Neutrophils direct preexisting matrix to initiate repair in damaged tissues.

Internal organs heal injuries with new connective tissue, but the cellular and molecular events of this process remain obscure. By tagging extracellular matrix around the mesothelium lining in mouse peritoneum, liver and cecum, here we show that preexisting matrix was transferred across organs into wounds in various injury models. Using proteomics, genetic lineage-tracing and selective injury in juxtaposed organs, we found that the tissue of origin for the transferred matrix likely dictated the scarring or regeneration of the healing tissue. Single-cell RNA sequencing and genetic and chemical screens indicated that the preexisting matrix was transferred by neutrophils dependent on the HSF-integrin AM/B2-kindlin3 cascade. Pharmacologic inhibition of this axis prevented matrix transfer and the formation of peritoneal adhesions. Matrix transfer was thus an early event of wound repair and provides a therapeutic window to dampen scaring across a range of conditions.

Annexin A1 based inflammation resolving mediators and nanomedicines for inflammatory bowel disease therapy.

Inflammatory bowel diseases (IBD) such as Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic, progressive, and relapsing disorders of the gastrointestinal tract (GIT), characterised by intestinal epithelial injury and inflammation. Current research shows that in addition to traditional anti-inflammatory therapy, resolution of inflammation and repair of the epithelial barrier are key biological requirements in combating IBD. Resolution mediators include endogenous lipids that are generated during inflammation, e.g., lipoxins, resolvins, protectins, maresins; and proteins such as Annexin A1 (ANXA1). Nanoparticles can specifically deliver these potent inflammation resolving mediators in a spatiotemporal manner to IBD lesions, effectively resolve inflammation, and promote a return to homoeostasis with minimal collateral damage. We discuss these exciting and timely concepts in this review.

Development of an image-based Random Forest classifier for prediction of surgery duration of laparoscopic sigmoid resections.

PURPOSE: Sigmoid diverticulitis is a disease with a high socioeconomic burden, accounting for a high number of left-sided colonic resections worldwide. Modern surgical scheduling relies on accurate prediction of operation times to enhance patient care and optimize healthcare resources. This study aims to develop a predictive model for surgery duration in laparoscopic sigmoid resections, based on preoperative CT biometric and demographic patient data. METHODS: This retrospective single-center cohort study included 85 patients who underwent laparoscopic sigmoid resection for diverticular disease. Potentially relevant procedure-specific anatomical parameters recommended by a surgical expert were measured in preoperative CT imaging. After random split into training and test set (75% / 25%) multiclass logistic regression was performed and a Random Forest classifier was trained on CT imaging parameters, patient age, and sex in the training cohort to predict categorized surgery duration. The models were evaluated in the test cohort using established performance metrics including receiver operating characteristics area under the curve (AUROC). RESULTS: The Random Forest model achieved a good average AUROC of 0.78. It allowed a very good prediction of long (AUROC = 0.89; specificity 0.71; sensitivity 1.0) and short (AUROC = 0.81; specificity 0.77; sensitivity 0.56) procedures. It clearly outperformed the multiclass logistic regression model (AUROC: average = 0.33; short = 0.31; long = 0.22). CONCLUSION: A Random Forest classifier trained on demographic and CT imaging biometric patient data could predict procedure duration outliers of laparoscopic sigmoid resections. Pending validation in a multicenter study, this approach could potentially improve procedure scheduling in visceral surgery and be scaled to other procedures.

The mesenteric entry site as a potential weak point in gastrointestinal anastomoses - findings from an ex-vivo biomechanical analysis.

PURPOSE: Gastrointestinal disorders frequently necessitate surgery involving intestinal resection and anastomosis formation, potentially leading to severe complications like anastomotic leakage (AL) which is associated with increased morbidity, mortality, and adverse oncologic outcomes. While extensive research has explored the biology of anastomotic healing, there is limited understanding of the biomechanical properties of gastrointestinal anastomoses, which was aimed to be unraveled in this study. METHODS: An ex-vivo model was developed for the biomechanical analysis of 32 handsewn porcine end-to-end anastomoses, using interrupted and continuous suture techniques subjected to different flow models. While multiple cameras captured different angles of the anastomosis, comprehensive data recording of pressure, time, and temperature was performed simultaneously. Special focus was laid on monitoring time, location and pressure of anastomotic leakage (LP) and bursting pressures (BP) depending on suture techniques and flow models. RESULTS: Significant differences in LP, BP, and time intervals were observed based on the flow model but not on the suture techniques applied. Interestingly, anastomoses at the insertion site of the mesentery exhibited significantly higher rates of leakage and bursting compared to other sections of the anastomosis. CONCLUSION: The developed ex-vivo model facilitated comparable, reproducible, and user-independent biomechanical analyses. Assessing biomechanical properties of anastomoses offers an advantage in identifying technical weak points to refine surgical techniques, potentially reducing complications like AL. The results indicate that mesenteric insertion serves as a potential weak spot for AL, warranting further investigations and refinements in surgical techniques to optimize outcomes in this critical area of anastomotic procedures.

