Miranda G. Kiernan

The mesentery in Crohn's disease: friend or foe?

Purpose of review This article assesses the role of the mesentery in Crohns disease. Recent findings The mesentery is centrally positioned both anatomically and physiologically. Overlapping mesenteric and submucosal mesenchymal contributions are important in the pathobiology of Crohns disease. Mesenteric contributions explain the topographic distribution of Crohns disease in general and mucosal disease in particular. Operative strategies that are mesenteric based (i.e. mesocolic excision) may reduce rates of postoperative recurrence. Summary The net effect of mesenteric events in Crohns disease is pathologic. This can be targeted by operative means. Video abstract http://links.lww.com/COG/A18.

Circulating fibrocytes and Crohn's disease.

Despite advances in medical therapy, there remains no effective preventive or non‐surgical therapeutic option for fibrostenotic Crohns disease (CD). Symptomatic recurrences are common, necessitating reintervention. Intestinal fibroblasts mediate stricture formation, but their exact source is unclear. Recent evidence indicates that circulating fibrocytes drive fibrosis through differentiation into fibroblasts and the production of extracellular matrix proteins. The aim of this review is to describe current understanding of the pathophysiology underlying fibrosis in CD, the cellular and molecular biology of fibrocytes and their role in CD.

Inclusion of the Mesentery in Ileocolic Resection for Crohn’s Disease is Associated With Reduced Surgical Recurrence

Abstract Background and Aims Inclusion of the mesentery during resection for colorectal cancer is associated with improved outcomes but has yet to be evaluated in Crohn’s disease. This study aimed to determine the rate of surgical recurrence after inclusion of mesentery during ileocolic resection for Crohn’s disease. Methods Surgical recurrence rates were compared between two cohorts. Cohort A [n = 30] underwent conventional ileocolic resection where the mesentery was divided flush with the intestine. Cohort B [n = 34] underwent resection which included excision of the mesentery. The relationship between mesenteric disease severity and surgical recurrence was determined in a separate cohort [n = 94]. A mesenteric disease activity index was developed to quantify disease severity. This was correlated with the Crohn’s disease activity index and the fibrocyte percentage in circulating white cells. Results Cumulative reoperation rates were 40% and 2.9% in cohorts A and B [P = 0.003], respectively. Surgical technique was an independent determinant of outcome [P = 0.007]. Length of resected intestine was shorter in cohort B, whilst lymph node yield was higher [12.25 ± 13 versus 2.4 ± 2.9, P = 0.002]. Advanced mesenteric disease predicted increased surgical recurrence [Hazard Ratio 4.7, 95% Confidence Interval: 1.71–13.01, P = 0.003]. The mesenteric disease activity index correlated with the mucosal disease activity index [r = 0.76, p < 0.0001] and the Crohn’s disease activity index [r = 0.70, p < 0.0001]. The mesenteric disease activity index was significantly worse in smokers and correlated with increases in circulating fibrocytes. Conclusions Inclusion of mesentery in ileocolic resection for Crohn’s disease is associated with reduced recurrence requiring reoperation.

An optimized work-flow to reduce time-to-detection of carbapenemase-producing Enterobacteriaceae (CPE) using direct testing from rectal swabs

ABSTRACT Rapid detection of patients with carbapenemase-producing Enterobacteriaceae (CPE) is essential for the prevention of nosocomial cross-transmission, allocation of isolation facilities and to protect patient safety. Here, we aimed to design a new laboratory work-flow, utilizing existing laboratory resources, in order to reduce time-to-diagnosis of CPE. A review of the current CPE testing processes and of the literature was performed to identify a real-time commercial polymerase chain reaction (PCR) assay that could facilitate batch testing of CPE clinical specimens, with adequate CPE gene coverage. Stool specimens (210) were collected; CPE-positive inpatients (n = 10) and anonymized community stool specimens (n = 200). Rectal swabs (eSwab™) were inoculated from collected stool specimens and a manual DNA extraction method (QIAamp® DNA Stool Mini Kit) was employed. Extracted DNA was then processed on the Check-Direct CPE® assay. The three step process of making the eSwab™, extracting DNA manually and running the Check-Direct CPE® assay, took <5 min, 1 h 30 min and 1 h 50 min, respectively. It was time efficient with a result available in under 4 h, comparing favourably with the existing method of CPE screening; average time-to-diagnosis of 48/72 h. Utilizing this CPE work-flow would allow a ‘same-day’ result. Antimicrobial susceptibility testing results, as is current practice, would remain a ‘next-day’ result. In conclusion, the Check-Direct CPE® assay was easily integrated into a local laboratory work-flow and could facilitate a large volume of CPE screening specimens in a single batch, making it cost-effective and convenient for daily CPE testing.

