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Background Post-marketing data are required to confirm the durability and the long-term benefit and safety of UST in CD in clinical practice. Our aims were: (1) to evaluate the retention rate of UST in CD patients and to identify predictive factors of UST discontinuation; (2) to assess UST short-term effectiveness; (3) to analyse the durability of the response to UST in the long-term; and (4) to evaluate the safety of UST in clinical practice. Methods Retrospective, multicentre study (>60 centres). Patients with active CD [(Harvey–Bradshaw (HBI) >4)] that received at least one dose of UST intravenously before July 2018 were included. Clinical activity plus biochemical parameters were assessed at every UST administration. Clinical remission was defined as HBI score ≤4, and clinical response as a decrease in HBI ≥3 points. Loss of efficacy was defined as reappearance of symptoms that led to intensify the treatment dose, add another medication to control CD, switching or surgery in patients with short-term remission. The retention rate of UST treatment and the cumulative incidence of loss of efficacy were evaluated by survival curves, and predictive factors were assessed by Cox-regression. The short-term response was evaluated at week 8 and after the induction (week 16). Factors associated with short-term remission were assessed by multivariate analysis. Adverse events were recorded. Data quality was assured by remote monitoring. Results 331 CD patients have been included up to date (Table 1). The incidence rate of UST discontinuation was 15% per patient-year of follow-up: 8%, 13% and 20% at 6, 12 and 18 months (Figure 1). Previous surgery was the only factor associated with a higher risk of UST discontinuation [Hazard ratio (HR) = 2.03, 95% confidence interval (CI) = 1.1–3.6]. Short-term efficacy is shown in Figure 2. Previous surgery (OR = 0.3, 95% CI = 0.2–0.6) and higher HBI score at baseline (OR = 0.8, 95% CI=0.8–0.9) were associated with an impaired response to UST at week 16. The cumulative incidence of loss of response was 32% per-patient-year of follow-up (Figure 3); A higher HBI score at baseline was associated with a higher risk of losing response (HR = 1.2, 95% CI = 1.1–1.3). Neither the concomitant treatment with immunosuppressants nor the number of previous biologics were associated with UST short- and long-term benefit. Thirty adverse events were reported in 25 (7%) patients (Table 2). Conclusion Sustain is the largest real clinical practice study of UST to treat CD patients with the longest follow-up reported to date. UST was demonstrated to be effective in real-world use in the short and long run. Safety was consistent with the known profile of UST.

Background Our aim was to evaluate the effectiveness and safety of tofacitinib in ulcerative colitis (UC) in real life. Methods Patients from the prospectively maintained ENEIDA registry treated with tofacitinib due to active UC were included. Clinical activity and effectiveness were defined based on Partial Mayo Score (PMS). The short-term response was assessed at week 4, 8 and 16. The last-observation-carried-forward method was used in patients that stopped tofacitinib before the time-points for clinical assessment. Variables associated with short-term remission at week 8 were identified by logistic regression analysis. The cumulative retention rate and the cumulative incidence of relapse over time were assessed by survival curves. Cox-regression analysis was performed to identify predictive factors of tofacitinib discontinuation or relapse over time. Data quality was assessed by remote monitoring. Results 113 patients were included (Table 1 and Figure 1) and exposed to tofacitinib a median of 44 (interquartile range = 30–66) weeks. Response and remission at week 8 were 60% and 31%, respectively (Figure 2). In multivariate analysis, higher PMS at week 4 [odds ratio (OR)=0.2; 95% confidence interval (CI) = 0.1–0.4] was the only variable associated with the likeliness of achieving remission at week 8. Higher PMS at week 4 (OR = 0.5; 95% CI = 0.3–0.7) and higher PMS at week 8 (OR = 0.2; 95% CI = 0.1–0.5) were associated with lower probability of achieving remission at week 16. Twenty per cent of those without remission at week 4, and 12% of those without remission at week 8, achieved remission at week 16. A total of 45 patients (40%) discontinued tofacitinib over time (Figure 3); the discontinuation rate was 34% and 46% at 24 and 52 weeks, respectively. PMS at week 8 was the only factor associated with tofacitinib discontinuation [Hazard ratio (HR) = 1.5; 95% CI = 1.3–1.6)]. A total of 33 patients had remission at week 8; from them, 65% relapsed 52 weeks after achieving remission; 9 patients increased the dose to 10 mg /12 h and 5 reached remission again. No factors associated with relapse over time were identified. Eighteen patients had adverse events (4 hypercholesterolaemia, 2 herpes zoster, 3 infections, 2 dyspnoea, 1 neoplasia, 1 lymphopenia, 1 headache, 1 hypertriglyceridaemia and 4 others). No thromboembolic events were reported. Conclusion Tofacitinib is relatively effective in UC patients in real practice even in a highly refractory cohort. Only 10% of the patients without remission at week 8 reached remission at week 16. A relevant proportion of patients discontinue the drug over time, mainly due to primary failure. Over 60% of patients that achieve remission, relapse over time. Safety was consistent with the known profile of tofacitinib

