Tryptophan Metabolites Improve Intestinal Mucosal Barrier via the Aryl Hydrocarbon Receptor-Interleukin-22 Pathway in Murine Dextran Sulfate Sodium-Induced Pouchitis.

Pouchitis is the most common complication after IPAA for ulcerative colitis. The protective effect of tryptophan metabolites on the mucosal barrier may be effective for treating pouchitis. The role of tryptophan metabolites on pouchitis remained unclear. We aimed to establish a murine model of dextran sulfate sodium-induced pouchitis to examine the roles of tryptophan metabolites in its pathogenesis. This is a study that combines clinical patient data and animal research. A total of 22 patients were enrolled: 5 patients with familial adenomatous polyposis after IPAA, 8 patients with ulcerative colitis after IPAA with pouchitis, and 9 patients with ulcerative colitis after IPAA with normal pouch. The demographic data and fecal samples of patients were collected. Male C57BL/6 mice were purchased from a licensed breeder and underwent IPAA to establish a murine model of the pouch. The blood, feces, and tissues of mice were collected. This study was performed in an academic medical center in China. The demographic data of patients were observationally collected. The mice that underwent IPAA were divided into a control group that received a chow diet and 5 study groups: 1) dextran sulfate sodium, 2) 6-formylindolo[3,2-b] carbazole + dextran sulfate sodium, 3) high tryptophan diet + dextran sulfate sodium, 4) CH-223191 + dextran sulfate sodium, and 5) indole-3-carboxaldehyde + dextran sulfate sodium. Animals were euthanized after receiving dextran sulfate sodium for 7 days. Fecal tryptophan metabolite level and microbiome composition, the severity of pouchitis, intestinal mucosal barrier function, and activation of the aryl hydrocarbon receptor-interleukin 22 pathway were assessed. Patients with pouchitis had lower fecal microbial diversity and indole-3-acetic acid levels. In the murine pouchitis model, high tryptophan diet increased fecal levels of 3-indoleglyoxylic acid, indole-3-aldehyde, and indole. A high tryptophan diet and intraperitoneal aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b] carbazole injection alleviated pouchitis. Tryptophan metabolites improved pouch mucosal barriers. Aryl hydrocarbon receptor inhibitors exacerbated experimental pouchitis and disrupted the mucosal barrier; however, the aryl hydrocarbon receptor ligand indole-3-carboxaldehyde reversed this effect. This study was limited by a small human sample size and lacked an aryl hydrocarbon receptor knockout mouse model. A high tryptophan diet and aryl hydrocarbon receptor ligand alleviated dextran sulfate sodium-induced pouchitis in a murine IPAA model, which might be achieved through regulating epithelial tight junctions and promoting goblet cell differentiation, as well as maintaining the integrity and function of the mucosal barrier. This study provides a rationale for the clinical application of aryl hydrocarbon receptor ligands in the treatment of pouchitis. See Video Abstract . ANTECEDENTES:La reservoritis es la complicación más frecuente después de la anastomosis del reservorio ileal con el ano en la colitis ulcerosa. El efecto protector de los metabolitos del triptófano sobre la barrera mucosa puede ser un método eficaz para tratar la reservoritis. El papel de los metabolitos del triptófano en la reservoritis sigue sin estar claro.OBJETIVO:Nuestro objetivo era establecer un modelo murino de reservoritis inducida por sulfato de dextrano sódico para examinar el papel de los metabolitos del triptófano en su patogenia.DISEÑO:Este es un estudio que combina datos clínicos de pacientes e investigación animal. Se inscribieron un total de 22 pacientes: 5 con poliposis adenomatosa familiar después de un reservorio ileal, ocho pacientes con colitis ulcerosa después de un reservorio ileal que desarrollaron reservoritis y 9 pacientes con colitis ulcerosa después de un reservorio ileal que no presentaron reservoritis. Se recogieron los datos demográficos y las muestras fecales de los pacientes. Se adquirieron ratones macho C57BL/6 de un criador autorizado y se les realizó un reservorio ileal para establecer un modelo murino del reservorio. Se recogieron sangre, heces y tejidos de los ratones.CONFIGURACIÓN:Este estudio se realizó en un centro médico académico en China.INTERVENCIONES:Los datos demográficos de los pacientes se recogieron de forma observacional. Los ratones sometidos a un reservorio ileal se dividieron en seis grupos: grupo de control con dieta normal, sulfato de dextrano sódico, 6-formilindolo[3,2-b] carbazol + sulfato de dextrano sódico, dieta rica en triptófano + sulfato de dextrano sódico, CH-223191 + sulfato de dextrano sódico, indol-3-carboxaldehído + sulfato de dextrano sódico. Los animales fueron sacrificados después de la administración de sulfato de dextrano sódico durante 7 días.PRINCIPALES MEDIDAS DE RESULTADOS:Se evaluaron los niveles de metabolitos de triptófano y la composición del microbioma fecal, la gravedad de la reservoritis, la función de barrera de la mucosa intestinal y la activación de la vía del receptor de hidrocarburos de arilo-interleucina 22.RESULTADOS:Los pacientes con reservoritis tenían una menor diversidad microbiana fecal y niveles de ácido indol-3-acético. En el modelo de reservoritis murino, la dieta rica en triptófano aumentó los niveles fecales de ácido 3-indolglioxílico, indol-3-aldehído e indol. Una dieta rica en triptófano y una inyección intraperitoneal del ligando del receptor de hidrocarburos de arilo 6-formilindolo[3,2-b] carbazol aliviaron la reservoritis. Los metabolitos de triptófano mejoraron las barreras de la mucosa de la reservoritis. Los inhibidores del receptor de hidrocarburos de arilo exacerbaron la reservoritis experimental y alteraron la barrera mucosa; sin embargo, el ligando del receptor de hidrocarburos de arilo indol-3-carboxaldehído revirtió este efecto.LIMITACIONES:Este estudio estuvo limitado por el pequeño tamaño de la muestra humana y la falta de un modelo de ratón con deficiencia del receptor de hidrocarburos arílicos.CONCLUSIONES:Una dieta rica en triptófano y un ligando del receptor de hidrocarburos arílicos aliviaron la reservoritis inducida por sulfato de dextrano sódico en un modelo murino de anastomosis de reservorio ileo-anal, lo que podría deberse a la regulación de las uniones estrechas epiteliales y la promoción de la diferenciación de las células caliciformes, así como al mantenimiento de la integridad y la función de la barrera mucosa. Este estudio proporciona una justificación para la aplicación clínica de los ligandos del receptor de hidrocarburos arílicos en el tratamiento de la reservoritis. (Traducción-Dr. Felipe Bellolio ).

