ABSTRACT Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) show a large overlap in clinical presentation, which presents diagnostic challenges. As a consequence, invasive and burdensome endoscopies are often used to distinguish between IBD and IBS. Here, we aimed to develop a noninvasive fecal test that can distinguish between IBD and IBS and reduce the number of endoscopies. We used shotgun metagenomic sequencing to analyze the composition and function of gut microbiota of 169 IBS patients, 447 IBD patients and 1044 population controls and measured fecal Calprotectin (FCal), human beta defensin 2 (HBD2), and chromogranin A (CgA) in these samples. These measurements were used to construct training sets (75% of data) for logistic regression and machine learning models to differentiate IBS from IBD and inactive from active IBD. The results were replicated on test sets (remaining 25% of the data) and microbiome data obtained using 16S sequencing. Fecal HBD2 showed high sensitivity and specificity for differentiating between IBD and IBS (sensitivity = 0.89, specificity = 0.76), while the inclusion of microbiome data with biomarkers (HBD2 and FCal) showed a potential for improvement in predictive power (optimal sensitivity = 0.87, specificity = 0.93). Shotgun sequencing–based models produced comparable results using 16S-sequencing data. HBD2 and FCal were found to have predictive power for IBD disease activity (AUC ≈ 0.7). HBD2 is a novel biomarker for IBD in patients with gastro-intestinal complaints, especially when used in combination with FCal and potentially in combination with gut microbiome data.

INTRODUCTION Momentary ecological assessment indicated alleviated abdominal pain in escitalopram treatment of irritable bowel syndrome (IBS) with comorbid panic disorder. Hitherto, little is known about symptom formation, i.e., how psychological impact physical symptoms, and vice versa, and about the effect of SSRI-treatment on symptom formation. OBJECTIVE To investigate how psychological and somatic symptoms co-vary over time in IBS patients with comorbid panic disorder and how they are affected by escitalopram treatment. METHODS Experience sampling data from 14 IBS patients with panic disorder were obtained from a single-centre, double-blind, parallel-group, randomized controlled trial on escitalopram versus placebo. At baseline, after three and six months, multilevel time-lagged linear regression analysis was used to construct symptom networks. Network connections represented coefficients between various affect and gastrointestinal items. RESULTS Connectivity increased up to 3 months in both groups. Between 3 and 6 months, connectivity decreased for placebo and further increased in the escitalopram group. Additionally, a steep increase in node strength for negative affect nodes was observed in the escitalopram network and the opposite for positive affect nodes. Over time, group symptom networks became increasingly different from each other. Anxious-anxious and enthusiastic-relaxed became significantly different between groups at 6 months. The connection that changed significantly in all analyses was anxious-anxious. CONCLUSIONS Escitalopram treatment was associated with changes in the symptom networks in IBS patients with panic disorder. While mood and physical symptoms improve over time, mainly connectivity between mood nodes changed, possibly pointing towards a healthier emotion regulation resulting in alleviation of physical symptoms.

A 31-year-old woman with hepatocellular carcinoma suffered from recurrent oesophageal variceal bleeding due to portal hypertension, which was caused by severe compression of the portal vein by metastatic lymph nodes. Endoscopic band ligation and pharmacological treatment did not suffice to prevent recurrence of variceal bleeding. Eventually, after the fifth variceal bleeding within 6 months, the patient was admitted to the intensive care unit in a haemodynamic shock. A Sengstaken-Blakemore tube was inserted and all treatment options were discussed, but only percutaneous transhepatic recanalisation of the portal vein with stent placement to reduce portal vein pressure was thought to be feasible with any chance to relieve portal vein pressure. After successful portal vein stenting, our patient did not have any recurrent bleeding in the remaining year of her life. We suggest that percutaneous transhepatic portal vein stenting may be a feasible and adequate last line treatment for complications of portal hypertension.