Background Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS) are two intestinal disorders with unknown aetiology. IBD presents two main forms which are Crohn’s disease (CD) and ulcerative colitis (UC). It has been reported recently that bacterial communities present in the colon of patients with either IBD or IBS are structurally different compared to those found in healthy individuals. This dysbiosis mainly consists of a decrease of butyrate producing bacteria and, therefore, the recovery of this metabolic group should be at the baseline of any successful treatment. The main goal of this proof-of-concept study was to test the capacity of a new prebiotic of selected dietary fibre obtained from grape to balance the dysbiosis found in patients with different intestinal disorders. Methods In this study, fresh faecal samples from 6 healthy subjects, 3 CD, 3 UC, and 3 IBS were collected at the Hospital Universitari Dr. Josep Trueta. Fresh samples were diluted 1:5 with fermentation buffer and incubated with 200 mg of prebiotic at 37 ºC under agitation for 72 h. Results were compared with those obtained with various commercial prebiotics after simulating in vitro digestion: inulin, grape pectin, and grape seed extract (GSPE). Total DNA was extracted and the abundance of butyrate-producing bacterial markers: F. prausnitzii (Fpra), its two phylogroups (PHGI and PHGII), Roseburia spp. (Ros) and S. variabile (Sva) was analysed by qPCR. Bacterial activity was determined by measuring short chain fatty acids (SCFA) concentration (butyrate, acetate, and propionate) by gas chromatography. Results The abundance of all butyrate-producing bacteria analysed increased after incubation with the new prebiotic. Among them, Ros presented significantly higher abundance values with respect to negative control in healthy, CU, and IBS patients. It also showed a significant increase in all individuals analysed compared to inulin, grape pectin, and GSPE. Fermentation of the tested new prebiotic, produced significantly higher concentrations of SCFA (p < 0.001) when compared to negative control and all other commercial fibres. Acetate concentration was a 241% higher than negative control, followed by butyrate (187%), and propionate (169%). Conclusion The studied prebiotic produces in vitro an increase of the abundance and enhancement of the metabolism of butyrate-producing bacteria, when compared to commercial prebiotics. These results suggest that this new fibre is a promising prebiotic to be used in promotion of intestinal microbiota restoration at mucosa.

Background Whether to use biologic treatment for inflammatory bowel disease as monotherapy or in combination with immunosuppressives has been a matter of debate in the last years. We aimed to evaluate if immunosuppressants influenced the retention rate of ustekinumab in Sustain, the largest study evaluating its use in clinical practice, having the longest follow-up period reported to date. Methods Retrospective, multicentre study (>60 sites) including patients with active Crohn′s Disease (CD) [(Harvey-Bradshaw (HBI)>4)] who received ≥1 dose of ustekinumab intravenously before July 2018. Data on concomitant immunomodulatory therapy (if any) with azathioprine, mercaptopurine, methotrexate or others at the start of ustekinumab treatment and during follow-up were documented. Clinical remission was defined as HBI≤4 and response as ≥3 points decrease from baseline. Loss of response (LoR) was defined as reappearance of symptoms that led to intensifying the treatment dose, adding another medication to control CD, switching or surgery in patients with short-term remission. The retention rate in patients on ustekinumab receiving or not immunosuppressive treatment was evaluated by descriptive analysis and Kaplan-Meier survival curves. Predictive factors were assessed by Cox-regression. Data quality was assured by remote monitoring. Results 463 CD patients were included. Prior CD treatments to ustekinumab were collected: the majority of patients received steroids, immunosuppressants and biologics. Figure 1 shows the percentage of patients on treatment with each type of drug and whether or not they continued to receive it when they started ustekinumab, in the case of steroids and immunosuppressants. Reasons for discontinuation of previous immunosuppressive treatments for CD were as follows: failure (37.5%), sustained remission (5.8%), adverse event (47.6%), medical decision (4%), other reasons (5.1%). During ustekinumab treatment, 163 patients (35.2%) received immunosuppressants (listed in figure 2). Sixty-six (14.3%) patients had their immunosuppressant withdrawn during treatment. Retention was observed in 77.9% of patients with concomitant immunosuppressive therapy versus 76.3% of patients without. There weren′t statistically significant differences between the two populations (p=0.712). Figure 3. The patient-year discontinuation rate for patients who didn′t receive concomitant immunosuppressants was 17.5 versus 18.9 in those who received them. Conclusion No effectiveness differences were seen by adding immunosuppressants to ustekinumab, reinforcing the low immunogenic profile of this drug and reducing the risk of additional side effects and toxicity.

