises that was caused by periodical colonic contractions. In the sceneries of colonic hypersensitivity that was generated post 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colonic inflammation, following chemogenetic activation of primary afferent neurons, or immediately after noxious stimulation of the colon by colorectal distension (CRD), the amplitude of intracolonic pressure (AICP) was markedly elevated which was accompanied by a faster pressure rising (ΔP/Δt). Colonic hypersensitivity-associated AICP elevation was a result of the enhanced strength of colonic stretch-reflex contraction which reflected the heightened activity of the colonic sensory reflex pathways. The increased value of ΔP/Δt in colonic hypersensitivity indicated a lower threshold of colonic mechanical sensation by which colonic stretch-reflex contraction was elicited by a smaller saline infusion volume during a shorter period of infusion time. Chemogenetic inhibition of primary afferent pathway that was governed by Nav1.8-expressing cells attenuated TNBS-induced up-regulations of AICP, ΔP/Δt, and colonic pain behavior in response to CRD. These findings support that colonometrograms can be used for analysis of colonic pain in mice.

HGF and TSG-6 Released by Mesenchymal Stem Cells Attenuate Colon Radiation-Induced Fibrosis.

Fibrosis is a leading cause of death in occidental states. The increasing number of patients with fibrosis requires innovative approaches. Despite the proven beneficial effects of mesenchymal stem cell (MSC) therapy on fibrosis, there is little evidence of their anti-fibrotic effects in colorectal fibrosis. The ability of MSCs to reduce radiation-induced colorectal fibrosis has been studied in vivo in Sprague-Dawley rats. After local radiation exposure, rats were injected with MSCs before an initiation of fibrosis. MSCs mediated a downregulation of fibrogenesis by a control of extra cellular matrix (ECM) turnover. For a better understanding of the mechanisms, we used an in vitro model of irradiated cocultured colorectal fibrosis in the presence of human MSCs. Pro-fibrotic cells in the colon are mainly intestinal fibroblasts and smooth muscle cells. Intestinal fibroblasts and smooth muscle cells were irradiated and cocultured in the presence of unirradiated MSCs. MSCs mediated a decrease in profibrotic gene expression and proteins secretion. Silencing hepatocyte growth factor (HGF) and tumor necrosis factor-stimulated gene 6 (TSG-6) in MSCs confirmed the complementary effects of these two genes. HGF and TSG-6 limited the progression of fibrosis by reducing activation of the smooth muscle cells and myofibroblast. To settle in vivo the contribution of HGF and TSG-6 in MSC-antifibrotic effects, rats were treated with MSCs silenced for HGF or TSG-6. HGF and TSG-6 silencing in transplanted MSCs resulted in a significant increase in ECM deposition in colon. These results emphasize the potential of MSCs to influence the pathophysiology of fibrosis-related diseases, which represent a challenging area for innovative treatments.

The gut microbiota and colorectal surgery outcomes: facts or hype? A narrative review.

BACKGROUND: The gut microbiota (GM) has been proposed as one of the main determinants of colorectal surgery complications and theorized as the "missing factor" that could explain still poorly understood complications. Herein, we investigate this theory and report the current evidence on the role of the GM in colorectal surgery. METHODS: We first present the findings associating the role of the GM with the physiological response to surgery. Second, the change in GM composition during and after surgery and its association with colorectal surgery complications (ileus, adhesions, surgical-site infections, anastomotic leak, and diversion colitis) are reviewed. Finally, we present the findings linking GM science to the application of the enhanced recovery after surgery (ERAS) protocol, for the use of oral antibiotics with mechanical bowel preparation and for the administration of probiotics/synbiotics. RESULTS: According to preclinical and translational evidence, the GM is capable of influencing colorectal surgery outcomes. Clinical evidence supports the application of an ERAS protocol and the preoperative administration of multistrain probiotics/synbiotics. GM manipulation with oral antibiotics with mechanical bowel preparation still has uncertain benefits in right-sided colic resection but is very promising for left-sided colic resection. CONCLUSIONS: The GM may be a determinant of colorectal surgery outcomes. There is an emerging need to implement translational research on the topic. Future clinical studies should clarify the composition of preoperative and postoperative GM and the impact of the GM on different colorectal surgery complications and should assess the validity of GM-targeted measures in effectively reducing complications for all colorectal surgery locations.