Introduction

Sepsis is defined as an organic dysfunction that threatens the life of patients due to an abnormally regulated response to infection [1]. The initial phase of sepsis is dominated by an increased production of proinflammatory cytokines, which leads to augmented capillary permeability, extravasation, hypercoagulability and myelopoiesis. One of the main sources of infection in sepsis is believed to be the intestinal microbiota via traslocation through the mucosa to the bloodstream. Systemic inflammation weakens intestinal barrier function (IBF) in animal models, resulting in increased bacterial traslocation [2]. Even if the management of sepsis has advanced in the last decades, mortality is still high and there is room for improvement. Thus, the search for effective treatments is clearly justified. Glucocorticoids (GC) constitute a therapeutic modality in sepsis, but they have only shown moderate benefit. This may be accounted for by the harmful effects of GCs on IBF, which may facilitate translocation of luminal microorganisms and molecules. Besides, GC treatment impairs epithelial healing in experimental colitis in mice [3]. Previous results of our research group have shown that mice with induced deletion of the GC receptor (GR) in intestinal epithelial cells (i.e. NR3C1^ΔIEC mice) are protected against dextran sulphate sodium (DSS)-induced colitis [4].

Aims & Methods

Our aim is to understand the role of the intestinal epithelial GR and its involvement in IBF regulation in experimental sepsis, with the ultimate goal of improving the management of sepsis with GCs.
The cecal ligation and puncture (CLP) model of sepsis was applied to WT C57BL/6J and NR3C1^ΔIEC mice. Caecum-exposed mice were used as control (sham). Mice were sacrificed 24 hours after surgery. Four hours before sacrifice, mice were administered 4 kD FITC-dextran, a fluorescent marker of permeability. Colon, jejunum, adrenes, kidney and liver RT-qPCRs were performed as well as determination of corticosterone plasma levels.

Results

After 24 h, CLP mice exhibited hypoglycemia and splenomegaly with elevated corticosterone plasma levels, which were associated to increased Cyp11a1 in the adrenes. Of note, both parameters were less pronounced in KO mice. Intestinal barrier function was weakened, as indicated by downregulation of Tjp1 and increased FITC-dextran plasma levels, which were similar in WT and KO mice. A modest increase in inflammatory markers was noted in the colon and jejunum. However, KO mice exhibited dampened inflammatory response in the colon, with lower expression of inflammatory markers such as S100a8 and S100a9, but not in the jejunum. Similarly, the colonic expression of Cyp11a1 and Lrh1, involved in local steroidogenesis, was lower in CLP mice, regardless of genotype. WT but not KO mice showed an increased in of tissue non-specific alkaline phosphatase (TNAP) in liver, an enzyme involved in detoxification of phosphorylated molecules such as bacterial lipopolysaccharide, but lower expression of Tsc22d3, whose role is described to be protective against sepsis [5]. Inflammation markers were also augmented in the lung and kidney.

Conclusion

In the early stages of the CLP model of sepsis the colon and jejunum are inflamed, and epithelial deletion of the glucocorticoid receptor appears to modulate colonic inflammation, but not barrier function or systemic status.

References

1. Singer, M, et al., Jama, 2016. 315(8): p. 801-10.
2. Carrico, CJ, et al., Arch Surg, 1986. 121(2): p. 196-208.
3. Ocon, B, et al., Biochem Pharmacol, 2016. 116: p. 73-88.
4. Arredondo-Amador, M, et al., Br J Pharmacol, 2021. 178(12): p. 2482-2495.
5. Ballegeer, M, et al., Shock, 2019. 52(2): p. 208-214.

Introduction

Dysbiosis is associated with gastric cancer (GC) development. However, no study was carried out to identify key bacteria that could predict for GC progression after H. pylori eradication.

Aims & Methods

Aim was to investigate salivary and gastric mucosal microbiome in the patients with a history of endoscopic submucosal dissection (ESD) for early gastric cancer detected after eradication and non-cancer eradicated controls. Saliva was collected from each subject just before endoscopic examination on the same day, and gastric mucus was obtained by gently scraping gastric mucosa from antrum greater curvature to corpus greater curvature using biopsy forceps. The samples were immediately placed in microcentrifuge tubes containing DNA stabilization reagent and analyzed using the next generation sequencer. Potential changes in the MAM at the functional level were evaluated using PICRUSt software and the KEGG database.

Results

24 patients with eradication and prior ESD history (the cancer group) and 27 controls were enrolled. Among the gastric mucous samples, the genera Rothia was significantly more abundant (p=0.006) in the gastric cancer group compared to the control group, and the abundance of the genera Parvimonas was significantly less (p=0.008) in the cancer group. The abundance of the genera Parvimonas and Alloprevotella among the gastric mucous samples were significantly less prevalent in the severe atrophy group compared to the mild atrophy group, while Rothia was not different between the two group. However, the difference was not detected among the salivary samples.

Conclusion

Gastric mucosal microbiota is possibly associated with GC carcinogenesis after eradication regardless of gastric atrophy.

Introduction

Dysbiosis is a hallmark of Crohn's disease (CD). However, its relation to CD course is still unclear. We asked whether microbial signatures identify CD phenotype.