Background The information regarding IBD patients with COVID-19 suggests that the factors related to bad outcome are older age and comorbidity whereas immunosuppressants do not have a significant impact worsening the disease evolution. To date, there is no information to assess if there are differences in epidemiological, demographical, and clinical characteristics between infected and non-infected IBD patients. Methods Case-control study in IBD patients with COVID-19 (cases) compared to IBD without COVID-19 (controls) in the period March-July/2020 within the ENEIDA registry (promoted by GETECCU and with more than 60.000 IBD patients included). Cases were matched 1:2 by age (±5y), type of disease (CD/UC), gender, and centre. All controls were selected from only one investigator blind to other clinical characteristics of the patients to avoid selection bias. Results 496 cases and 964 controls from 63 Spanish centres were included. No differences were found within the basal characteristics including CD location, CD behaviour, extraintestinal manifestations, family history of IBD or smoking habits. Cases had ≥ 1 comorbidities (cases:43%vs. controls:36%, p=0.01) and occupational risk (cases:27% vs. controls:10.6%, p Conclusion Comorbidities and epidemiological risk factors are the most relevant aspects for the risk of COVID-19 in IBD patients. This risk of COVID-19 seems to be increased by aminosalicylates but not by immunosuppressants or biologics. The attitude regarding treating IBD patients with aminosalicylates during the COVID-19 pandemic deserves a deeper analysis. Funded by the Carlos III Health Institute COV20/00227.

Background Crohn’s disease (CD) can develop fistulizing complications at any time during the disease course. Enterocutaneous fistulas (ECF) are disabling lesions with a significant impact on quality of life. The aim of this study was to describe the characteristics and natural history of ECF complicating CD, and to analyze its medical and/or surgical management. Methods A retrospective analysis of all adult patients with fistulizing CD with at least one episode of ECF from the ENEIDA registry (over 68,000 patients) was performed. ECF were defined as a communication between the gastrointestinal tract and the skin producing leakage of luminal contents. Additional data describing the ECF and its medical or surgical management were gathered. The main endpoint was any ECF-related surgical intervention. Fistula closure was defined as the absence of drainage, with no new abscess or surgery for at least 6 months. A comparison of the characteristics and outcomes after the availability of biologic agents (Jan/2000) was also performed. The baseline characteristics were analyzed by means of descriptive statistics and were compared by non-parametric tests. Factors associated with surgery were further evaluated in a binary multivariable regression and survival analysis. Results A total of 301 ECF in 286 patients from 46 hospitals diagnosed between Jan/1970-Sept/2020 were included (median age 34 years (IQR, 27–46); 59% male; 67% L3). ECF had a median of 1 external opening (range 1–10), 59% with concomitant internal fistulas, and usually involved the ileum (67%) or colon (23%). After 146 months (IQR, 69–233) of follow-up, 37% received thiopurines, 40% anti-TNF, 6% ustekinumab and 2% vedolizumab. Surgery was performed in 208 patients (69%) after a median of 4 months (IQR, 1.4–12). Fistula closure was achieved in 253 patients (84%) after 30 months (IQR, 4–84), mostly after surgery (54%) and in one third after medical therapy. Fistula recurrence was uncommon (11%) after closure. Patient and fistula characteristics were significantly different after the availability of biologics. In fact, anti-TNF biologics and thiopurines reduced surgery risk (HR 0.5; 0.38–0.67; HR 0.64; 0.47–0.86, respectively). The surgery rate in the biologic era tends to be lower than before (OR 0.63;0.33–1.09) while timing is similar. Closure rates are also comparable, but it was obtained more frequently after medical therapy once biologicals were available (OR 2.21; 1.13–4.29). Conclusion ECF complicating CD entail a high burden of medical and surgical resources. Closure rates are high, usually after surgery, and fistula recurrence is uncommon. A number of patients can benefit from medical therapy and achieve fistula closure.