OBJECTIVE Irritable bowel syndrome (IBS) has a high comorbidity with mental disorders. The present paper aims to visualise the interplay between IBS and affect (anxiety and mood) in daily life. Furthermore, this interplay may be different depending on risk factors such as childhood trauma. METHODS Using momentary assessment (Experience Sampling Method), data of 24 individuals diagnosed with both IBS and panic disorder were analysed (15 non-trauma and 9 low-trauma-score patients). Networks were constructed, based on multilevel time-lagged linear regression analysis. Regression coefficients present network connections including three negative affect items (down, irritated, rushed), three positive affect items (happy, enthusiastic, cheerful), three abdominal complaints (abdominal pain, bloating, nausea) and one social item (feeling lonely). Those networks were stratified by levels of childhood trauma based on the Childhood Trauma Questionnaire. RESULTS Connections within the group of mood items and within the group of abdominal complaints were more frequent than between abdominal complaints and mood items. When data were stratified by childhood trauma, networks were different. In addition, node strengths were stronger in low-trauma than in non-trauma, although only one was significantly different (enthusiastic). Overall, there were mainly non-significant connections and a clear pattern was not visible. CONCLUSIONS A time-lagged network provides additional insight in connections between abdominal complaints and affective complaints, in patients with IBS and panic disorder, with different levels of childhood trauma. More research is needed to gain a better understanding of symptom formation and the impact of variation in context on individual symptom experiences in IBS with affective comorbidity. Baseline data of a clinical trial: NCT01551225 (http://www.clinicaltrials.gov).

INTRODUCTION: Gastrointestinal symptoms in irritable bowel syndrome (IBS) have been correlated with psychological factors using retrospective symptom assessment. However, real-time symptom assessment might reveal the interplay between abdominal and affective symptoms more reliably in a longitudinal perspective. The aim was to evaluate the association between stress and abdominal pain, using the Experience Sampling Method (ESM) as a real-time, repeated measurement method. METHODS: Thirty-seven patients with IBS (26 women; mean age 36.7 years) and 36 healthy controls (HC; 24 women; mean age 31.1 years) completed an electronic ESM during 7 consecutive days. Abdominal pain and stress were scored on an 11-point Numeric Rating Scale at a maximum of 10 random moments each day. RESULTS: Abdominal pain scores were 2.21 points higher in patients with IBS compared with those in HC (P < 0.001), whereas stress levels did not differ significantly (B: 0.250, P = 0.406). In IBS, a 1-point increase in stress was associated with, on average, 0.10 points increase in abdominal pain (P = 0.017). In HC, this was only 0.02 (P = 0.002). Stress levels at t = −1 were not a significant predictor for abdominal pain at t = 0 in both groups, and vice versa. DISCUSSION: Our results demonstrate a positive association between real-time stress and abdominal pain scores and indicate a difference in response to stress and not a difference in experienced stress per se. Furthermore, an in-the-moment rather than a longitudinal association is suggested. This study underlines the importance of considering the individual flow of daily life and supports the use of real-time measurement when interpreting potential influencers of abdominal symptoms in IBS.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed whole-genome genotypes and 16S fecal microbiome data from 18,473 individuals (25 cohorts). Microbial composition showed high variability across cohorts: we detected only 9 out of 410 genera in more than 95% of the samples. A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 30 loci affecting microbome taxa at a genome-wide significant (P<5×10-8) threshold. Just one locus, the lactase (LCT) gene region, reached study-wide significance (GWAS signal P=8.6×10−21); it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.94×10−10<P<5×10−8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization analyses identified enrichment of microbiome trait loci SNPs in the metabolic, nutrition and environment domains and indicated food preferences and diseases as mediators of genetic effects.

