A specific microbiota signature is associated to various degrees of ulcerative colitis as assessed by a machine learning approach

Ulcerative colitis (UC) is a complex immune-mediated disease in which the gut microbiota plays a central role, and may determine prognosis and disease progression. We aimed to assess whether a specific microbiota profile, as measured by a machine learning approach, can be associated with disease severity in patients with UC. In this prospective pilot study, consecutive patients with active or inactive UC and healthy controls (HCs) were enrolled. Stool samples were collected for fecal microbiota assessment analysis by 16S rRNA gene sequencing approach. A machine learning approach was used to predict the groups’ separation. Thirty-six HCs and forty-six patients with UC (20 active and 26 inactive) were enrolled. Alpha diversity was significantly different between the three groups (Shannon index: p-values: active UC vs HCs = 0.0005; active UC vs inactive UC = 0.0273; HCs vs inactive UC = 0.0260). In particular, patients with active UC showed the lowest values, followed by patients with inactive UC, and HCs. At species level, we found high levels of Bifidobacterium adolescentis and Haemophilus parainfluenzae in inactive UC and active UC, respectively. A specific microbiota profile was found for each group and was confirmed with sparse partial least squares discriminant analysis, a machine learning-supervised approach. The latter allowed us to observe a perfect class prediction and group separation using the complete information (full Operational Taxonomic Unit table), with a minimal loss in performance when using only 5% of features. A machine learning approach to 16S rRNA data identifies a bacterial signature characterizing different degrees of disease activity in UC. Follow-up studies will clarify whether such microbiota profiling are useful for diagnosis and management

Adverse events in trials of licensed drugs for irritable bowel syndrome with constipation or diarrhea: Systematic review and meta‐analysis

Background Nocebo effects occurring in patients receiving placebo frequently impact on adverse events reported in randomized controlled trials (RCTs) in irritable bowel syndrome (IBS). Therefore, we conducted a systematic review and meta-analysis to assess the proportion of patients randomized to placebo or active drug experiencing any adverse event in trials of licensed drugs for IBS with constipation (IBS-C) or diarrhea (IBS-D), and to estimate the risk of developing adverse events among patients randomized to placebo. Methods We searched MEDLINE, EMBASE CLASSIC and EMBASE, and the Cochrane central register of controlled trials (through June 2021) to identify RCTs comparing licensed drugs with placebo in adults with IBS-C or IBS-D. We generated Forest plots of pooled adverse event rates in both active drug and placebo arms and pooled risk differences (RDs) with 95% confidence intervals (CIs). Key results There were 21 RCTs of licensed drugs versus placebo in IBS-C (5953 patients placebo) and 17 in IBS-D (3854 patients placebo). Overall, 34.9% and 46.9% of placebo patients in IBS-C and IBS-D trials, respectively, developed at least one adverse event, with a statistically significantly higher risk of any adverse event and withdrawal due to an adverse event with active drug. In IBS-C and IBS-D trials, rates of each individual adverse event were generally higher with active drug. However, in IBS-C trials, only diarrhea or headache was significantly more common with active drug (RD 0.066 (95% CI 0.043–0.088) and RD 0.011 (95% CI 0.002–0.021), respectively), and in IBS-D trials only constipation, nausea, or abdominal pain (RD 0.096 (95% CI 0.054–0.138), 0.014 (95% CI 0.002–0.027), and 0.018 (95% CI 0.002–0.034), respectively). Conclusions & Inferences Patients with IBS randomized to placebo have a high risk of reporting adverse events, which might relate to both nocebo and non-nocebo factors. Although patients’ expectations and psychosocial factors may be involved, further understanding of the mechanisms are important to control or optimize these effects in RCTs, as well as in clinical practice

Ciclosporin or Infliximab as Rescue Therapy in Acute Glucorticosteroid-refractory Ulcerative Colitis: Systematic Review and Network Meta-Analysis

