Introduction

Postoperative recurrence (POR) in patients with Crohn’s disease (CD) occurs mostly within the first year after ileocolic resection. POR can be prevented efficiently with early postoperative use of thiopurines or anti-TNF agents. Recently, it has been reported that medical prevention for POR might also reduce the risk of delayed POR.

Aims & Methods

Aims: To assess the long-term risk of a second intestinal resection for CD according to the use of early medical prevention of POR.
Methods: Adult patients with CD who underwent a first ileocolic resection with ileocolic anastomosis between 1990 and 2020 and at least one year of clinical follow-up were identified from the Spanish ENEIDA registry. Patients in whom ileocolic resection was due to cancer were excluded. Medical prevention of POR was defined as any immunomodulator or biological agent started within the first 6 months after the ileocolic resection and maintained for at least 3 months. Medical treatment of POR was defined as any immunomodulator or biological agent started at least 6 months after the index surgery. Surgical POR was defined as the need for a second intestinal resection at least 6 months after the first ileocolic resection.

Results

A total of 5,084 patients were included. Main characteristics of the whole cohort were as follows: 51% men, 39% active smokers at the first surgery, 40% penetrating and 40% stricturing behaviour, 25% perianal disease. 34% exposed to immunomodulators and 25% to biologicals before the first surgery. Median disease duration at first surgery of 3 years (range, 0-46), median age at index surgery was 35 years (range, 9-89), median follow-up until second resection or last visit of 125 months (range 6-408). 55% followed medical prophylaxis (33% thiopurines, 10% biological monotherapy, 12% combotherapy). Surgical POR occurred in 17% of the whole cohort. Kaplan-Meier survival curves showed a significantly higher risk of surgical POR among patients who did not follow medical prevention (P<0.0001), whether with thiopurines (P<0.0001) or biologicals (P<0.0001). No differences in surgical POR were observed between medical prevention with biologicals in monotherapy or combotherapy (P=0.588) nor between thiopurines and biologicals (P=0.114). In the Cox regression analysis, medical prevention with thiopurines (HR 0.65, 95%CI 0.56-0.76; P<0.0001) and medical treatment with biologicals (HR 0.87, 95%CI 0.80-0.94; P<0.0001) or thiopurines (HR 0.88, 95%CI 0.78-0.99; P<0.032) were independent protective factors of surgical POR.

Conclusion

Early medical prevention (particularly with thiopurines) seems to have a long-term beneficial effect on preventing surgical POR. Our findings support the systematic use of early medical prevention instead of endoscopy-driven strategies in the postoperative setting of CD.

Introduction

Colorectal cancer, with an estimated two million new cases each year worldwide, poses a significant socioeconomic burden on modern society. It is the second leading cause of cancer-related deaths, accounting for nearly one million premature deaths annually.

Aims & Methods

The role of Signal Transducer and Activator of Transcription 2 (STAT2) in this context is not yet understood, and no therapies targeting this transcription factor are currently being pursued. We explored the function of STAT2 in colorectal cancer by employing experimental mouse models, as well as conducting functional assays with three-dimensional tumoroids in the context of anticancer therapy.

Results

In vivo studies showed that Stat2KO mice were more resistant to developing tumors in both inflammation-driven and inflammation-independent models of experimental colorectal cancer. This unexpected outcome could not be reconciled with the known role of STAT2 in inducing cell death downstream of type I interferon signaling. We consequently performed ex vivo experiments with tumoroids derived from Stat2KO mice carrying the multiple intestinal neoplasia (Min) mutant allele of the adenomatous polyposis coli (Apc) gene. These tumoroids exhibited slower growth, were generally smaller in size, and showed a higher degree of differentiation compared to those derived from ApcMin/+ wildtype mice. Remarkably, when treated with anti-tumor agents that induce cell death through various mechanisms, tumoroids derived from ApcMin/+ Stat2KO mice were found to be highly sensitive. Additional functional studies indicated that the underlying mechanism might involve a STAT2-dependent disruption of innate immune DNA sensing.