Exhaled breath analysis has become a promising monitoring tool for various ailments by identifying volatile organic compounds (VOCs) as indicative biomarkers excreted in the human body. Throughout the process of sampling, measuring, and data processing, non-biological variations are introduced in the data leading to batch effects. Algorithmic approaches have been developed to cope with within-study batch effects. Batch differences, however, may occur among different studies too, and up-to-date, ways to correct for cross-study batch effects are lacking; ultimately, cross-study comparisons to verify the uniqueness of found VOC profiles for a specific disease may be challenging. This study applies within-study batch-effect-correction approaches to correct for cross-study batch effects; suggestions are made that may help prevent the introduction of cross-study variations. Three batch-effect-correction algorithms were investigated: zero-centering, combat, and the analysis of covariance framework. The breath samples were collected from inflammatory bowel disease (n=213), chronic liver disease (n=189), and irritable bowel syndrome (n=261) patients at different periods, and they were analysed via gas chromatography-mass spectrometry. Multivariate statistics were used to visualise and verify the results. The visualisation of the data before any batch-effect-correction technique was applied showed a clear distinction due to probable batch effects among the datasets of the three cohorts. The visualisation of the three datasets after implementing all three correction techniques showed that the batch effects were still present in the data. Predictions made using partial least squares discriminant analysis and random forest confirmed this observation. The within-study batch-effect-correction approaches fail to correct for cross-study batch effects present in the data. The present study proposes a framework for systematically standardising future breathomics data by using internal standards or quality control samples at regular analysis intervals. Further knowledge regarding the nature of the unsolicited variations among cross-study batches must be obtained to move the field further.

The human gut microbiota has now been associated with drug responses and efficacy, while chemical compounds present in these drugs can also impact the gut bacteria. However, drug–microbe interactions are still understudied in the clinical context, where polypharmacy and comorbidities co-occur. Here, we report relations between commonly used drugs and the gut microbiome. We performed metagenomics sequencing of faecal samples from a population cohort and two gastrointestinal disease cohorts. Differences between users and non-users were analysed per cohort, followed by a meta-analysis. While 19 of 41 drugs are found to be associated with microbial features, when controlling for the use of multiple medications, proton-pump inhibitors, metformin, antibiotics and laxatives show the strongest associations with the microbiome. We here provide evidence for extensive changes in taxonomy, metabolic potential and resistome in relation to commonly used drugs. This paves the way for future studies and has implications for current microbiome studies by demonstrating the need to correct for multiple drug use. Here, via a metagenomics analysis of population-based and disease cohorts, Vich Vila et al. study the impact of 41 commonly used medications on the taxonomic structures, metabolic potential and resistome of the gut microbiome, underscoring the importance of correcting for multiple drug use in microbiome studies.

Animal studies have shown that intestinal barrier function is compromised with aging. We aimed to assess the effects of aging on intestinal barrier function in humans in vivo and ex vivo. In this cross-sectional study, healthy subjects and subjects with irritable bowel syndrome (IBS) of older (65–75 years) and young adult age (18–40 years) were compared. In vivo gastrointestinal site-specific permeability was assessed by a multi-sugar test, taking into account potential confounders. Sigmoid biopsies were collected from subgroups of healthy young adults and elderly for ex vivo Ussing chamber experiments, gene transcription of barrier-related genes and staining of junctional proteins. No significant differences between healthy young adults and elderly were found for small intestinal, colonic and whole gut permeability (P ≥ 0.142). In IBS patients, gastroduodenal and colonic permeability did not differ significantly (P ≥ 0.400), but small intestinal and whole gut permeability were higher in elderly versus young adults (P ≤ 0.009), mainly driven by the IBS-diarrhea subtype. Ussing chamber experiments with or without stressor (P ≥ 0.052), and relative expression of intestinal barrier-related genes (P ≥ 0.264) showed no significant differences between healthy elderly and young adults, as confirmed by immunofluorescent stainings. Overall, the functional capacity of the intestinal barrier is maintained in elderly.