Background Despite randomized controlled trials (RCTs) and trial-based meta-analyses, the optimal rescue therapy for patients with acute glucorticosteroid-refractory ulcerative colitis (UC), to avoid colectomy and improve long-term outcomes, remains unclear. We conducted a network meta-analysis examining this issue. Methods We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register to June 2020. We included RCTs comparing ciclosporin and infliximab, either with each other, or with placebo, in patients with glucorticosteroid-refractory UC. Results We identified seven RCTs containing 534 patients (415 in head-to-head trials of ciclosporin versus infliximab). Risk of colectomy at ≤1 month was reduced significantly with both treatments, compared with placebo (relative risk (RR) of colectomy with infliximab versus placebo = 0.37; 95% CI 0.21-0.65, RR with ciclosporin versus placebo = 0.40; 95% CI 0.21-0.77). In terms of colectomy between >1 month and <1 year both drugs ranked equally (P-score 0.75). Neither treatment was more effective than placebo in reducing risk of colectomy at ≥1 year. Both ciclosporin and infliximab were significantly more efficacious than placebo in achieving a response. Neither treatment was more effective than placebo for inducing remission, nor more likely to cause serious adverse events than placebo. Conclusions Both ciclosporin and infliximab were superior to placebo in terms of response to therapy and avoiding colectomy up to 1 year, with no significant differences in efficacy or safety between the two. Ciclosporin is still a valid option to treat refractory UC patients, especially those who do not respond to previous treatment with infliximab, or as a bridge to other biologic therapies

Colorectal Cancer in Inflammatory Bowel Diseases: Epidemiology and Prevention: A Review

Simple Summary Colorectal cancer (CRC) is one of the most serious potential complications of inflammatory bowel diseases (IBDs). The aging of patients affected by IBDs makes this issue a challenge that will increasingly be faced by clinicians in clinical practice, especially in light of the poorer prognosis for CRC in this group of people when compared with the general population. In this review, we summarize the current epidemiology, risk factors and various prevention strategies proposed for CRC in patients with IBDs. Colorectal cancer (CRC) is currently the third most frequent form of malignancy and the second in terms of mortality. Inflammatory bowel diseases (IBDs) are recognized risk factors for this type of cancer. Despite a worldwide increase in the incidence of CRC, the risk of CRC-related death in IBD patients has declined over time, probably because of successful surveillance strategies, the use of more effective drugs in the management of remission and improved indications to colectomy. This notwithstanding, CRC 5-year survival in patients with IBD is poorer than in the general population. This review provides a summary of the epidemiological features, risk factors and various prevention strategies proposed for CRC in IBD patients. Moreover, there is a special focus on reporting and highlighting the various prevention strategies proposed by the most important international scientific societies, both in terms of chemoprevention and endoscopic surveillance. Indeed, in conducting the analysis, we have given attention to the current primary, secondary and tertiary prevention guidelines, attempting to emphasize unresolved research and clinical problems related to this topic in order to improve diagnostic strategies and management

Prevalence of symptoms of anxiety and depression in patients with inflammatory bowel disease: a systematic review and meta-analysis

