Introduction

Inflammatory bowel diseases (IBD) are mainly represented by Crohn's Disease (CD) and Ulcerative Colitis (UC). Among several factors related to these diseases, dysbiosis is considered an immediate environmental factor for the development of IBD. Dysbiosis is related to the imbalance of the intestinal microbiota, which affects the existing symbiotic relationship between the intestinal microbiota and its host that provides a nutrient-rich environment for intestinal bacteria, while the microbiota plays a fundamental role in maintaining the intestinal function of its host. Among these functions, the microbiota has its participation in the digestion of complex polysaccharides present in the host diet, important for the formation of monosaccharides and short-chain fatty acids (SCFA), such as acetate, propionate, and butyrate. These SCFA are important in maintaining the intestinal barrier and intestinal homeostasis, in proliferation, differentiation and modulation of gene expression of intestinal cells, in the production of essential vitamins in the intestinal lumen, in addition to acting in regulation of the mechanisms that provide balance between the intestinal mucosa and its immune system, resulting in the tolerance of harmless bacteria and immune responses against pathogenic bacteria. There are several studies on the intestinal microbiota in patients with IBD, however, there are still few studies on the SCFA profile in these patients. Therefore, the present study aimed to evaluate and compare the SFCA profile in patients with IBD and healthy individuals.

Aims & Methods

94 patients from a public outpatient healthcare service in Brazil and 63 healthy individuals were included in the study. Exclusion criteria: diagnosis of other chronic diseases, use of antibiotics, prebiotics, probiotics or symbiotics in the last 4 weeks. Participants were divided into two groups, IBD group and control group (healthy), fecal samples from all participants were collected for qualitative and quantitative analysis of SCFA, which was performed by gas chromatography technique coupled with mass spectrometry (GC/MS). Statistical analysis: descriptive statistics and association tests. Values of p ≤ 0.05 were considered significant. Data presented in mean (SD).

Results

The SCFA profiles were different in IBD patients compared to healthy individuals, with higher SCFA values in the IBD group when compared to the control group: acetic acid (0.32 ± 0.18 vs 0.12 ± 0.11, with p< 0.0001), propionic acid (0.24 ± 0.10 vs 0.15 ± 0.09, with p< 0.0001), butyric acid (0.19 ± 0.11 vs 0.39 ± 0.25, with p< 0.0001) and sum of SCFA (0.75 ± 0.32 vs 0.39 ± 0.25, with p< 0.0001) concentration.

Conclusion

The SFCA profile in patients with IBD showed a difference when compared to healthy individuals, where the values of SFCA fecal were higher in patients with IBD compared to healthy individuals. Such a difference may occur because the IBD group, due to the inflammatory process characteristic of the disease, may have greater difficulty in absorbing the SCFA produced in the intestine, releasing more SCFA in the feces, since most of the SCFAs produced in the colonic lumen (90-95%) are absorbed by the intestinal mucosa and only 5 to 10% are excreted in the feces. However, to confirm this hypothesis, further studies would be needed to evaluate and compare the SFCA systemic between these groups, through blood test, and thus determine the SFCA profile of these individuals, being able to propose therapies that help in the modulation of the microbiota of these patients and in the development of new treatment targets in the future.

References

1. García‐Villalba R, et al. Journal of separation science. 2012; 35(15): 1906-1913.
2. Kaplan GG. Nature reviews Gastroenterology & hepatology.2015; 12(12): 720-727.
3. Sánchez-Tapia M, Tovar AR, Torres N. Archives of Medical Research. 2019; 50(5): 259–268.
4. Schirmer M, et al. Nature Reviews Microbiology. 2019; 17(8): 497-511.
5. Zhao G, Nyman M, and Jönsson, A J. Biomedical Chromatography. 2006; 20(8): 674-682.

Introduction

Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory bowel disease, whose cause involves the interaction between genetic and environmental factors. At present, the pathogenesis of IBD has not been fully understood. Although there is a recognized link between immune response and IBD, the causal relationship between circulating immune cell counts and IBD remains controversial.

Aims & Methods

This study aimed to elucidate the causal relationship between genetically predicted circulating immune cell counts and IBD. We conducted a bidirectional two-sample Mendelian randomization (MR) study using aggregated statistics from genome-wide association studies. The causal relationship between five circulating leukocytes cells (monocytes, lymphocytes, eosinophils, basophils and neutrophils) counts and IBD, including Ulcerative colitis (UC) and Crohn's disease (CD) was analyzed. Inverse variance weighting (IVW) was used as the primary MR analysis method, and horizontal pleiotropy test and heterogeneity test were used to ensure the stability of the results.

