Altered immunity to microbiota, B cell activation and depleted γδ/resident memory T cells in colorectal cancer.

The role of microbiota:immune system dysregulation in the etiology of colorectal cancer (CRC) is poorly understood. CRC develops in gut epithelium, accompanied by low level inflammatory signaling, intestinal microbial dysbiosis and immune dysfunction. We examined populations of intraepithelial lymphocytes in non-affected colonic mucosa of CRC and healthy donors and circulating immune memory to commensal bacterial species and yeasts. γδ T cells and resident memory T cells, populations with a regulatory CD39-expressing phenotype, were found at lower frequencies in the colonic tissue of CRC donors compared to healthy controls. Patterns of T cell proliferative responses to a panel of commensal bacteria were distinct in CRC, while B cell memory responses to several bacteria/yeast were significantly increased, accompanied by increased proportions of effector memory B cells, transitional B cells and plasmablasts in blood. IgA responses to mucosal microbes were unchanged. Our data describe a novel immune signature with similarities to and differences from that of inflammatory bowel disease. They implicate B cell dysregulation as a potential contributor to parainflammation and identify pathways of weakened barrier function and tumor surveillance in CRC-susceptible individuals.

Altered Mucosal Immune-Microbiota Interactions in Familial Adenomatous Polyposis.

INTRODUCTION: Familial adenomatous polyposis (FAP) is a condition caused by a constitutional pathogenic variant of the adenomatous polyposis coli gene that results in intestinal adenoma formation and colorectal cancer, necessitating pre-emptive colectomy. We sought to examine interaction between the mucosal immune system and commensal bacteria in FAP to test for immune dysfunction that might accelerate tumorigenesis. METHODS: Colonic biopsies were obtained from macroscopically normal mucosal tissue from 14 healthy donors and 13 patients with FAP during endoscopy or from surgical specimens. Intraepithelial and lamina propria lymphocytes were phenotyped. Intraepithelial microbes were labeled with anti-IgA/IgG and analyzed by flow cytometry. RESULTS: Proportions of resident memory CD103-expressing CD8 + and γδ T-cell receptor + intraepithelial lymphocytes were dramatically reduced in both the left and right colon of patients with FAP compared with healthy controls. In lamina propria, T cells expressed less CD103, and CD4 + CD103 + cells expressed less CD73 ectonucleotidase. IgA coating of epithelia-associated bacteria, IgA + peripheral B cells, and CD4 T-cell memory responses to commensal bacteria were increased in FAP. DISCUSSION: Loss of resident memory T cells and γδ T cells in mucosal tissue of patients with FAP accompanies intestinal microbial dysbiosis previously reported in this precancerous state and suggests impaired cellular immunity and tumor surveillance. This may lead to barrier dysfunction, possible loss of regulatory T-cell function, and excess IgA antibody secretion. Our data are the first to implicate mucosal immune dysfunction as a contributing factor in this genetically driven disease and identify potentially critical pathways in the etiology of CRC.

Anterior Resection Syndrome and Quality of Life With Long-term Follow-up After Rectal Cancer Resection.