Background Inflammatory bowel disease (IBD) is a lifelong condition with no cure. Patients with IBD might experience symptoms of common mental disorders such as anxiety and depression because of bidirectional communication via the gut–brain axis and chronicity of symptoms, and because of impaired quality of life and reduced social functioning. However, uncertainties remain about the magnitude of this problem. We aimed to assess prevalence of symptoms of anxiety or depression in adult patients with IBD. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, Embase Classic, and PsycINFO for papers published from inception to Sept 30, 2020, reporting observational studies that recruited at least 100 adult patients with IBD and that reported prevalence of symptoms of anxiety or depression according to validated screening instruments. We excluded studies that only used a structured interview to assess for these symptoms and studies that did not provide extractable data. We extracted data from published study reports and calculated pooled prevalences of symptoms of anxiety and depression, odds ratios (OR), and 95% CIs. Findings Of 5544 studies identified, 77 fulfilled the eligibility criteria, including 30 118 patients in total. Overall, pooled prevalence of anxiety symptoms was 32·1% (95% CI 28·3–36·0) in 58 studies (I2=96·9%) and pooled prevalence of depression symptoms was 25·2% (22·0–28·5) in 75 studies (I2=97·6%). In studies that reported prevalence of anxiety or depression in patients with Crohn's disease and ulcerative colitis within the same study population, patients with Crohn's disease had higher odds of anxiety symptoms (OR 1·2, 95% CI 1·1–1·4) and depression symptoms (1·2, 1·1–1·4) than patients with ulcerative colitis. Overall, women with IBD were more likely to have symptoms of anxiety than were men with IBD (pooled prevalence 33·8% [95% CI 26·5–41·5] for women vs 22·8% [18·7–27·2] for men; OR 1·7 [95% CI 1·2–2·3]). They were also more likely to have symptoms of depression than men were (pooled prevalence 21·2% [95% CI 15·4–27·6] for women vs 16·2% [12·6–20·3] for men; OR 1·3 [95% CI 1·0–1·8]). The prevalence of symptoms of anxiety (57·6% [95% CI 38·6–75·4]) or depression (38·9% [26·2–52·3]) was higher in patients with active IBD than in patients with inactive disease (38·1% [30·9–45·7] for anxiety symptoms and 24·2% [14·7–35·3] for depression symptoms; ORs 2·5 [95% CI 1·5–4·1] for anxiety and 3·1 [1·9–4·9] for depression). Interpretation There is a high prevalence of symptoms of anxiety and depression in patients with IBD, with up to a third of patients affected by anxiety symptoms and a quarter affected by depression symptoms. Prevalence was also increased in patients with active disease: half of these patients met criteria for anxiety symptoms and a third met criteria for depression symptoms. Encouraging gastroenterologists to screen for and treat these disorders might improve outcomes for patients with IBD. Funding None

Efficacy of Oral, Topical, or Combined Oral and Topical 5-Aminosalicylates, in Ulcerative Colitis: Systematic Review and Network Meta-analysis

Background 5-Aminosalicylates [5-ASAs] are the mainstay of treatment for ulcerative colitis [UC]. The optimum preparation, dose, and route of administration for UC remain unclear. We conducted a network meta-analysis to examine this issue. Methods We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials from inception to December 2020. We included randomised controlled trials [RCTs] comparing oral, topical, or combined oral and topical 5-ASAs, with each other or placebo for induction of remission or prevention of relapse of UC. Results were reported as pooled relative risks [RRs] with 95% confidence intervals [CIs] to summarise effect of each comparison tested, with treatments ranked according to P-score. Results We identified 40 RCTs for induction of remission and 23 for prevention of relapse. Topical mesalazine [P-score 0.99], or oral and topical mesalazine combined [P-score 0.87] ranked first and second for clinical and endoscopic remission combined. Combined therapy ranked first in trials where ≥50% of patients had left-sided/extensive disease, and topical mesalazine first in trials where ≥50% of patients had proctitis/proctosigmoiditis. High-dose [≥3.3 g/day] oral mesalazine ranked third in most analyses, with the most trials and most patients. For relapse of disease activity, combined therapy and high-dose oral mesalazine ranked first and second, with topical mesalazine third. 5-ASAs were safe and well tolerated, regardless of regimen. Conclusions Our results support previous evidence; however, higher doses of oral mesalazine had more evidence for induction of remission than combined therapy and were significantly more efficacious than lower doses. Future RCTs should better establish the role of combined therapy for induction of remission, as well as optimal doses of oral 5-ASAs to prevent relapse

Prevalence of Primary Sclerosing Cholangitis in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