Results

Our findings indicated that monocytes, lymphocytes, eosinophils, and basophils count were not significantly associated with IBD, however, elevated circulating neutrophils count was significantly associated with higher risk of IBD [odds ratio (OR): 1.002; 95% confidence interval (CI): 1.001–1.003; p = 0.009] and UC [OR: 2.465; 95%CI: 1.236–4.916; p = 0.01]. In addition, we also found that IBD [ OR: 12.07; 95% CI: 1.909-76.316; P = 0.008] and UC [OR: 2.465; 95% CI: 1.236 - 4.916; P = 0.01] were significantly associated with higher circulating neutrophils count in reverse MR.

Conclusion

This MR study provides genetic evidence for the causal relationship between the genetically predicted increase in circulating neutrophils count and the risk of IBD (UC and CD). This finding stresses the need for further exploring physiological functions of neutrophils in order to develop effective strategies against IBD.

Disclosure

The authors state that the study was conducted in the absence of any business or financial relationships that could be interpreted as potential conflicts of interest.

Introduction

Prior studies suggest an increased risk of non-alcoholic fatty liver disease (NAFLD) in patients (pts) with inflammatory bowel disease (IBD). There is no data available on the risk of cirrhosis in IBD. Our aim was to investigate the risk of cirrhosis (compensated or decompensated) in IBD pts compared to a matched non-IBD population in a population-based cohort.

Aims & Methods

A registry-based cohort study was conducted in the Danish health registries (including the pathology register) using data, between (and including) 1998 and 2018. Incident IBD was identified using ICD-8/10 codes for Crohn’s disease (CD) or ulcerative colitis (UC), with two IBD registrations up to two years apart, living in Denmark for at least one year prior to their first IBD registration and without a diagnosis of cirrhosis prior to their IBD registrations. Those with IBD were matched 1:10 to non-IBD persons on the basis of sex, age, calendar year, and the municipality of residence. Persons were followed from index date (IBD diagnosis date/matching date) until a diagnosis of cirrhosis (study outcome), death, emigration, or end of follow-up, whichever came first. The diagnosis of cirrhosis, including both compensated and decompensated cirrhosis, and the underlying etiology, were recorded by ICD-8/10 and SNOMED codes. Kaplan-Meier approach was used to calculate the cumulative incidence of cirrhosis and Cox proportional regression analysis to calculate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for cirrhosis among pts with IBD, compared to the non-IBD population.

Results

In a study population of 495,220 persons, a total of 2,741 cirrhosis cases were identified (median [IQR] time in years between index date and diagnosis of cirrhosis: 6.3 [3.0-10.7]), with a higher proportion of cases among pts with IBD (N = 45,020) compared to non-IBD persons (0.9% vs. 0.5%, respectively). After adjusting for sex, age, and index year, pts with IBD had a higher risk of cirrhosis, compared to non-IBD persons (adjusted HR (95% CI): 1.84 [1.65 – 2.04]). Cirrhosis was diagnosed on the basis of liver biopsy and/or imaging (ultrasound, CT or MRI) in 77.3% of IBD pts vs. 69.3% of non-IBD persons. The leading etiology of cirrhosis was NAFLD (51.6%) followed by alcohol (39.0%). The risk of cirrhosis among IBD pts (compared to non-IBD persons) was more pronounced among younger persons (adjusted HR (95% CI): 3.08 [2.45-3.87] among ≤ 40 years of age; 1.63 [1.45-1.84] among > 40 years of age, p-value <0.001) and CD pts (adjusted HR (95% CI): 2.20 [1.80-2.67] among CD; 1.72 [1.52-1.95]; among UC, p-value 0.0402). The risk was also consistent across the year of cohort entry (IBD diagnosis year/index year): 1998-2001 (794 events, 1.37 [1.07-1.66]), 2002-2005 (776 events, 1.98 [1.63-2.40]), 2006-2009 (612 events, 1.94 [1.56-2.41]), 2010-2013 (378 events, 2.01 [1.53-2.64]), 2014-2018 (181 events, 2.89 [2.03-4.10]).