Background Crohn’s disease (CD) and ulcerative colitis (UC) evolve with alternate outbreaks and remissions of variable duration. Tumour necrosis factor α antagonists (anti-TNFα) have enhanced the treatment of patients with inflammatory bowel disease (IBD), improving the patient’s quality of life by reducing the number of surgeries and hospitalizations. Despite these advances, about 10–30% of patients do not respond to the treatment after the induction period. Recent studies have pointed, on one hand, gut microbiota can play a role in the anti-TNFα treatment response as gram-positive bacteria can modulate the response of NOD proteins and, on the other hand, gram-negative bacteria can stimulate TLR4 receptors causing activation of NFkß. This study aimed to define a microbial signature that could be used to predict the response of patients with CD and UC to anti-TNFα treatment. Methods This observational study consisted of obtaining a stool sample from 38 IBD patients before starting an anti-TNFα treatment. Patients were recruited at Hospital Universitari Dr. Josep Trueta (Girona) and Hospital Universitari de Bellvitge (l’Hospitalet de Llobregat). During the one-year follow-up period, disease activity levels, faecal calprotectin evolution, and anti-TNFα antibody levels were analysed to assess response to treatment, differentiating 2 groups: responders and non-responders. From each sample, DNA was purified and used in a qPCR for the quantification of the following markers: F. prausnitzii (Fpra) and its phylogroups (PHG-I and PHG-II), E. coli (Eco), A. muciniphila (Akk), Ruminococcus sp. (Rum), Bacteroidetes (Bac), M. smithii (Msm), and the total bacterial load (Eub). Results In this proof of concept, the predictive ability to identify anti-TNFα treatment responders was analysed. Individually, none of biomarkers demonstrated the ability to differentiate between groups with high sensitivity and specificity. However, an algorithm consisting of the combination of 5 microbial markers (Msm, Fpra, PHGII, Rum, and Eub) showed a high capacity to discriminate between responders and non-responders. The algorithm proved high sensitivity and specificity reporting values ​​of 93.33% and 100%, respectively, with a positive predictive value of 100% and a negative predictive value of 75% for predicting response to biologic treatment. Conclusion A specific microbial signature could beneficiate patients with IBD by predicting the therapeutic effectiveness of an anti-TNFα treatment, which could lead to a personalized therapy, improving the patients’ quality of life, saving costs, and gaining time in patient recovery.A larger prospective study will be needed to validate these results.