A nationwide population-based study on the clinical and economic burden of anastomotic leakage in colorectal surgery.

AIM: Anastomotic leakage (AL) is one of the most dreaded complications in colorectal surgery. In 2013, the International Classification of Diseases code K91.83 for AL was introduced in Germany, allowing nationwide analysis of AL rates and associated parameters. The aim of this population-based study was to investigate the current incidence, risk factors, mortality, clinical management, and associated costs of AL in colorectal surgery. METHODS: A data query was performed based on diagnosis-related group data of all hospital cases of inpatients undergoing colon or sphincter-preserving rectal resections between 2013 and 2018 in Germany. RESULTS: A total number of 690,690 inpatient cases were included in this study. AL rates were 6.7% for colon resections and 9.2% for rectal resections in 2018. Regarding the treatment of AL, the application of endoluminal vacuum therapy increased during the studied period, while rates of relaparotomy, abdominal vacuum therapy, and terminal enterostomy remained stable. AL was associated with significantly increased in-house mortality (7.11% vs. 20.11% for colon resections and 3.52% vs. 11.33% for rectal resections in 2018) and higher socioeconomic costs (mean hospital reimbursement volume per case: 14,877€ (no AL) vs. 37,521€ (AL) for colon resections and 14,602€ (no AL) vs. 30,606€ (AL) for rectal resections in 2018). CONCLUSIONS: During the studied time period, AL rates did not decrease, and associated mortality remained at a high level. Our study provides updated population-based data on the clinical and economic burden of AL in Germany. Focused research in the field of AL is still urgently necessary to develop targeted strategies to prevent AL, improve patient care, and decrease socioeconomic costs.

Retrospective study of prognosis of patients with multiple colorectal carcinomas: synchronous versus metachronous makes the difference.

PURPOSE: Little is known about difference between synchronous colorectal cancer (SCRC) and metachronous colorectal cancer (MCRC) despite the relevance for this selected patient group. The aim of this retrospective review was to analyze patients with SCRC and MCRC. METHODS: All patients who underwent surgery for SCRC and MCRC between 1982 and 2019 were included in this retrospective analysis of our tertiary referral center. Clinical, histological, and molecular genetic characteristics were analyzed. The primary endpoint was cause-specific survival, evaluated by the Kaplan-Meier method. Secondary endpoints were recurrence-free survival and the identification of prognostic factors. RESULTS: Overall, 3714 patients were included in this analysis. Of those, 3506 (94.4%) had a primary unifocal colorectal cancer (PCRC), 103 (2.7%) had SCRC, and 105 (2.8%) had MCRC. SCRC occurred more frequently in elderly (p=0.009) and in male patients (p=0.027). There were no differences concerning tumor stages or grading. Patients with SCRC did not show altered recurrence or survival rates, as compared to unifocal tumors. However, MCRC had a lower rate of recurrence, compared to PCRC (24% vs. 41%, p=0.002) and a lower rate of cause-specific death (13% vs. 37%, p<0.001). Five-year cause-specific survival rates were 63±1% for PCRC, 62±6% for SCRC (p=0.588), and 88±4% for MCRC (p<0.001). Multivariable analysis revealed that MCRC were an independent favorable prognostic parameter regarding case-specific survival. CONCLUSION: Patients with SCRC seem to not have a worse prognosis compared to patients with PCRC. Noteworthy, patients with MCRC showed better survival rates in this retrospective analysis.

Crohn's disease: a population-based study of surgery in the age of biological therapy.