Conclusion

IBD pts had a higher incident risk of cirrhosis compared to matched non-IBD persons, especially with age at IBD diagnosis ≤ 40 years and those with CD. These data point towards a need for focused screening for cirrhosis among IBD pts, especially in certain risk groups.

Introduction

Nowadays, Non-Alcoholic Fatty Liver Disease (NAFLD) is a leading cause of liver disease and liver transplantation. Although obesity is a well-recognized risk factor for NAFLD, there are data to support that not all patients with NAFLD are necessarily obese. However, the evidence on the prevalence and risk factors for NAFLD in lean individuals with Inflammatory Bowel Disease (IBD) is scarce.

Aims & Methods

The aim of the study was to assess the prevalence and risk factors for NAFLD in lean population with IBD. This is a cross-sectional, case control study including lean individuals with IBD (cases) and lean individuals without IBD (controls), matched for age and sex. Patients with risky alcohol consumption, previous diagnosis of chronic liver disease (immune, viral, genetic) and secondary causes of NAFLD were excluded. All included patients were performed a liver ultrasound, transient elastography and laboratory tests. Lean individuals were defined as Body Mass Index < 25 kg/m², and NAFLD as ultrasound steatosis and/or Controlled Attenuation Paremeter >248 dB/m. A descriptive analysis was carried out, and the relationship between variables was assessed using Chi square test/Fisher´s test (categorical variables) or T-student/Mann-Whitney U test (quantitative variables), as appropiate. In addition, a multivariate analysis was performed, presented as adjusted Odds Ratio (OR) and 95% Confidence Interval (95%CI).

Results

A total of 443 participants, 363 lean cases and 80 lean controls, were included in the study. No differences were observed in terms of age, sex and metabolic risk factors between both groups (Table 1). The prevalence of NAFLD in lean individuals with IBD was significantly higher compared to lean individuals without NAFLD (22% vs. 10%, p=0.015). Multivariate analysis confirmed that IBD was an independent risk factor for NAFLD in lean population (OR 2.75 95%CI (1.18-6.41)). In addition, male sex (OR 1.78 95%CI (1.04-3.05)) and older age (OR 1.03 95%CI (1.01-1.05)) were identified as risk factors for NAFLD in lean individuals.

Table 1. Baseline characteristics of cases and controls.

Conclusion

The prevalence of NAFLD is significantly higher in lean population with IBD, suggesting that IBD could play a role in the development of NAFLD in lean individuals.

Disclosure

This project has received funding from “Diputación General de Aragón” (code: DGACOVID-02).

Introduction

Inflammatory bowel diseases (IBD) are a distinct class of gastrointestinal disorders mainly represented by Crohn’s Disease (CD) and Ulcerative Colitis (UC). The dysregulation of microRNAs (miRNAs), a class of conserved endogenous, small non-coding RNA molecules, both tissue-derived and circulating, have shown to be promising biomarkers in IBD. These biomarkers can be useful for differential diagnosis, drug response prediction and can have prognostic value for the evolution of the disease. Moreover, miRNAs are interesting tools for potential future therapeutic approaches by miRNA antagonists or mimics [1].

Aims & Methods

In this study we aimed to perform a preliminary screening of a large panel of 179 miRNAs in the plasma of 6 patients with IBD and 12 non-IBD patients (CTRL) in order to identify a set of highly dysregulated miRNAs to be investigated in a larger cohort. Isolation of miRNAs has been conducted using miRNeasy Serum/Plasma Kit and the miRNAs expression has been evaluated using the Human serum/plasma focus, MIRCURY LNA miRNA Focus PCR panel (Qiagen) by qRT-PCR. After excluding 29 miRNAs that were not expressed in the investigated samples, we identified miR-19a-3p and miR-17-5p as the most stable miRNAs by the RefFinder analysis. Thus, the Ct values of the other 148 miRNAs have been normalized against the geometric mean of these two miRNAs as endogenous controls using the 2^-DCt method. All the clinical, sociodemographic and miRNAs expression data have been analyzed using SPSS. Categorical variables were tested by means of the chi-square test, and continuous variables with t-test or the non-parametric Man Whitney test, according to the normality of the data distribution.