Background Dysbiosis is a widely used but unspecific term. It has been defined as any change in the composition of resident microbial communities relative to the ones found in healthy individuals. But it is still unclear which are the appropriate communities to define it and the reference values to measure it. Different studies have described dysbiosis in various diseases such as Inflammatory Bowel Disease (IBD), diabetes, rheumatoid arthritis, and autism, among others. Besides, the microbiota can be altered by transient factors such as antibiotics, diet, stress, or infections. Therefore, different degrees of severity can be associated with the term dysbiosis from which pathological and transient dysbiosis can be differentiated. This work aimed at defining more specifically the term intestinal dysbiosis and to differentiate both transient and pathological dysbiosis. Methods Fifteen key microbial markers belonging to the principal families, classes and orders found in the human intestinal microbiota were accurately selected based on its functionality: F. prausnitzii (Fpra), E. coli (Eco), Firmicutes (Fir), Bacteroidetes (Bac), A. muciniphila (Akk), Ruminococcus sp. (Rum), Roseburia sp. (Ros), Gammaproteobacteria (Gam), Clostridia cluster I (Clo), Clostridia cluster XIV (XIV), Enterococcus sp., Lactobacillus sp. (Lac), C. albicans (Can), M. smithii (Msm), and the total bacterial load (Eub). The dysbiosis was defined using stool samples in a cohort of healthy subjects (n=24) and then validated with 9 patients diagnosed with intestinal diseases 4 IBD and 2 Irritable Bowel Syndrome (IBS)). Total DNA was extracted and the abundance of microbial markers was analysed by qPCR. Together with the establishment of the most common range in which each microbial marker was found, an index to define the pathological dysbiosis was calculated. Results Almost all healthy subjects analysed presented one or two slightly altered markers. The affected microbial markers in this “transient dysbiosis” were Fpra, Akk, and Ros, which are indicative of the mucous layer state, Firm as indicative of the lifestyle and fiber intake, Gam as characteristic of the pro-inflammatory state of the gut, and Msm as an altered intestinal habit and gas production. All patients analyzed (IBD and IBS) presented alterations mainly of the bacteria inhabiting the mucosa and an alteration of the opportunistic species related to the disrupted mucous layer and defining “pathological dysbiosis”. Conclusion This study establishes an appropriate abundance range of key microbial markers in the gut, leading to a specific definition of dysbiosis which allows to differentiate the pathological from the transient dysbiosis. These results need further validation in a larger patient cohort.

Background Methotrexate (MTX) is currently used in steroid-dependent patients with moderate-to-severe Crohn’s disease (CD) when thiopurines have failed or are contraindicated. Although its efficacy has been proved for both induction and maintenance of remission, its use is limited due to the rate of associated adverse events. Polymorphisms in the folate pathway might predict the efficacy and toxicity of MTX. Our aims were to evaluate the predictive value of these polymorphisms of MTX efficacy and safety in CD. Methods Patients from ENEIDA registry of GETECCU who were treated with MTX on monotherapy and of whom genomic DNA was available, were identified. Clinical efficacy and MTX-related toxicity were collected, and 10 variants from ATIC, DHFR, MTHFR, RFC1, ABCB1 and ABCC3 genes were genotyped with TaqMan assays. Results One hundred and twenty nine patients were included, 55% were female and 31% active smokers. MTX was used as first and second-line therapy in 10% and 60% of patients, respectively, at a mean dose of 22 mg and for a median time of 14 months. Thirty-seven per cent of patients achieved clinical remission, whereas 34% were non-responders (MTX failure). Forty patients (30%) developed MTX-related toxicity, with nausea and vomiting, myelotoxicity and hepatotoxicity as the most frequent adverse events (37%, 15% and 15%, respectively). MTX was discontineud in 19% of the patients due to toxicity. In the multivariable analysis, patients with the AA genotype for the rs408626 DHFR variant was predictive of a higher efficacy as compared to the G allele carriers (RR 0.372, p=0.026), and smoking was associated with a higher risk of MTX therapy failure (RR 2.676, p=0.015). Moreover, the CC genotype for the rs1476413 MTHFR variant and the TT genotype for the rs4793665 ABCC3 variant were independently associated with a higher risk of MTX toxicity (RR 2.357, p=0.038 and RR 2.368, p=0.044, respectively). Conclusion Genetic polymorphisms related to the folate pathway (mainly the variant rs408626 of DHFR, rs1476413 of MTHFR and rs4793665 of ABCC3) seem to impact on MTX efficacy and toxicity in CD. Smoking could also influence MTX efficacy.