BACKGROUND: Surgical and systemic therapies continue to advance, enabling restorative resections for distal rectal cancer. These operations are associated with low anterior resection syndrome. Recent studies with methodological and size limitations have investigated the incidence of low anterior resection syndrome after anterior resection. However, the long-term trajectory of low anterior resection syndrome and its effect on health-related quality of life remain unclear. OBJECTIVE: The purpose of this study was to assess the impact of anterior resection and reversal of ileostomy on long-term health-related quality of life and low anterior resection syndrome. DESIGN: Patient demographics were analyzed alongside low anterior resection syndrome and health-related quality-of-life qualitative scores (EORTC-QLQ-C30) obtained through cross-sectional postal questionnaires. SETTING: Patients who underwent anterior resection of the rectum for cancer with defunctioning ileostomy between 2003 and 2016 at 2 high-volume centers in the United Kingdom were identified, excluding those experiencing anastomotic leakage. PATIENTS: Among 478 eligible patients, 311 (65.1%) participated at a mean of 6.5 ± 0.2 years after anterior resection. Demographics and neoadjuvant chemoradiotherapy rates were similar ( p > 0.05) between participants and nonparticipants. RESULTS: The percentage of patients who experienced major low anterior resection syndrome was 53.4% (166/311). Health-related quality-of-life functional domain scores improved in the years after reversal of ileostomy, with significant changes in constipation ( p = 0.01), social function ( p = 0.03), and emotional scores ( p = 0.02), as well as a reduction in the prevalence of major low anterior resection syndrome ( p = 0.003). LIMITATIONS: The main limitation of this study was that the data collected were cross-sectional rather than longitudinal, and that nonresponders may have had worse cancer symptoms. CONCLUSIONS: In this first large-scale study assessing long-term function after anterior resection and reversal of ileostomy, there is a linear improvement in major low anterior resection syndrome beyond 6 years, alongside improvements in key quality-of-life measures. See Video Abstract at http://links.lww.com/DCR/B825 . SEGUIMIENTO A LARGO PLAZO DEL SNDROME DE RESECCIN ANTERIOR BAJA Y LA CALIDAD DE VIDA POR CNCER DE RECTO: ANTECEDENTES:Los tratamientos tanto quirúrgicos como sistémicos continúan evolucionando día a día, así éstos permiten resecciones restaurativas por cáncer de recto distal. Estas operaciones están asociadas con el síndrome de resección anterior baja. Estudios recientes con limitaciones tanto metodológicas como de talla han estudiado la incidencia del síndrome de resección anterior bajo post-quirúrgico. Sin embargo, la evolución a largo plazo del síndrome de resección anterior baja y su acción sobre la calidad de vida relacionadas con la salud siguen sin estar claros.OBJETIVO:Evaluar el impacto de la resección anterior baja y el cierre de la ileostomía en la calidad de vida relacionadas con la salud a largo plazo y el síndrome post-resección anterior.AJUSTE:Se incluyeron todos los pacientes sometidos a una reseccción anterior baja de recto por cáncer asociada a una ileostomía de protección entre 2003 y 2016 en dos centros de gran volumen en el Reino Unido, se excluyeron los pacientes que presentaron fuga anastomótica.DISEÑO:Se revisaron los datos demográficos de todos los pacientes que presentaban el síndrome de resección anterior baja, se revisaron las puntuaciones de la calidad de vida relacionadas con el estado general de salud (EORTC-QLQ-C30) obtenidas a través de cuestionarios transversales enviados por correo.PACIENTES:478 pacientes fueron escogidos, 311 (65,1%) participaron del estudio en una media de 6,5 ± 0,2 años después de la resección anterior. Las tasas demográficas y de radio-quimioterapia neoadyuvante fueron similares (p > 0,05) entre los participantes y los no participantes.RESULTADOS:El porcentaje de pacientes que experimentaron síndrome de resección anterior baja mayor fue del 53,4% (166/311).PRINCIPALES MEDIDAS DE RESULTADO:Las puntuaciones funcionales en la calidad de vida relacionadas con estado general de salud mejoraron en los años posteriores al cierre de la ileostomía de protección, los cambios fueron significativos con relación al estreñimiento (p = 0,01), con relación a la actividad social (p = 0,03) y con las puntuaciones emocionales (p = 0,02), así como con la reducción de la prevalencia del síndrome de resección anterior baja mayor (p = 0,003).LIMITACIONES:La principal limitación del presente estudio mostró que los datos recopilados fueron transversales y no longitudinales, y que los pacientes no respondedores pueden haber tenido peores síntomas relacionados con el cáncer.CONCLUSIONES:Este primer estudio a gran escala, evalúa la función a largo plazo después de la resección anterior baja y el cierre de la ileostomía, demuestra una mejoría lineal en el síndrome de resección anterior baja de grado importante, más allá de los 6 años, asociado con la mejoría en las medidas clave de calidad de vida. Consulte Video Resumen en http://links.lww.com/DCR/B825 . (Traducción-Dr. Xavier Delgadillo ).

Distal feeding-bowel stimulation to treat short-term or long-term pathology: a systematic review.

BACKGROUND: Distal feeding (DF) describes the insertion of a feeding tube into a fistula or stoma to administer a liquid feed into the distal bowel. It is currently used clinically in patients who are unable to absorb enough nutrition orally. This systematic review investigates DF as a therapeutic measure across a spectrum of patients with stomas and fistulae. METHODS: A total of 2825 abstracts and 44 full-text articles were screened via OVID. Fifteen papers were included for analysis. Randomised controlled trials, cohort and observational studies investigating DF as a therapeutic measure were included. RESULTS: Three feeds were used across the studies-reinfusion of effluent, infusion of prebiotic or a mixture. The studies varied the length of feeding between 24 hours and 61 days, and the mode of feeding, bolus or continuous varied.DF was demonstrated to effectively wean patients from parenteral nutrition in two papers. Two papers demonstrated a significant reduction in stoma output. Three papers demonstrated improved postoperative complication rates with distal feeding regimens, including ileus (2.85% vs 20% in unfed population, p=0.024). One paper demonstrated a reduction in postoperative stool frequency. CONCLUSIONS: This review was limited by study heterogeneity and the lack of trial data, and in the patient groups involved, the variability in diet and length of regimen. These studies suggest that DF can significantly reduce stoma output and improve renal and liver function; however, the mechanism is not clear. Further mechanistic work on the immunological and microbiological action of DF would be important.

Is fistulotomy with immediate sphincter reconstruction (FISR) a sphincter preserving procedure for high anal fistula? A systematic review and meta-analysis.