PURPOSE: Despite primary conservative therapy for Crohn's disease, a considerable proportion of patients ultimately needs to undergo surgery. Presumably, due to the increased use of biologics, the number of surgeries might have decreased. This study aimed to delineate current case numbers and trends in surgery in the era of biological therapy for Crohn's disease. METHODS: Nationwide standardized hospital discharge data (diagnosis-related groups statistics) from 2010 to 2017 were used. All patients who were admitted as inpatient Crohn's disease cases in Germany were included. Time-related development of admission numbers, rate of surgery, morbidity, and mortality of inpatient Crohn's disease cases were analyzed. RESULTS: A total number of 201,165 Crohn's disease cases were included. Within the analyzed time period, the total number of hospital admissions increased by 10.6% (n = 23,301 vs. 26,069). While gender and age distribution remained comparable, patients with comorbidities such as stenosis formation (2010: 10.1%, 2017: 13.4%) or malnutrition (2010: 0.8%, 2017: 3.2%) were increasingly admitted. The total number of all analyzed operations for Crohn's disease increased by 7.5% (2010: n = 1567; 2017: n = 1694). On average, 6.8 ± 0.2% of all inpatient patients received ileocolonic resections. Procedures have increasingly been performed minimally invasive (2010: n = 353; 2017: n = 687). The number of postoperative complications remained low. CONCLUSION: Despite the development of novel immunotherapeutics, the number of patients requiring surgery for Crohn's disease remains stable. Interestingly, patients have been increasingly hospitalized with stenosis and malnutrition. The trend towards more minimally invasive operations has not relevantly changed the rate of overall complications.

Innovative approaches for induction of gastrointestinal anastomotic healing: an update on experimental and clinical aspects.

PURPOSE: In most cases, traditional techniques to perform an anastomosis following gastrointestinal resections lead to successful healing. However, despite focused research in the field, in certain high-risk situations leakage rates remain almost unchanged. Here, additional techniques may help the surgeon to protect the anastomosis and prevent leakage. We give an overview of some of the latest developments on experimental and clinical techniques for induction of anastomotic healing. METHODS: We performed a review of the current literature on approaches to improve anastomotic healing. RESULTS: Many promising approaches with a high clinical potential are in the developmental pipeline. Highly experimental approaches like inhibition of matrix metalloproteinases, stem cell therapy, hyperbaric oxygen therapy, induction of the hypoxic adaptive response, and the administration of growth factors are still in the preclinical phase. Other more clinical developments aim to strengthen the anastomotic suture line mechanically while shielding it from the influence of the microbiome. Among them are gluing, seaming the staple line, attachment of laminar biomaterials, and temporary intraluminal tubes. In addition, individualized bowel preparation, selectively reducing certain detrimental microbial populations could become the next stage of bowel preparation. Compression anastomoses are evolving as an equivalent technique additional to established hand-sewn and stapled anastomoses. Fluorescence angiography and flexible endoscopy could complement intraoperative quality control additionally to the air leak tests. Virtual ileostomy is a concept to prepare the bowel for the easy formation of a stoma in case of leakage. CONCLUSION: A variety of promising diagnostic and prophylactic measures that may support the surgeon in identifying high-risk anastomoses and support them according to their potential deficits is currently in development.

Radiologic predictors for failure of non-operative management of complicated diverticulitis: a single-centre cohort study.

PURPOSE: Modern non-operative management of diverticulitis consists of a complex therapeutic regimen and is successful in most cases even of complicated diverticulitis. Still, a certain proportion of patients requires urgent surgery due to failure of the conservative approach. This study aims to identify predictors for failure of conservative treatment of complicated diverticulitis with the need for subsequent urgent resection during the acute episode. METHODS: A single-centre retrospective cohort study was performed at our tertiary centre including cases of acute complicated diverticulitis (characterized by localized abscess formation and/or pericolic air) between 2007 and 2019 that were treated guideline-conform by multimodal conservative treatment. Radiologic characteristics of disease in CT scans upon admission were analysed by uni- and multivariable logistic regression to determine predictors for resection within 30 days after onset of the conservative therapy approach. RESULTS: A total of 669 cases of acute diverticulitis were identified, of which 141 patients met the inclusion criteria. Overall, 13% (n = 19) of patients were operated within 30 days despite initial conservative management. Multivariable logistic regression identified length of inflamed bowel greater than 7 cm (p < 0.011) and abscess formations >1 cm (p < 0.001) as significant risk factors for failure of conservative treatment. CONCLUSION: Patients with length of inflamed bowel >7 cm or abscess formation >1 cm have increased risk for failure of conservative treatment of acute episodes of diverticulitis with contained perforations with subsequent need for urgent surgery. Therefore, conservative treatment of those patients should be monitored with special caution.