Results

The two groups were age matched (mean age IBD= 45.83±21.27, mean age CTRL = 50.08±8.16, p=0.543) and did not differ for sex distribution (IBD= 33.3% female, CTRL=58.3% female, χ2= 1.00 and p=0.317). The statistical analysis revealed 45 miRNAs differentially expressed (p<0.05). In particular, we identified 29 overexpressed miRNAs (miR-223-3p, miR-143-3p, let-7f-5p, miR-30b-5p, miR-26a-5p, let-7a-5p, miR-142-3p, miR-374a-5p, miR-339-5p, miR-150-5p, miR-454-3p, let-7d-5p, miR-29a-3p, miR-146a-5p, miR-199a-3p, miR-221-3p, miR-142-5p, miR-191-5p, miR-338-3p, let-7g-5p, miR-103a-3p, miR-23a-3p, miR-145-5p, miR-374b-5p, miR-24-3p, miR-107, miR-27b-3p, let-7c-5p, miR-26b-5p) in the IBD group compared with the CTRL showing a fold regulation (FR)>1.5 and 7 miRNAs underexpressed reporting a FR<-1.5 (miR-421, miR-320d, miR-106b-3p, miR-320c, miR-20b-5p, miR-320b, miR-486-5p).
Notably, the expression of let-7a-5p that was upregulated in the IBD group (FR=2.45; p=0.001) positively correlated with the years of disease duration (p=0.01, Pearson r=0.919). The same positive correlation was observed for miR-30b-5p (p=0.049, Pearson r=0.812).

Conclusion

The reported data, showing 45 miRNAs differentially expressed in the plasma of IBD patients compared to controls, represent preliminary results that must be validated. The most statistically significant dysregulated miRNAs, as well as those that correlated with the years of disease duration and other clinical parameters will be investigated in a large IBD cohort in order to examine the potential value of these miRNAs as diagnostic and prognostic biomarkers.
This investigation received financial support from ICGEB (Contract No. CRP/22/019, ICGEB Ref. No. CRP/ROU21-01)

References

1. James JP, Riis LB, Malham M, Høgdall E, Langholz E, Nielsen BS. MicroRNA Biomarkers in IBD-Differential Diagnosis and Prediction of Colitis-Associated Cancer. Int J Mol Sci. 2020 Oct 24;21(21):7893. doi: 10.3390/ijms21217893. PMID: 33114313; PMCID: PMC7660644.

Introduction

Background and objectives: Small intestinal neuroendocrine tumours (SI-NETs) are slow growing but have often metastasized at the time of diagnosis. Most patients are operated either with the intention of curation or to prolonged survival. Improved surgical resection, more comprehensive oncological treatment as well as earlier diagnoses may improve survival, but only few studies have examined survival trends. In this study we aimed to examine the trend in overall survival in patients diagnosed with SI-NETs.

Aims & Methods

Patients with a histological and / or imaging-based diagnosis of SI-NET in Central Norway from 2005 to 2021 were identified. Patient, disease and treatment characteristics including histological grade (G), European Neuroendocrine Tumour Society (ENETS) stage, surgical and oncological treatment types and survival were retrospectively recorded. The cohort was divided in those diagnosed in period one (June 2005-November 2012) and period two (November 2012-December 2021), with 121 patients in each sub-cohort. Overall survival was analyzed using the Kaplan Meier method and a Cox multivariate analysis was performed to identify factors independently associated with survival.

Results

The 242 patients had a median age 70 (17-91) years at diagnosis or surgery and 55.8% were males. The majority of patients underwent surgery (n=205, 84.7%) which was considered curative in 137 (66.8%) patients. Median estimated overall survival was 10.1 years (95% CI 8.5-11.7) and the median overall survival for localized, regional and distant disease stage was 10.6 years (95% CI 7.9-13.2), 11.0 years (95% CI 8.8-13.2) and 7.1 years (3.4-10.8), p=0.005, respectively.
Patients diagnosed in period one had a median survival of 9.0 years (95% CI 6.4-11.7), while median survival for period two was significantly longer and was not reached, p = 0.014. Five year survival for period one was vs. period two was 63.5% and 83.5%. The Kaplan-Meier curves for period one and two separated the first year after diagnosis and the difference persisted. For resected patients the median survival was 9.6 years (95% CI 8.4-10.9) in period one, whereas median survival was not reached for period two, p = 0.008. The ENETs disease stage did not differ between period one and two, but a higher proportion had carcinoid heart disease in period one (7.4% vs. 1.7%, p=0.031). A higher proportion of patients who underwent SI-NET resection were considered tumour free after surgery in period two than in period one (74.3% vs 59.6%, p=0.027). There was also a higher proportion of patients with resection of multiple primary SI-NETs in period two (37.6% vs. 24.0%, p=0.049), which was explained by a higher proportion of multifocal tumours being resected during elective surgery (42.9% vs. 21.1%, p 0.005). There was also a higher number of retrieved lymph nodes in period two (p=0.014). Similar proportions of patients received somatostatin analogues, PRRT or transarterial embolization of liver metastases in period one vs. period two. In a Cox proportional hazard regression model age at diagnosis, ENETS stage, tumour resection and diagnosis before November 2012 were independently associated with overall survival, whereas sex and tumour grade were not.