Conclusion

Our results establish STAT2 as a promoter of colorectal cancer and a contributor to resistance against anti-tumor therapy. These findings suggest that targeting STAT2-dependent signaling could be a promising therapeutic strategy for patients with colorectal cancer.

Introduction

Irritable bowel syndrome (IBS) is a highly prevalent and challenging condition with limited therapeutic options. Chitin-glucan (CG) is a novel dietary prebiotic considered as a safe food ingredient by EFSA. To provide an alternative approach to the management of IBS patients, we evaluated in preclinical studies the roles of CG on visceral analgesia, intestinal inflammation and barrier function and performed an open-label trial in IBS patients.

Aims & Methods

Analgesic effect of CG used at a human equivalent dose (HED) of 1.5-3 g/d was evaluated in rats and compared to negative-tap water and positive-phloroglucinol control groups. Mice with DSS-induced colitis were used to analyze the anti-inflammatory properties of CG. Molecular mechanisms underlying analgesic, anti-inflammatory, and intestinal barrier-strengthening functions of CG were evaluated in human intestinal HT-29 epithelial cells. CG molecular modeling was developed to study its interactions with microbial cell walls.
A multicenter open-label trial was conducted in 120 patients with IBS (Rome IV criteria) treated with CG 1.5 g/d and simethicone 0.75 mg/d for 4 weeks. The primary endpoint was the responder rate, defined as the number of patients whose abdominal pain score decreased by ≥30% from baseline at week (W) 4. The analysis was performed using the per-protocol set. Cardinal symptoms, impact of global symptoms on daily life, change in stool consistency, and improvement in defecatory disorders were evaluated.

Results

CG in animals was well tolerated. CG at 3g/d HED significantly decreased visceral perception by 14% after 2 weeks (p<0.01) and reduced inflammation by 50% promoting mucosal regeneration in DSS-induced colitis mice. CG at 1.5g/d HED reduced visceral pain perception by 20% after 5 weeks of treatment (p<0.01). At 3g/d HED, this analgesic effect was superior to phloroglucinol with a faster onset of action and a 50% inhibition of pain perception (p<0.0001). The molecular mechanisms contributing to these analgesic and anti-inflammatory effects of CG involved a significant induction of µ-opioid receptor (MOR), cannabinoid-2 (CB2) receptor, IL-10 and a significant decrease of pro-inflammatory cytokines IL-1b and IL-8 mRNA. CG also significantly up-regulated barrier-related genes like muc5AC, claudin-2 and ZO-2. CG molecular modelling revealed a new property of the molecule as a chelator of gram–negative lipopolysaccharide (LPS), gram–positive lipoteichoic acid (LTA) and phospholipomannan (PLM) in fungi.
Overall, 100 IBS patients were evaluated. At week 4, 67% were abdominal pain responders (score: 5.8 ± 2.4 vs. 2.9 ± 2.0, p<0.0001). Similar improvements were observed for bloating (8.0 ± 1.7 vs. 4.7 ± 2.9, p<0.0001; 60% responders), abdominal distension (7.2 ± 2.1 vs. 4.4 ± 3.1, p<0.0001; 53% responders), and impact of global symptoms on daily life (7.1 ± 2.0 vs. 4.6 ± 2.9, p<0.0001; 54% responders). Stool consistency improved in most patients (90% and 57% for patients with liquid and hard stools, respectively). Overall, 42% of patients with defecatory disorders reported very much/considerable improvements by 2 weeks. No severe adverse event occurred, and tolerability was rated “good” or “very good” by 93%.

Conclusion

CG decreased visceral perception and intestinal inflammation. It also impacted master genes regulation and direct binding of microbial products. CG-simethicone was well tolerated and improved IBS symptoms in an uncontrolled trial. A placebo-controlled trial with longer follow-up is now ongoing to confirm the benefits of CG in IBS patients.

Disclosure

Prof Pierre Desreumaux is President of the Scientific Board of BiOkuris SA
Prof Edouard Louis is member of the Scientific Board of BiOkuris SA

Introduction

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms, such as gastrointestinal symptoms. Emerging evidence suggests that gut permeability and inflammation play a role in PD pathophysiology via the gut-brain axis. According to Braak’s theory, the pathological degeneration associated with PD may originate from the gut and subsequently develop in the brain through the vagus nerve.