Annexin A1 Expression Capacity as a Determinant for Disease Severity in Crohn's Disease.

INTRODUCTION: Crohn's disease (CD) is characterized by relapsing intestinal inflammation. The anti-inflammatory protein annexin A1 (ANXA1) has been linked to inflammatory processes in the gut. OBJECTIVE: To examine ANXA1 expression patterns in the inflamed intestine of patients with CD and associate ANXA1 expression capacity with disease characteristics. METHODS: Surgical specimens of patients with CD operated between 2003 and 2015 were examined. Immunohistochemistry and immunofluorescence were performed to delineate ANXA1 expression. Those with pronounced ANXA1 expression were included in further analysis by qPCR. ANXA1 mRNA expression ratio of the inflamed to non-inflamed tissue was determined and defined as expression capacity of the tissue. Depending on their expression capacity, patients were divided into 2 groups (ANXA1-low vs. ANXA1-high), which were associated with clinical characteristics. RESULTS: Immunohistochemical ANXA1 expression was localized in inflamed regions of the intestine. In immunofluorescence, ANXA1 costained with myeloperoxidase as neutrophil marker, CD4 and CD8 as T cell marker but not CD20 as B cell marker or CD68 as macrophage marker. In qPCR, ANXA1 mRNA expression was upregulated by 20-fold in inflamed to noninflamed tissues. Patients with higher intrinsic ANXA1 expression capacity had significantly less severity of inflammation. Furthermore, the ANXA1-high group had significantly more locally restricted disease (p = 0.0070), more stricturating disease (p = 0.0037), and was less frequently treated by preoperative steroid therapy (p = 0.030). CONCLUSIONS: ANXA1 expression was strongly associated with intestinal inflammation and expressed in T cells and neutrophils of the CD tissues. Patients with higher intrinsic ANXA1 expression capacity of the inflamed tissue presented milder inflammatory changes and indolent clinical course.

Meta-analysis and single-center experience on the protective effect of negative suction drains on wound healing after stoma reversal.

BACKGROUND: Compromised wound healing following stoma reversal is a frequent problem. The use of negative suction drainage for reduction of complications remains controversial. METHODS: The patient database of our center was reviewed for patients with ileostomy reversal between 2007 and 2017. Risk factors for wound complications were analyzed using multivariate regression analysis. Systematic review and meta-analysis was performed. Ultimately, results of this study were integrated into meta-analysis to assess the effect of drainage placement on wound healing. RESULTS: In our institutional analysis, a total of 406 patients with ileostomy reversal were included (n = 240 (59.1%) with drainage vs. n = 166 (40.8%) without drainage). In multivariate analysis, body mass index (BMI) was a risk factor for wound complications (odds ratio (95% CI) 1.06 (1.02-1.12)). Patients with drainage needed significantly fewer interventions than those without drainage (17.1% vs. 28.9%, p = 0.005). Placement of drainage significantly reduced the risk of wound complications even in the group with elevated BMI (odds ratio (95% CI) 0.462 (0.28-0.76), p = 0.003). Meta-analysis identified 6 studies with a total of 1180 patients eligible for further analysis (2 prospectively randomized trials; 4 retrospective cohort studies). Overall analysis revealed a significantly beneficial effect of wound drainage following ileostomy reversal (RR (95% CI) 0.47 (0.34, 0.66); p < 0.0001). CONCLUSION: In our institutional analysis as well as meta-analysis, the use of subcutaneous suction drains was beneficial for prevention of wound healing complications following ostomy reversal. Drainage placement is especially valuable in high-risk situations such as in obese patients.

The immunologic changes during different phases of intestinal anastomotic healing.

Intestinal anatomosis is a complex and multicellular process that involving three overlapped phases: exudative phase, proliferative phase, and reparative phase. Undisturbed anastomotic healings are crucial for the recovery of patients after operations but unsuccessful healings are linked with a considerable mortality. This time, we concentrate on the immunologic changes during different phases of intestinal anastomotic healing and select several major immune cells and cytokines of each phase to get a better understanding of these immunologic changes in different phases, which will be significant for more precise therapy strategies in anastomoses.

Cutting Edge: IL-36 Receptor Promotes Resolution of Intestinal Damage.