Background Mycophenolate mofetil (MMF) is an immunomodulatory drug that inhibits T and B cells, through a reversible inhibition of inositol monophosphate dehydrogenase. MMF is commonly used for prophylaxis of organ rejection after transplant. Studies to evaluate its use in inflammatory bowel disease (IBD) are limited especially after the appearance of biological treatments (BT). The aim of this study was to evaluate the efficacy and safety of MMF in IBD. Methods IBD patients who had received MMF were identified in the ENEIDA registry (prospective database of GETECCU). Patients with Crohn′s disease (CD) or Ulcerative colitis (UC) in whom oral MMF was prescribed for this condition were evaluated. Demographic and IBD clinical data were collected. Clinical activity was assessed through Harvey-Bradshaw Index (HBI) and partial Mayo score (pMS); C-reactive protein (CRP) and faecal calprotectin (FC) were reviewed at baseline (at MMF starting), 3 and 6 months and at the end of follow-up (at MMF stopping or the last visit while on MMF). Adverse events (AEs) during MMF treatment were documented. Statistical analyses were performed by descriptive statistics and non-parametric tests. Results Between June 1999 and November 2018 a total of 83 patients received MMF (mean age 36.4 (SD12.3) years; 52F/31M; 66 CD and 17 UC). Indication for MMF use was maintenance of remission (50%), induction of remission (44%) and post-surgical prophylaxis (6%). Mean MMF dose used was 1269.8 (SD 741) mg/day. In 61% of cases, systemic steroids were administered starting MMF and it was used concomitantly to BT in 27% of patients. In CD, statistically significant differences in HBI at 6 months (mean 5.9 (SD 4.8), p = 0.04) and at the end of follow-up (mean 5.7 (SD 5), p = 0.014) compared with baseline (mean 7.6 (SD 4.3)) were observed. In UC, statistically significant differences in pMS at 6 months (mean 2.1 (SD 2.7), p = 0.018) and at the end of follow-up (mean 1.8 (SD 2.6), p = 0.003) compared with baseline (mean 4.8 (SD 2.5)) were determined. No significant differences in CRP or CF values during follow-up were observed. Concomitant use of BT was significantly associated with clinical response (OR 1.36 95% CI 1.08–1.73). MMF was maintained for a median time of 28.9 months (IQR 20.4–37.5) and was stopped in 84% of patients due to lack of response (50%), loss of response (17%) and remission (15%). Overall, 23% of patients presented MMF-related AEs (60% abdominal pain). MMF was withdrawn in 11% of patients due to AEs. Conclusion MMFshows a clinical benefit in the long term in both CD and UC patients with a favourable safety profile. MMF could be a treatment option alone or in combination with biologics in patients with IBD in clinical practice.

Background INFEII registry (ClinicalTrials.gov: NCT02904590) is a prospective study promoted by GETECCU to determine the incidence and risk factors of infection in an inception cohort of IBD patients. Despite preventive measures and recommendations of scientific societies, TB remains a problem in patients with IBD treated with immunosuppressants (IMM) and biologics. AIMS To asses: (1) the screening of TB performed at the time of inclusion of a patient in the INFEII registry, (2) the incidence of latent TB; and (3) compliance with national and European recommendations. Methods A longitudinal prospective study of incident cases with IBD, initiated in October 2016 and with a planned follow-up of 5 years. In September 2019, INFEII registry had 1241 patients from 28 centres throughout Spain. The study protocol determines the mandatory fulfilment of TB screening in every patient, leaving to the centre the freedom of decision on what procedures to perform. Guidelines recommend a mandatory study before starting immunosuppression, especially with biological treatment, using the combination of tuberculin skin test (TST) and interferon-gamma release assay (IGRA) or at least one TST with a booster test1,2. Results Of the 1241 patients 233 (19%) had no screening, 494 (40%) had one [TST 158, IGRA 299, thorax-X-ray 37], 288 (23%) two [TST + IGRA 87, IGRA + thorax-X-ray 130, TST + thorax-X-ray 30, TST + booster 41], 128 (10%) three [TST + IGRA + thorax-X-ray 65, TST + booster + IGRA 23, TST + booster + thorax-X-ray 40] and 98 (7.9%) the four tests [TST + booster + IGRA + thorax-X-ray]. 486 patients (48%) receive pharmacological immunosuppression (172 IMMS, 195 biologics, 119 COMBO) and from them 198 (41%) followed the guidelines recommendation (131 TST and IGRA and 118 TST-booster), 245 (50%) had some method for TB screening [TST 43, IGRA 112, thorax-X-ray 15, IGRA + thorax-X-ray 57, TST + thorax-X-ray 18] and 43 patients (8.8%) had no screening. With the baseline screening, latent TB was detected in 134 patients (13%), 63 (47%) receiving anti-TB chemotherapy. In patients initiating immunosuppression, latent TB was detected in 35 cases [of which 28 received prophylaxis but 7 under IMM did not]. Active TB was detected in 4 cases: 2 during baseline screening, one without screening and one with negative screening (negative TST and IGRA, without booster receiving biological treatment). Conclusion Despite TB in IBD is a relevant problem, there is ample room for improvement for the implementation of mandatory minimum screening recommendations, even in prospective protocolised projects. References