Although the association between inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) is well recognised, uncertainties remain about the magnitude of this problem. We conducted a systematic review and meta-analysis assessing prevalence of PSC in IBD to investigate whether type of IBD, how presence of PSC was defined, sex, disease extent or location, time period, or geographical location influenced prevalence.MethodsMEDLINE, EMBASE, and EMBASE Classic were searched (from inception to 10th April 2021) to identify observational studies recruiting ≥50 adult patients with IBD reporting prevalence of PSC. Data were extracted, and pooled prevalence, odds ratios (OR), and 95% confidence intervals (CIs) calculated.ResultsOf 1204 citations, 64 studies were eligible, containing 776,700 patients. Overall, pooled prevalence of PSC in IBD was 2.16%, and was highest in South America and lowest in Southeast Asia. Pooled prevalence in patients with UC, CD, or IBD-U was 2.47%, 0.96% and 5.01%, respectively. Pooled prevalence was significantly higher in UC versus CD (OR = 1.69; 95% CI 1.24-2.29). In subgroup analyses according to method used to define presence of PSC, the highest prevalence was 2.88% in studies performing both liver biochemistry and ERCP/MRCP, and the lowest was 1.79% in studies using a clinical diagnosis. Prevalence was generally higher in men, patients with more extensive, compared with left-sided, UC or ileocolonic or colonic, compared with ileal, CD.ConclusionsOur findings provide the first pooled estimates of the burden of PSC in IBD, as well as potential risk factors, which may be important in establishing a prompt diagnosis and initiating appropriate surveillance for relevant gastrointestinal malignancies

Global prevalence of irritable bowel syndrome according to Rome III or IV criteria: a systematic review and meta-analysis

Background: Irritable bowel syndrome (IBS) is one of the most common functional bowel disorders, but community prevalence appears to vary widely between different countries. This variation might be due to the fact that previous cross-sectional surveys have neither applied uniform diagnostic criteria nor used identical methodology, rather than being due to true global variability. We aimed to determine the global prevalence of IBS. Methods: We did a systematic review and meta-analysis of data from all population-based studies using relatively uniform methodology and using only the most recent iterations of the Rome criteria (Rome III and IV). We searched MEDLINE, Embase, and Embase Classic (from Jan 1, 2006, to April 30, 2020) to identify cross-sectional surveys reporting the prevalence of IBS in adults (≥90% of participants aged ≥18 years) according to the Rome III or Rome IV criteria. We also hand-searched a selection of conference proceedings for relevant abstracts published between 2006 and 2019. We extracted prevalence data for all studies, according to the criteria used to define the presence of IBS. We did a meta-analysis to estimate pooled prevalence rates, according to study location and certain other characteristics (eg, sex and IBS subtype). Findings: We identified 4143 citations, of which 184 studies appeared relevant. 57 of these studies were eligible, and represented 92 separate adult populations, comprising 423 362 participants. The pooled prevalence of IBS in 53 studies that used the Rome III criteria, from 38 countries and comprising 395 385 participants, was 9·2% (95% CI 7·6–10·8; I 2=99·7%). By contrast, pooled IBS prevalence among six studies that used the Rome IV criteria, from 34 countries and comprising 82 476 individuals, was 3·8% (95% CI 3·1–4·5; I 2=96·6%). IBS with mixed bowel habit (IBS-M) was the most common subtype with the Rome III criteria, reported by 33·8% (95% CI 27·8–40·0; I 2=98·1%) of people fulfilling criteria for IBS (ie, 3·7% [2·6–4·9] of all included participants had IBS-M), but IBS with diarrhoea (IBS-D) was the most common subtype with the Rome IV criteria (reported by 31·5% [95% CI 23·2–40·5; I 2=98·1% 61·6%] of people with IBS, corresponding to 1·4% [0·9–1·9] of all included participants having IBS-D). The prevalence of IBS was higher in women than in men (12·0% [95% CI 9·3–15·0] vs 8·6% [6·3–11·2]; odds ratio 1·46 [95% CI 1·33–1·59]). Prevalence varied substantially between individual countries, and this variability persisted even when the same diagnostic criteria were applied and identical methodology was used in studies. Interpretation: Even when uniform symptom-based criteria are applied, based on identical methodology, to define the presence of IBS, prevalence varies substantially between countries. Prevalence was substantially lower with the Rome IV criteria, suggesting that these more restrictive criteria might be less suitable than Rome III for population-based epidemiological surveys. Funding: None