Aims & Methods

A cohort of patients with newly diagnosed CD (all-comers) were recruited and prospectively followed. Clinical data, inflammatory and serologic markers, dietary habits, microbial and fungal composition were detected. Complicated disease course was defined as steroid dependency, CD-related hospitalization, or surgery, and >1 biologics/year. Unsupervised analysis was used to construct baseline microbial clusters. Linear mixed effect models were used to evaluate the clinical, dietary, and fungal associations with microbial clusters, adjusted for treatment.

Results

A total of 251 patients with newly diagnosed CD were recruited (females- 50.6%, median age- 28 [IQR 22-39]) and followed up for a median of 25 months (IQR 14.5-39.8). During follow-up 131 (52.2%) patients were treated with biologics (93.8% with anti-tumor necrosis factor). Sixty-eight (27.1%) patients had complicated disease course, median time to first complication 3.9 months (IQR 2.3-7.7). Two baseline distinct microbial clusters were noticed. A “pathogenic cluster” identified patients with a complicated disease course (52.6% vs. 20.8%, p<0.001). This cluster was characterized by an increase of potentially harmful bacterial taxa including Escherichia coli, Klebsiella, Gemmella; and depletion of beneficial bacterial taxa including Faecalibacterium, Lachnospiraceae and Roseburia. The “pathogenic cluster” had lower Shannon diversity and higher microbial dysbiosis index (both, p<0.001). Additionally higher abundances of multiple fungal taxa including Cladosporium and Aspergillus were observed in the “pathogenic cluster” as well as a trend towards higher ASCA titer levels (p=0.08). Baseline macro and micronutrients composition were comparable between microbial clusters. Of note, in a sub-cohort of 109 patients, who presented with uncomplicated phenotype, only 11 patients developed complicated disease course. However, no specific bacterial signature was detected.

Conclusion

A distinct microbial cluster identified patients with newly diagnosed CD who had complicated disease course. Thus, baseline microbial signatures might be used to predict CD course.

Introduction

A major difficulty in treating Crohn’s disease (CD) lies in the unreliable association between clinical symptoms and underlying inflammation, hindering effective monitoring. Intestinal ultrasound (IUS) has emerged as a valuable, non-invasive, and well tolerated tool for assessing inflammatory activity in CD. The "Selecting Therapeutic Targets in Inflammatory Bowel Disease" (STRIDE-II) guidelines recognize the transformative impact of IUS in inflammation assessment but hesitate to endorse transmural healing as a primary treatment target due to current limitations of available therapies in achieving this outcome. However, limited data exist on the applicability of IUS in patients with newly diagnosed CD who might not have developed irreversible fibrotic alterations.

Aims & Methods

The primary aim of this study was to characterize the sonographic features of CD at diagnosis and throughout the initial year post-diagnosis. Additionally, we sought to assess the predictive capability of IUS herein.
We conducted a prospective, population-based cohort study involving newly diagnosed patients with CD. Patients were systematically monitored using IUS in tandem with symptomatic, biochemical, and endoscopic evaluations throughout the first year following diagnosis. Transmural remission (TR) was defined as BWT ≤ 3 mm without colour Doppler signal, and symptomatic remission as Harvey-Bradshaw Index ≤ 4.

Results

During the study period (May 2021 – May 2023), 201 patients with adult-onset CD were included. No significant associations were observed between sonographic characteristics of inflammation and diagnostic delay.
At three months post-diagnosis, TR was achieved in 38% of patients, with a higher proportion observed in those with colonic disease (L1: 33%, L2: 52%, L3: 27%; p= 0.05). TR at three months was significantly associated with symptomatic remission at subsequent follow-ups during the first year (3 months: 87% vs. 51%, p < 0.001; 6 months: 87% vs. 61%, p = 0.004; 9 months: 76% vs. 49%, p = 0.012; 12 months: 87% vs. 64%, p = 0.013), as well as a reduced risk of treatment escalation (20% vs. 65%, p < 0.0001) during this period.
By 12-month, 41% of patients achieved TR, with no significant association observed with disease location. In a multivariable analysis adjusted for age, sex, smoking, disease location, and baseline sonographic inflammation, a higher body mass index (BMI) significantly decreased the likelihood of achieving transmural remission (overweight: Odds ratio (OR) = 0.13, 95% confidence interval (CI): 0.02–0.93; obesity: OR = 0.06, 95% CI: 0.01–0.64).
Among the 126 patients with ileal or ileocolonic disease, 16 (13%) underwent ileocecal resection (ICR) within the first year. In an analysis of receiver operating characteristic area under the curve (ROC AUC), which included endoscopic, symptomatic, sonographic, and biochemical findings, the International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) in the terminal ileum at diagnosis emerged as the most accurate predictor of ICR during this period: IBUS-SAS 63 (AUC = 0.92, sensitivity = 100%, specificity = 73%).

Conclusion

The findings of this study highlight TR as an attainable goal for newly diagnosed CD patients with a positive impact on the disease course. Moreover, the negative influence of high BMI on the likelihood of achieving TR underscores the necessity for further investigation into the impact of weight on the disease course of IBD. The study also reveals that sonographic inflammation in the terminal ileum at diagnosis is the most accurate predictor of the need of ICR within the first year.