Background Inflammatory Bowel Disease (IBD) is a clinical condition of the gastrointestinal tract of unknown aetiology. The two main forms of IBD are Crohn’s disease (CD) and Ulcerative colitis (UC). Recently, it has been reported that the bacterial communities present in the colon of patients with IBD are structurally different compared with those in healthy individuals. This particular dysbiosis consists of a decrease of butyrate producing bacteria and an increase of the pro-inflammatory species. The goal of this work was to test a new prebiotic of selected dietary fibre made from grape for its capacity to balance the dysbiosis typically found in patients with intestinal disorders. Methods Faecal samples from 16 healthy subjects and 11 IBD patients (5 CD and 6 UC) were collected by the Hospital Universitari Dr. Josep Trueta. Fresh stool samples were incubated with 200 mg, 600 mg of prebiotic, and 200 mg of apple pectin. A negative control without substrate addition was also performed. The tubes were incubated under continuous stirring for 72 hours at 37 ºC in semi-anaerobic atmosphere. Total DNA was extracted and the abundances of butyrate-producing bacterial markers (Faecalibacterium prausnitzii, and its phylogroups I and II, Roseburia hominis and Subdolinogranulum variabile) were analysed by qPCR. Concentrations of both butyrate and acetate were determined by gas chromatography as an indication of the bacterial metabolic activity. Results A significant increase of butyrate producing species, such as S. variabile, R. hominis and F. prausnitzii was observed in CD and UC samples when incubated with 200 mg of prebiotic compared with the negative control. F. prausnitzii phylogroup II, which is underrepresented in UC patients, also increased. No differences were found when samples were incubated with 600 mg. Regarding apple pectin, the increase on the abundance of butyrate producing bacteria was higher than the prebiotic in UC samples. In samples from healthy subjects, an increase in the butyrate producing species abundances was observed in both concentrations of prebiotic when compared with the negative control. In those samples no differences were observed when comparing apple pectin with the prebiotic. Concerning butyrate and acetate production, these substances increased in all prebiotic-supplemented samples when compared with the negative control. Conclusion The studied prebiotic causes an increase of the abundance and activity of butyrate-producing bacteria in both IBD patients and healthy subjects. These results points to this new dietary fibre as a promising prebiotic to maintain eubiosis and to promote the microbiota restoration of the intestinal mucosa.

Background: The composition of the intestinal microbiota is altered in Crohn’s disease [CD] patients. The objective of this study was to evaluate the qualitative and quantitative changes in the microbiota of CD patients in 3 months of treatment with adalimumab [ADA], and determine whether or not these changes are produced towards the recovery of the normal, healthy-like microbiota. Methods: The microbiota composition, and the Faecalibacterium prausnitzii / Escherichia coli quantitative relationship as dysbiosis indicator, were studied at baseline [T0], one month [T1], and 3 months [T3] after starting treatment using a polymerase chain reaction–denaturing gradient gel electrophoresis [PCR-DGGE] of 16S rRNA gene fragments and quantitative PCR, respectively, in rectal mucosal biopsies from 15 CD patients and four healthy subjects. Results: T0 and T3 fingerprints were different in all patients; whereas T1 and T3 presented similar patterns. Recovered phylogroups were Firmicutes \[79.1%], Bacteroides [12.5%], and Actinobacteria [6.25%]. The prevalence of E. coli decreased during treatment. Relative E. coli loads in CD samples were significantly reduced at every analysed step [T1 and T3\] \[ p < 0.005\] whereas no significant changes were observed in relative F. prausnitzii counts. Conclusion: Treatment with ADA induces short-term changes in the microbiota composition which seem to parallel the partial recovery of the gut bacterial ecology, with recovery parameters tending to eubiosis recovery. The quantitative determination of dysbiosis-representative bacteria, such as E. coli, may provide a fast and reliable indicator of the healing state of the intestinal mucosa.