Aims & Methods

The aims were to assess the relationship between gut permeability and neuroinflammation in a cohort of patients with PD and REM behavior disorder (RBD), a condition that often precedes the onset of PD. The study prospectively included 28 PD patients and 18 RBD patients both complaining of GI symptoms. No serious organic diseases or therapies potentially affecting GI motility were reported. Relevant demographic and clinical data were collected for all patients. There was the inclusion of 14 healthy controls (HCs). A serum ELISA assay of tumor necrosis factor (TNF), caspase-1, and lipopolysaccharide-binding protein (LBP) was performed in all participants to investigate systemic inflammatory status and gut permeability, respectively. In a total of 10 PD patients, 4 RBD patients and 9 HCs, multiple colic biopsies were obtained to assay tissue expression of inflammation markers by both western blot (WB) (i.e. caspase-1 and procaspase-1) and immunofluorescence (IF) (i.e. ASC and CD68). Data were expressed as mean ± SD, and ANOVA and Dunnett's tests were used to compare the three groups.

Results

All three groups were comparable in age and sex. Serum assays showed significantly increased LBP, in patients with PD (35.0 ± 0.25; p = 0.002) and RBD (32.2 ± 1.1; p = 0.009) compared with HCs. TNF (0.1 ± 0.02; p = 0.03) and caspase-1 (16.9 ± 9.4; p = 0.04) were significantly raised only in the PD group in comparison with HCs (Table 1). WB analysis showed significant differences in the expression of procaspase-1 (157.3 ± 17.8; p = 0.02) and caspase-1 (168.3 ± 23.3; p = 0.03) only in PD patients compared with HCs. IF showed a qualitative increase in both CD68+ macrophage infiltration and ASC expression in PD and RBD groups compared with HCs.

	PD	RBD	HCs	P-value
LBP (ng/ml)	35.0 ± 0.25	32.2 ± 1.1	23.1 ± 2.1	0.009 (RBD vs HCs) 0.002 (PD vs HCs)
Caspasi-1 (ng/ml)	16.9 ± 9.4	11.4 ± 2.1	9.9 ± 2.7	0.04 (PD vs HCs)
TNF (pg/ml)	0.1 ± 0.02	0.05 ± 0.02	0.04 ± 0.02	0.03 (PD vs HCs)

Conclusion

Our results show a bowel activation of NLRP3 inflammasome in PD, as demonstrated both by the levels of procaspase-1 and caspase-1 on WB analysis and by the increase of CD68+ macrophages and ASC in the lamina propria of colonic mucosa. Only a qualitative increase in NLRP3 activation at IF could be observed in RBD patients. However, findings from colonic biopsies, if related to elevated serum levels of TNF and caspase-1 in PD patients, and LBP in PD and RBD patients, suggest that bowel inflammation, sustained by increased gut permeability, may represent an early stage in the develop of RBD and PD.

Introduction

The detection of cancer within large non-pedunculated colorectal polyps (LNPCPs) is suboptimal in non-expert settings. Identification of 6 macroscopic (Blink) features (6BF) of deep submucosal invasive cancer (SMI) has shown significant improvement in the sensitivity of cancer detection by inexperienced endoscopists at the expense of decreased specificity. This study investigates the impact of endoscopic resection scars, which can resemble deep SMI, on the accuracy of non-expert endoscopists using the 6BF evaluation system known as Blink Impression.

Aims & Methods

An online survey was disseminated containing 20 overview images of LNPCPs (1 image/polyp). Images (randomized) were shown before, and after a 2-minute educational video (the intervention) introducing the 6BF - fold deformation, extra redness, depression, chicken skin mucosa, ulceration and spontaneous bleeding. Before and after the intervention participant Blink Impression was elicited (cancer/no cancer) and only after, the presence of the 6BF. Responses were analysed relative to histopathology (no vs superficial vs deep SMI) and expert opinion on the presence of the 6BF and endoscopic resection scars.