The Human Mesenteric Lymph Node Microbiome Differentiates Between Crohn’s Disease and Ulcerative Colitis

Abstract Background and Aims Mesenteric lymph nodes are sites in which translocated bacteria incite and progress immunological responses. For this reason, understanding the microbiome of mesenteric lymph nodes in inflammatory bowel disease is important. The bacterial profile of Crohn’s disease mesenteric lymph nodes has been analysed using culture-independent methods in only one previous study. This study aimed to investigate the mesenteric lymph node microbiota from both Crohn’s disease and ulcerative colitis patients. Methods Mesenteric lymph nodes were collected from Crohn’s disease and ulcerative colitis patients undergoing resection. Total DNA was extracted from mesenteric lymph nodes and assessed for the presence of bacterial DNA [16S]. All work was completed in a sterile environment using aseptic techniques. Samples positive for 16S DNA underwent next-generation sequencing, and the identity of bacterial phyla and species were determined. Results Crohn’s disease mesenteric lymph nodes had a distinctly different microbial profile to that observed in ulcerative colitis. The relative abundance of Firmicutes was greater in nodes from ulcerative colitis patients, whereas Proteobacteria were more abundant in Crohn’s disease. Although species diversity was reduced in the mesenteric lymph nodes of patients with Crohn’s disease, these lymph nodes contained greater numbers of less dominant phyla, mainly Fusobacteria. Conclusion This study confirms that there are distinct differences between the Crohn’s disease and ulcerative colitis mesenteric lymph node microbiomes. Such microbial differences could aid in the diagnosis of Crohn’s disease or ulcerative colitis, particularly in cases of indeterminate colitis at time of resection, or help explain their mechanisms of development and progression.

Adipocyte-Epithelial Interactions and Crohn's Disease - An Emerging Drug Target

Article history: Received 31 August 2017 Accepted 31 August 2017 Available online 5 September 2017 Takahashi et al. demonstrated a novel cellular axis involving intestinal epithelial cells (IECs) and adipocytes. Several properties of this axis were important. Firstly, they observed an increase in MMP-9 mRNA in IECs when co-cultured with adipocytes that had differentiated from murine embryonic fibroblasts. Importantly, no increase in MMP-9

P061 Identification of the mesocolic mesothelium as a novel source of fibroblasts – implications for Crohn's disease

Background: Regulatory Foxp3+ T cells (Treg) maintain immune tolerance by controlling systemic autoimmune and allergic diseases but are also crucial for control of intestinal homeostasis and oral tolerance to dietary antigens and to the microbiota. Breakdown of intestinal homeostasis in chronic inflammatory bowel disease is associated with inability of Treg to control inflammation, suggesting that the inflamed intestinal microenvironment is deleterious for Treg. Methods: In this study we explored, using two models of colitis (DSS colitis and TNBS colitis), the impact of intestinal inflammation on the number, survival, phenotype and regulatory function of Treg and conversion from CD4+ T cells. Results: We found that intestinal inflammation increased the number Foxp3+ Treg in Mesenteric Lymph Nodes (MLN), although their frequency decreased due to the inflammatory infiltrate. Colitis was associated with increased proliferation of Foxp3+Ki67+ Treg in MLN and LP. MLN Foxp3+ Treg at the steady state comprised both Helios+Neuropilin+ and Helios Neuropilin , which are believed to represent natural (nTreg) versus induced (iTreg) Treg, respectively and intestinal inflammation decreased the frequency of nTreg. Ex vivo Treg suppression assay showed that MLN Treg from colitic mice maintain their suppressive function, when removed from the inflamed intestine. Adoptive transfer of naive CD4+ T cells (containing nTreg) in congenic recipient mice showed that colon inflammation exacerbated recruitment of CD4+ T cells into the lamina propria. However, in vivo conversion of CD4+CD25+ Foxp3 pre-Treg (sorted from Foxp3-egfp transgenic mice) into Foxp3+ Treg was impaired in colitic recipient mice. Finally, transfer of Foxp3-egfp+ cells in DSS mice showed a significant decrease of colitis severity. Conclusions: Taken together our data illustrate that Treg can be activated and recruited in the inflamed intestine but that intestinal inflammation impairs Treg conversion from CD4+ T cells.