Background Inflammatory bowel disease (IBD) is defined as a group of autoimmune diseases that affects the digestive tract by causing chronic inflammatory processes. Crohn’s disease (CD) is one of the major types of IBD. Although there are several efficient drugs for its treatment, almost 80% of patients will require an intestinal resection throughout their lives. Some bacterial species found in faecal samples can be used as indicators to diagnose and monitor activity in CD patients. However, this methodology has not yet been tested in patients that underwent an intestinal resection. The aim of this study was to investigate the changes in the abundance of these species associated with total or partial intestinal resection. Methods In this study, we used 30 faecal samples from patients diagnosed with CD in remission withdrawn from the Biobank of the Hospital Universitari Dr. Josep Trueta of Girona. Fifteen samples corresponded to patients who underwent an intestinal resection. The following markers were quantified by qPCR: Faecalibacterium prausnitzii (Fpra), F. prausnitzii phylogroup I (PHG-I), F. prausnitzii phylogrup II (PHG-II), Escherichia coli (Eco), Akkermansia muciniphila (Akk), Ruminococcus sp. (Rum), Bacteroidetes (Bac) and Methanobrevibacter smithii (Msm). Results The abundances of Fpra, PHG-I, PHG-II, Rum, and Msm were significantly lower (p < 0.05) in resected CD patients, whereas Eco was significantly more abundant in those patients. No significant differences were observed in the abundances of Akk and Bac. Conclusion In resected CD patients, beneficial butyrate-producing bacteria are underrepresented, whereas pro-inflammatory species are overpopulated. Any quantitative relationship of these indicators with the relapse probability would help to stratify these patients for a better orientation of therapeutic strategies.

Background Crohn disease (CD) and Ulcerative colitis (UC) are characterised by episodes of exacerbations and remissions. Monitoring disease activity based on intestinal lesion is mandatory prior to any change in the therapeutic strategy. Colonoscopy is the gold standard technique to monitor the disease activity in IBD patients, but it is usually discarded because of costs and risk issues. The concentration of Faecal Calprotectin (FC) is widely used as a non-invasive marker of inflammation of the intestinal mucosa, allowing the assessment of the disease activity. Recently, different studies have demonstrated that certain microbial species, part of intestinal microbiota which can be detected in stool samples, are capable of correlating with disease activity in CD and UC patients. The purpose of this study was to analyse the correlation between these microbial indicators and the FC to monitor the disease activity in CD and UC patients. Methods FC levels were used to define inflammatory disease activity, the predetermined cut-off of 250 μg/g of faeces was used, higher values indicated an active inflammation and lower values indicated disease in remission. Two cohorts consisting of 61 patients of CD (25 with active inflammation and 36 with remission) and 90 of UC (42 with active inflammation and 48 with remission) were recruited by the Gastroenterology department of 4 Catalan hospitals. A sample of faeces was collected from each patient. FC and the following markers were quantified by qPCR: Faecalibacterium prausnitzii (Fpra), Escherichia coli (Eco), Akkermansia muciniphila (Akk), Ruminococcus sp. (Rum), Bacteroidetes (Bac) and Methanobrevibacter smithii (Msm) for each sample. Results The bacterial markers presented different behaviour depending on the disease analysed. The abundances of Eco and Bac were higher in CD with active inflammation compared with CD with remission. In contrast, no significant differences were found for Fpra, Akk, Rum, and Msm. Besides, a significant positive correlation between Eco abundance and FC levels (0.280, p = 0.029) and a significant negative correlation between Msm and FC levels (−0.299, p = 0.021) were observed. According UC patients, while the abundance of Eco was higher in patients with active inflammation, the abundance of Rum was significantly less abundant. No significant differences were found for Fpra, Akk, Bac, and Msm. Moreover, we also observed a significant negative correlation between Rum and FC levels (−0.308, p = 0.003, respectively). Conclusion The abundance of Eco and Msm in CD patients and the abundance of Rum in UC patients correlate to FC in order to determine inflammatory disease activity. So, these markers can also be an accurate discriminator of active disease in CD and UC patients.

Dear Sir, Both medications and surgery have been used to treat ulcerative colitis (UC).1,2 Treatment with anti-TNF has shown to be effective in UC resistant to steroid or immunomodulator treatments.3 In this sense, the European Commission has recently approved adalimumab for the treatment of moderately to severely active UC in adult patients who have had an inadequate response to conventional therapy. We present a retrospective analysis of nine anti-TNF-naive patients with UC in whom adalimumab was administered as compassionate use …