Results

7/20 LNPCPs contained cancer (3 superficial, 4 deep SMI), 3 contained scars. 191 participants from 21 countries completed 3,755 observations. 129/191 (67.5%) participants were inexperienced. Expert-identified scarred LNPCPs contained median 1.0 (IQR 2.0) BF vs 1.0 (IQR 2.0) for no cancer, 2.0 (IQR 2.0) for superficial SMI and 3.0 (IQR 2.0) for deep SMI (all P<.001). Presence of ≥2 BF therefore reliably identifies cancer within LNPCPs but not scars. Fold deformation was the only BF identified more commonly amongst scarred LNPCPs (44.6%) vs no cancer (22.5%, P<.001) and vs superficial SMI (33.0%, P<.001), but similar to deep SMI (44.6%, P=1.000). Depression, chicken skin mucosa and spontaneous bleeding were less commonly identified in scarred polyps (12.3%, 7.6% and 1.8%) than both no cancer (33.1%, 14.4% and 8.6%, all P<.001), superficially invasive (68.6%, 14.3% and 5.8%, all P<.001) or deeply invasive polyps (45.9%, 19.6% and 40.5%, all P<.001). Extra redness and ulceration were identified with similar frequency to no cancer in scars (26.4% vs 26.8%, P=0.891 and 10.2% vs 9%, P=0.441 respectively), but less commonly than superficial (64.2%, P<.001 and 15.7%, P<.001) or deep SMI (60.2%, P<.001 and 24.7%, P<.001) (Table 1).

Conclusion

The presence of ≥2BF reliably discriminates LNPCPs with cancer from non-cancer even in the presence of scarred lesions amongst non-expert endoscopists. Scarred LNPCPs exhibit fold deformation at a similar rate to LNPCPs with deep SMI but other BF are not present.

References

Debels LK, Smeets S, Poortmans PJ, Argenziano ME, Desomer L, Anderson J, Valori R, David J Tate. Identification of 6 key features of colorectal polyps increases the sensitivity of cancer detection and ability to discriminate deep submucosal invasion The basis of the Blink (first) impression? United European Gastroenterology Journal 2023; Vol.11

Introduction

Ulcerative colitis, a type of inflammatory bowel disease, is characterised by chronic colonic inflammation often resulting in uncontrolled crypt lengthening and the development of colitis-associated colorectal cancer (CA-CRC). Orally administered Emu Oil, derived from Emu adipose tissue, has demonstrated protective and reparative properties in preclinical models of bowel disease, including CA-CRC. However, its long-term potential to reduce colonocyte proliferation and inhibit CA-CRC progression remains undetermined. Protein Ki-67 has been used widely as a proliferation marker for human tumour cells and may serve as a potential predictive biomarker for cancer progression.

Aims & Methods

We hypothesized that orally administered Emu Oil would reduce colonocyte proliferation, evidenced by decreased Ki-67 expression, in a mouse model of CA-CRC. Female C57BL/6 mice were injected with saline or azoxymethane (7.4mg/kg; intraperitoneal), followed by ad libitum access to either water or three dextran sulphate sodium (DSS)/water cycles (each cycle comprising seven days DSS [2%w/v] and 14 days water). Mice (n=9/group) were orally administered either water (80μL) or Emu Oil (low 80μL or high 160μL dose) thrice weekly for nine weeks. Proximal and distal colonic sections were stained with haematoxylin and eosin for crypt depth, cell count and size measurements and stained immunohistochemically to detect and quantify the proliferation marker Ki-67 in upper and lower colonocyte crypt zones. p<0.05 was considered statistically significant.

Results

In the proximal colon, numbers of Ki-67-positive cells in the upper and lower crypt regions of CA-CRC mice were increased by up to 100% compared with normal controls; low dose Emu Oil significantly decreased numbers of Ki-67-positive cells by 47% (p<0.05) compared with CA-CRC controls. Numbers of Ki-67-positive cells in the distal colon increased only in the upper crypt region in CA-CRC controls compared with normal mice (157%), with no further impact following Emu Oil administration (p>0.05). The overall percentage of Ki-67-positive cells remained unchanged in proximal and distal colonic crypts across treatment groups (p>0.05). Proximal and distal colonic crypt depth increased in mice with CA-CRC (20% and 37%, respectively; p<0.01), with greater distal colonocyte count, compared with normal controls (37%; p<0.05). Emu Oil did not impact proximal and distal colonic crypt depth nor cell counts in normal or CA-CRC mice (p>0.05). Furthermore, proximal colonocyte count, proximal and distal colonic cell diameter, and number of cells per 100μm remained unchanged among treatment groups (p>0.05).