AIM: This systematic review aimed to assess the outcomes of fistulotomy or fistulectomy and immediate sphincter repair (FISR) in relation to healing, incontinence and sphincter dehiscence both overall and in patients with high anal fistulae. METHODS: Medline, Embase and The Cochrane library were searched for studies of patients undergoing FISR for anal fistula. Data regarding healing, continence and sphincter dehiscence were extracted overall and for high anal fistulae. The DerSimonian-Laird random-effects method was used for pooled analysis, heterogeneity between studies was assessed based on the significance of between-study heterogeneity, and on the size of the I2  value. Risk of bias was assessed using the Cochrane risk of bias tool and the Newcastle-Ottawa scale. RESULTS: We identified 21 studies evaluating 1700 patients. Pooled analysis of healing reached 93% (95% CI: 91%-95%, I2  = 51% p-value for heterogeneity = 0.004), with continence disturbance and worsening continence reaching 11% (95% CI: 6%-18%, I2  = 87% p < 0.001) and 8% (95% CI: 4%-13%, I2  = 74% p < 0.001), respectively. Subgroup analysis according to fistula height could only be conducted on limited data. Pooled healing in high anal fistulae was 89% (95% CI: 84%-94%, I2  = 76% p < 0.001), 16% suffered disturbance of continence (95% CI: 7%-27%, I2  = 89% p < 0.001), 8% worsening continence from baseline (95% CI: 2%-16%, I2  = 80% p < 0.001) and 2% suffered sphincter dehiscence (95% CI: 0%-10%, I2  = 89% p < 0.001). CONCLUSION: The evidence suggests FISR is a safe, effective procedure. However, data are limited by inconsistencies in reporting of continence and definition of fistula height, particularly high anal fistulae. Significant heterogeneity means that outcomes in high fistulae remain uncertain.

Prognostic factors associated with unhealed perineal wounds post-proctectomy for perianal Crohn's disease: a two-centre study.

AIM: The aim of this work was to determine the factors associated with poor wound healing in patients with perianal Crohn's disease (pCD) who had undergone proctectomy in the era of biologic therapies. METHOD: Case record review was performed on 103 patients with pCD who underwent proctectomy at St Mark's Hospital, Harrow and the Western General Hospital, Edinburgh between 2005 and 2017. Healing rates at 6 and 12 months post-proctectomy were considered; univariate analysis was performed. RESULTS: Sixty out of 103 patients (58.3%) had failure of wound healing at 6 months and 41/103 (39.8%) at 12 months. In total, 63.1% (65/103) patients received biologic therapies prior to proctectomy; however, exposure to biologics was not a significant factor in predicting failure of wound healing at 12 months (infliximab p = 0.255; adalimumab p = 0.889; vedolizumab p = 0.153). Male gender was the only variable associated with poor wound healing at 12 months on univariate analysis (p = 0.017). A lower pre-operative C-reactive protein was associated with early wound healing at 6 months compared with at 12 months (p = 0.041) on univariate analysis. Other parameters not associated with rates of wound healing included smoking status, corticosteroid exposure, thiopurine exposure, number of previous biologics, perianal sepsis on MRI within the last 12 months, duration of CD prior to proctectomy and pre-operative albumin. CONCLUSION: More than a third of patients had unhealed wounds 12 months after proctectomy. We report that unhealed wounds are more common in male patients. Importantly, our results also suggest that exposure to biologics does not affect rates of wound healing.

Bacteroides thetaiotaomicron-derived outer membrane vesicles promote regulatory dendritic cell responses in health but not in inflammatory bowel disease.

BACKGROUND: Bacteroides thetaiotaomicron (Bt) is a prominent member of the human intestinal microbiota that, like all gram-negative bacteria, naturally generates nanosized outer membrane vesicles (OMVs) which bud off from the cell surface. Importantly, OMVs can cross the intestinal epithelial barrier to mediate microbe-host cell crosstalk involving both epithelial and immune cells to help maintain intestinal homeostasis. Here, we have examined the interaction between Bt OMVs and blood or colonic mucosa-derived dendritic cells (DC) from healthy individuals and patients with Crohn's disease (CD) or ulcerative colitis (UC). RESULTS: In healthy individuals, Bt OMVs stimulated significant (p < 0.05) IL-10 expression by colonic DC, whereas in peripheral blood-derived DC they also stimulated significant (p < 0.001 and p < 0.01, respectively) expression of IL-6 and the activation marker CD80. Conversely, in UC Bt OMVs were unable to elicit IL-10 expression by colonic DC. There were also reduced numbers of CD103+ DC in the colon of both UC and CD patients compared to controls, supporting a loss of regulatory DC in both diseases. Furthermore, in CD and UC, Bt OMVs elicited a significantly lower proportion of DC which expressed IL-10 (p < 0.01 and p < 0.001, respectively) in blood compared to controls. These alterations in DC responses to Bt OMVs were seen in patients with inactive disease, and thus are indicative of intrinsic defects in immune responses to this commensal in inflammatory bowel disease (IBD). CONCLUSIONS: Overall, our findings suggest a key role for OMVs generated by the commensal gut bacterium Bt in directing a balanced immune response to constituents of the microbiota locally and systemically during health which is altered in IBD patients. Video Abstract.