被引量：- 发表：1970

Retroperitoneal Approach to D3-Lymph Node Dissection With Left Colic Artery Preservation in the Treatment of Sigmoid Cancer.

被引量：1 发表：1970

What To Do With Suspected Nodal Regrowth on Magnetic Resonance Imaging During Follow-up in an Organ Preservation Approach for Rectal Cancer?

For nodal regrowth in patients with rectal cancer following watch-and-wait standardized protocols on diagnostic procedures and subsequent treatment are lacking. Evaluate the diagnosis and treatment of suspected nodal regrowth following an organ preservation approach. Patients were included from national and institutional watch-and-wait -databases. Thirty-five rectal cancer patients with suspected nodal regrowth on magnetic resonance imaging were retrospectively identified during watch-and-wait follow-up. Twenty-seven of 35 patients followed watch-and-wait after neoadjuvant (chemo)radiotherapy and 8/35 followed watch-and-wait schedule after local excision for early rectal cancer. Diagnostic procedures, treatment and histopathological outcome. Median follow-up was 34 months. Median time from end of (chemo)radiotherapy or local excision to first detection of suspected nodal regrowth on magnetic resonance imaging following watch-and-wait was 9 and 10 months. After first detection, 17 of 35 patients underwent immediate treatment without further diagnostics, of whom 7 also had luminal regrowth. In 18 of 35 patients, additional diagnostic procedures were performed. In 4 of 18 patients, positron emission tomography-computed tomography or endorectal ultrasound-guided biopsy was performed and treatment was initiated based on increased nodal regrowth suspicion. In 14 of 18 patients, MRI was repeated after 8-12 weeks: growth of suspected lymph nodes was the most decisive factor to proceed to treatment. In 8 patients, repeated magnetic resonance imaging was combined with positron emission tomography-computed tomography and/or endorectal ultrasound-guided biopsy: in half of them it contributed to treatment initiation. In total, 34/35 patients were treated: 9 received (re-)irradiation and 33 underwent total mesorectal excision. In 27 of 33 patients, nodal regrowth was pathologically confirmed in the total mesorectal excision-resection specimen; 5 of 6 patients without nodal involvement had pathologically confirmed luminal regrowth. Highly selected study population. During watch-and-wait follow-up of patients with rectal cancer in an organ preservation strategy, magnetic resonance imaging plays an important role in diagnosis of nodal regrowth. Repeated magnetic resonance imaging after an interval can be helpful in making treatment decisions, and the role of positron emission tomography-computed tomography and endorectal ultrasound-guided biopsy appears limited. See Video Abstract.

被引量：- 发表：1970

Localized Administration of Mesenchymal Stem Cell-Derived Exosomes for the Treatment of Refractory Perianal Fistula in Crohn's Disease Patients: A Phase II Clinical Trial.

Crohn's disease perianal fistulae are often resistant to standard anti-TNF-α therapies. Mesenchymal stem cell (MSC)-derived exosomes are extracellular vesicles that have highly potent anti-inflammatory effects, and the previous phase of this study demonstrated their safety in the treatment of refractory perianal fistulas. To evaluate the efficacy of mesenchymal stem cell-derived exosomes for the treatment of refractory perianal fistulas. Nonrandomized, nonblinded single-center phase II clinical trial. Tertiary university hospital. Twenty-three patients were enrolled, 20 of whom completed the study. Refractory perianal fistula was defined as resistance to at least one course of treatment with anti-tumor necrosis facto-α therapy. After clinical assessment and magnetic resonance imaging, the patients were subjected to general anesthesia, and 5 mL of exosome solution was injected directly into the fistula tracts. The injections were repeated three times at 2-month intervals, and patients were followed monthly for 6 months after the last injection. Tissue samples from the tracts were obtained before each injection and subjected to immunohistopathological assessment. MRI data were obtained before and six months after the last injection. The primary outcome of this study was fistula tract closure on clinical examination and magnetic resonance imaging. The secondary outcome was an improvement in the discharge from the tracts. Fistula tracts were fully closed in 12 (60%) of the patients. Four patients showed clinical improvement, with some tracts remaining open, and four patients were completely resistant to treatment. A total of 43 fistula tracts were treated during the trial, 30 (69.7%) of which showed complete closure. Histopathological analysis revealed substantial reductions in local inflammation and signs of enhanced tissue regeneration. Immunohistochemical analysis of cluster of differentiation-68, 20 and 31 reaffirmed these results. MSC-derived exosomes are safe and effective for treating refractory perianal fistulas in patients with Crohn's disease. See Video Abstract.

被引量：1 发表：1970

How do you code colonoscopies correctly?

被引量：- 发表：1970