Conclusion

Survival of patients with SI-NET improved over the study period and this seemed related to lower mortality the first year after diagnosis. Disease stage or oncological treatment did not change, but several factors associated with surgical quality improved during the study period.

Introduction

As the therapeutic armamentarium for inflammatory bowel diseases (IBD) is rapidly expanding, it is of increasing importance to optimize treatment sequencing. However, head-to-head trials comparing efficacy of vedolizumab (VDZ) in bio-naïve versus bio-experienced patients are scarce.

Aims & Methods

Aim: To compare the effectiveness of VDZ in bio-naïve versus bio-experienced patients with IBD in a real world setting.
Methods: A retrospective monocentric study was performed in IBD patients treated with VDZ at a Belgian University Hospital, from January 2018 to June 2021 with follow-up until December 2021. Primary endpoints considering efficacy after induction and after 1 year of therapy were: clinical response (CRp) and remission (CRm), biochemical response (BRp) and remission (BRm) and endoscopic response (ERp) and remission (ERm). Secondary endpoint was treatment survival during follow-up. For assessment of risk factors influencing efficacy and treatment survival, a multivariate logistic regression and Cox regression model (CRM) were applied.

Results

A total of 84 patients were treated with VDZ, 42 bio-naïve and 42 bio-experienced. At baseline, significantly more bio-experienced patients had prior intestinal resection (IR) (40.5% (17/42) vs. 16.7% (7/42), P=0.016), used an immunomodulator (IMM) (35.7% (15/42) vs. 16.7% (7/42), P=0.047) and had a longer disease duration (12.5 vs. 3.5 years, P<0.001). Bio-naïve patients had more moderate to severe comorbidities (21.4% (9/42) vs. 2.4% (1/42), P=0.007). After VDZ induction, CRp rate was higher in bio-naïve patients (60.9% (39/42) vs 39.1% (25/42), P<0.001). Multiple logistic regression analyses revealed that bio-naïve patients had a higher chance reaching CRp (aOR 14.69, 95%CI [3.12-69.14], P<0.001)(table). CRm was reached in 35.7% bio-naïve and 19% bio-experienced patients (P=0.087). No significant difference in BRp (P=0.932) or BRm (P=0.730) rate was found . A significantly higher ERp rate was seen in bio-naïve patients (90.3% (28/31) vs. 66.7% (18/27), P=0.027). Multiple logistic regression analyses showed a trend towards higher ERp rate in bio-naïve patients (aOR 4.65, [0.99-21.84], P= 0.051)(table). No significant difference was seen for ERm (32.3 % (10/31) vs. 11.1% (3/27), P=0.054). After 1 year of VDZ, CRp was significantly higher in bio-naïve patients (82.9% (34/41) vs. 62.5% (25/40), P=0.039). Multiple logistic regression analyses showed no significant difference between both groups. Univariate analyses showed significantly higher CRm rate in bio-naïve patients (70.7% (29/41) vs. 37.5% (15/40), P=0.003). After adjustment for age, disease duration, IMM use and prior IR, this difference was no longer significant. Patients without prior IR had significantly higher odds of reaching CRm (aOR 4.33,[1.13-16.59], P=0.032). No significant difference was seen for BRp (P=0.443) and BRm (P=0.313), nor for ERp (P=0.184) or ERm (P=0.061) in univariate analyses. Cox regression analysis showed significantly longer treatment survival in bio-naïve patients (aHR 2.32, [1.03-5.23], P=0.043).

Conclusion

In this tertiary real-world cohort of patients treated with VDZ, overall, a better efficacy was seen in bio-naïve compared to bio-experienced patients.

Disclosure

No conflict of interest