IL-1 family members are central mediators of host defense. In this article, we show that the novel IL-1 family member IL-36γ was expressed during experimental colitis and human inflammatory bowel disease. Germ-free mice failed to induce IL-36γ in response to dextran sodium sulfate (DSS)-induced damage, suggesting that gut microbiota are involved in its induction. Surprisingly, IL-36R-deficient (Il1rl2(-/-)) mice exhibited defective recovery following DSS-induced damage and impaired closure of colonic mucosal biopsy wounds, which coincided with impaired neutrophil accumulation in the wound bed. Failure of Il1rl2(-/-) mice to recover from DSS-induced damage was associated with a profound reduction in IL-22 expression, particularly by colonic neutrophils. Defective recovery of Il1rl2(-/-) mice could be rescued by an aryl hydrocarbon receptor agonist, which was sufficient to restore IL-22 expression and promote full recovery from DSS-induced damage. These findings implicate the IL-36/IL-36R axis in the resolution of intestinal mucosal wounds.

[Peri- and postoperative nutrition in colorectal cancer patients]. / Peri- und postoperative Ernährung bei Darmkrebs.

Peri- and postoperative nutrition in colorectal cancer patients Abstract. The long multimodal therapy regimens for colorectal cancer require a sufficient nutritional status of the patient. The "Enhanced Recovery After Surgery" concept aims for minimization of the interruption of nutrient intake and has been validated prospectively. Preoperative malnutrition as a strong risk factor for complications should be detected and treated early after cancer diagnosis by screening tools as the "Nutritional Risk Screening" (NRS-2002) or the "Malnutrition Universal Screening Tool" (MUST). High-caloric oral supplementation, enteral nutrition and parenteral nutrition are possible measures, which should be escalated stepwise. The recent concept of "prehabilitation" additionally includes short­term optimization of the physical and psychological status. Postoperative attention should be paid to possible deficiency syndromes of single nutrients due to reduced resorption after bowel segment resection or stoma creation. Risk- and preventive factors in primary prevention of colorectal carcinoma are well-known, in secondary prevention knowledge is less clear. There is only low evidence for a positive effect of omega-3 fatty acids, coffee, high-fiber diet and vitamin D in secondary prevention of colorectal carcinoma, requiring further studies.

Pre-emptive endoscopic vacuum therapy for treatment of anastomotic ischemia after esophageal resections.

Background and study aims Endoscopic vacuum therapy (EVT) is a promising new approach for the treatment of anastomotic leakage in the gastrointestinal tract. Here, we present the first case series demonstrating successful use of EVT for the treatment of post-esophagectomy anastomotic ischemia prior to development of leakage. Patients and methods Between 2012 and 2015, intraluminal EVT was performed in eight patients with anastomotic ischemia following esophagectomy. The primary outcome measure was successful mucosal recovery. Secondary outcome measures were duration of treatment, number of sponge changes, septic course, and associated complications. Results Complete mucosal recovery was achieved in six patients (75 %) with different degrees of anastomotic ischemia. In two patients (25 %), small anastomotic leaks developed, which resolved by continuing the EVT treatment. Median duration of EVT treatment until mucosal recovery was 16 days (range 6 - 35), with a median of 5 sponge changes per patient (range 2 - 11). No EVT-associated complications were noted. Three patients developed anastomotic stenoses, which were treated by endoscopic dilation therapy. Conclusion This is the first case series to demonstrate that the early use of EVT potentially modulates clinical outcomes and infection parameters in patients with anastomotic ischemia following esophagectomy. Further studies are needed to define the indications and patients who are most likely to benefit from early EVT.

Gut commensal bacteria and regional Wnt gene expression in the proximal versus distal colon.

Regional expression of Wingless/Int (Wnt) genes plays a central role in regulating intestinal development and homeostasis. However, our knowledge of such regional Wnt proteins in the colon remains limited. To understand further the effect of Wnt signaling components in controlling intestinal epithelial homeostasis, we investigated whether the physiological heterogeneity of the proximal and distal colon can be explained by differential Wnt signaling. With the use of a Wnt signaling-specific PCR array, expression of 84 Wnt-mediated signal transduction genes was analyzed, and a differential signature of Wnt-related genes in the proximal versus distal murine colon was identified. Several Wnt agonists (Wnt5a, Wnt8b, and Wnt11), the Wnt receptor frizzled family receptor 3, and the Wnt inhibitory factor 1 were differentially expressed along the colon length. These Wnt signatures were associated with differential epithelial cell proliferation and migration in the proximal versus distal colon. Furthermore, reduced Wnt/ß-catenin activity and decreased Wnt5a and Wnt11 expression were observed in mice lacking commensal bacteria, an effect that was reversed by conventionalization of germ-free mice. Interestingly, myeloid differentiation primary response gene 88 knockout mice showed decreased Wnt5a levels, indicating a role for Toll-like receptor signaling in regulating Wnt5a expression. Our results suggest that the morphological and physiological heterogeneity within the colon is in part facilitated by the differential expression of Wnt signaling components and influenced by colonization with bacteria.