Conclusion

Crypt lengthening in CA-CRC was primarily attributed to crypt cell hyperplasia, determined by increased cell numbers with no change in cell size. Low-dose Emu Oil administration in mice with CA-CRC resulted in attenuation of proximal colonic crypt cell proliferation, with no impact on crypt depth or cell size. Importantly, crypt depth and proliferation in normal mice remained unchanged following Emu Oil treatment, supporting its safety for long-term use to treat intestinal disorders. Future studies would benefit from an assessment of Emu Oil and its impact on expression of the oncogene Kras, tumour suppressor genes p53 and Apc, and inflammatory cytokines, including interleukin- 6, tumor necrosis factor-alpha and interferon-gamma, which are implicated in colorectal cancer progression.

Introduction

Peroxisome proliferator-activated receptor delta (PPARδ) agonists, such as seladelpar, emerged as potential therapies for PBC and other cholestatic diseases. PPARδs are nuclear receptors widely expressed in hepatocytes, cholangiocytes, Kupffer cells, and hepatic stellate cells. Activation of this receptor may modify the progression of PBC, particularly through its bile acid retention mechanism and antifibrotic and anti-inflammatory effects, inducing biochemical and clinical improvement in PBC patients.

Aims & Methods

We aimed to compare the efficacy and safety of seladelpar vs placebo for treating patients with primary biliary cholangitis (PBC) and inadequate response or intolerance to ursodeoxycholic acid (UDCA). We systematically searched MEDLINE, Embase, and Cochrane databases from inception to March 12, 2024. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were employed for dichotomous and continuous outcomes, respectively, using a random-effects model. We used Review Manager 5.4.1 for statistical analyses.

Results

We included 3 randomized clinical trials (395 patients). The results of the pooled analyses are shown in Table 1. Compared with placebo, seladelpar increased the probability of achieving composite biochemical response both at week 4 (RR 6.7; 95% CI 4.0 to 11.1) and at week 12 (RR 6.1; 95% CI 3.7 to 9.9), decreased alkaline phosphatase levels both at week 4 (MD -34.3%; 95% CI -39.6 to -29.0%) and at week 12 (MD -40.8%; 95% CI -47.9 to -33.6), increased the probability of achieving alkaline phosphatase normalization at week 12 (RR 18.6; 95% CI 3.8 to 90.4), and decreased pruritus scores at week 12 in both the overall population (MD -0.6; 95% CI -1.1 to -0.2) and the population with baseline pruritus score ≥4 (MD -1.2; 95% CI -2.0 to -0.4). Additionally, there was a non-significant difference between seladelpar and placebo in the risk of any adverse event (RR 1.0; 95% CI 0.9 to 1.1), any serious adverse event (RR 0.9; 95% CI 0.3 to 2.4), or any adverse event leading to treatment discontinuation (RR 0.7; 95% CI 0.2 to 2.0).

Table 1. Results from the pooled analyses

Conclusion

Seladelpar may be an effective and safe treatment option for patients with PBC and inadequate response or intolerance to UDCA. However, new large RCTs assessing long-term efficacy and safety outcomes are necessary to better evaluate its place in PBC management.

References

1. Hirschfield GM, Shiffman ML, Gulamhusein A, et al. Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study. Hepatology 2023;78:397–415.
2. Hirschfield GM, Bowlus CL, Mayo MJ, et al. A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis. N Engl J Med 2024;390:783–794.
3. Jones D, Boudes PF, Swain MG, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. The Lancet Gastroenterology & Hepatology 2017;2:716–726.

Disclosure

The authors have no ​conflict of interest