Growth factors and gastrointestinal anastomotic healing.

BACKGROUND: Failure of anastomotic healing in the gastrointestinal tract is a major source of surgery-related morbidity, repeated surgical procedures, and impaired quality of life. Growth factors have been shown to be involved in healing processes in various tissues including the gastrointestinal tract. This opens the perspective to use growth factors therapeutically to support impaired anastomotic healing. The aim of the present study was to review the particular role of several growth factors in different phases of anastomotic healing, experimental approaches of growth factor application, and to discuss possibilities and limitations of growth factor-directed interventions in gastrointestinal surgery. MATERIALS AND METHODS: A PubMed search was performed to examine the potential role of fibroblast growth factor, epidermal growth factor, heparin binding EGF-like growth factor, transforming growth factor ß, insulin-like growth factor I, vascular endothelial growth factor, and platelet-derived growth factor during anastomotic healing. RESULTS: Growth factors show beneficial effects on a broad range of cell types and regulate various processes during all phases of tissue healing. Despite extensive research in the field of growth factors, additional evidence is needed before translating into a clinical setting. CONCLUSIONS: Future research should focus on adequate sustained but limited drug delivery. Undesired side effects, such as formation of strictures, development of peritoneal adhesions, and potential induction of malignancies, have to be reflected. Although growth factor application is currently far from clinical routine in gastrointestinal surgery, it might find application in selected patients at risk for impaired anastomotic healing, such as patients with long-time steroid therapy, immunosuppressives, inflammatory disorders, sepsis, hemodynamic shock, malnutrition, or neoadjuvant radiochemotherapy.

Fractal analysis of extracellular matrix for observer-independent quantification of intestinal fibrosis in Crohn's disease.

Prevention of intestinal fibrosis remains an unresolved problem in the treatment of Crohn's disease (CD), as specific antifibrotic therapies are not yet available. Appropriate analysis of fibrosis severity is essential for assessing the therapeutic efficacy of potential antifibrotic drugs. The aim of this study was to develop an observer-independent method to quantify intestinal fibrosis in surgical specimens from patients with CD using structural analysis of the extracellular matrix (ECM). We performed fractal analysis in fibrotic and control histological sections of patients with surgery for CD (n = 28). To specifically assess the structure of the collagen matrix, polarized light microscopy was used. A score to quantify collagen fiber alignment and the color of the polarized light was established. Fractal dimension as a measure for the structural complexity correlated significantly with the histological fibrosis score whereas lacunarity as a measure for the compactness of the ECM showed a negative correlation. Polarized light microscopy to visualize the collagen network underlined the structural changes in the ECM network in advanced fibrosis. In conclusion, observer-independent quantification of the structural complexity of the ECM by fractal analysis is a suitable method to quantify the degree of intestinal fibrosis in histological samples from patients with CD.

B cell-mediated CD4 T-cell costimulation via CD86 exacerbates pro-inflammatory cytokine production during autoimmune intestinal inflammation.

Dysregulated B cell responses have been described in inflammatory bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here provide evidence for the detrimental role of activated B cells during the onset of autoimmune intestinal inflammation. Using Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1-/-) mice as a mouse model of chronic colitis, we identified clusters of differentiation (CD)86 expression on activated B cells as a crucial factor exacerbating pro-inflammatory cytokine production of intestinal CD4 T cells. Depleting B cells through anti-CD20 antibody treatment or blocking costimulatory signals mediated by CD86 through cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) diminished intestinal inflammation in our mouse model of chronic IBD at the onset of disease. This was due to a reduction in aberrant humoral immune responses and reduced CD4 T cell pro-inflammatory cytokine production, especially interferon-g (IFN-g) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Interestingly, in addition to B cells isolated from the inflamed colon of Wipf1-/- mice, we also found CD86 mRNA and protein expression upregulated on activated B cells isolated from inflamed tissue of human patients with IBD. B cell activation and CD86 expression were boosted by soluble CD40L in vitro, which we found in the serum of mice and human patients with IBD. In summary, our data provides detailed insight into the contribution of B cells to intestinal inflammation, with implications for the treatment of IBD.