With great interest, we have read the article by Backes et al ,1 on the pre-resection accuracy of the real-time optical diagnosis of T1 colorectal cancer (T1CRC) in large non-pedunculated colorectal polyps. In this multicentre, prospective study, the authors developed and validated the OPTICAL model, in which a sensitivity of 78.7% (95% CI: 64.3 to 89.3) for optical diagnosis of T1CRC was obtained. With the implementation of the Dutch bowel cancer screening programme (BCSP) in 2014, a shift has occurred towards the more frequent diagnoses of early AJCC (American Joint Committee on Cancer) stage I cancers.2 Estimating the risk of a T1CRC is crucial to determine the optimal treatment strategy, and to select cases for more elaborative and expensive endoscopic en bloc resection techniques such as endoscopic submucosal dissection, transanal minimally invasive surgery or endoscopic full-thickness resection. Current studies mainly report on the outcomes of advanced imaging by expert centres with dedicated endoscopists,3 4 whereas …

We thank dr Yuanjun Dong for his interest in our publication.1 Dr Dong points out that previous and current stressful life events mod‐ ulate gastrointestinal (GI) symptom severity and quality of life (QoL) in patients with irritable bowel syndrome (IBS),2 which is indeed based on recent findings.3 In addition, we would like to note that abdominal pain is the predominant symptom in IBS, as per Rome IV definition. The primary treatment outcome for IBS in clinical tri‐ als, in accordance with FDA and EMA requirements, is reduction in daily abdominal pain.4 Whether a successful treatment, based on these criteria, improves patients’ life satisfaction and QoL remains an item of debate. In the current study, we performed an extensive prospective evaluation of the natural course of IBS which included demographics, gastrointestinal symptoms, symptoms of anxiety and depression, GI‐specific anxiety, satisfaction with life, and QoL. With regard to QoL, we showed among others that general anxiety and depression levels at follow‐up were independently associated with mental quality of life scores at the same time point. Furthermore, no associations were found between GI symptom severity, including abdominal pain, and the change in QoL scores over time.1 With regard to a possible interaction between GI symptoms and stress, in Table 1 we provide data on specific questions and answers from the database of Maastricht IBS cohort regarding the patients’ perspective on this matter. No statistically significant differences were found between Rome‐positive and Rome‐negative IBS patients at follow‐up. However, the current understanding on the relationship between abdominal pain and stress, whether current or related to life events, may be limited by the methods used to assess these factors. Traditionally, data from retrospective reports have been used to de‐ scribe this relationship, but it is known that these questionnaires are limited by recall and ecological bias.4 We therefore believe that the best available method to study the relationship between GI symp‐ toms, comorbid psychological complaints, and daily life stress is re‐ peated momentary symptom assessment.5 Such methodology has been used recently to assess the temporal relationship between ab‐ dominal pain and (preceding) daily life stress.6 We have developed and are currently validating specific questionnaires based on experience sampling method (ESM) which may provide additional leads in this matter.7 In a recently completed study, we demonstrate that real‐time stress scores are positively associated with concurrent abdominal pain scores in IBS, but not in healthy subjects, whereas abdominal pain could not be predicted by preceding stress levels, and vice versa, suggesting an in‐the‐moment rather than a longitudinal association.8 Taken together, we postulate that reduction in abdominal pain is not necessarily accompanied by long‐term improvement in quality of life in patients with IBS. This may indicate that the primary treat‐ ment focus in IBS should shift from solely abdominal pain reduction and improvement of bowel habits, toward a holistic approach, which includes quality of life, comorbid psychological symptoms, and im‐ provement of coping strategies with regard to GI symptoms as well as daily life stress. However, the evidence to support a change in the approach of IBS management is still inconclusive, and further research is needed.

The human gut microbiome is influenced by numerous factors including commonly used drugs, but it has also been shown that the gut microbiome by itself influences drug responses and efficacy. We studied the relations between commonly used drugs and microbial changes considering factors like polypharmacy and multi-morbidity. We performed metagenomics sequencing of 1883 faecal samples from three cohorts: 1) a population-based cohort, 2) patients with inflammatory bowel diseases and 3) patients with irritable bowel syndrome. Differences between drug users and non-users were analysed per cohort, followed by a meta-analysis. 17 of 41 drugs were associated with changes in microbial features. For example, metformin users showed enrichment of Escherichia-coli -derived metabolic pathways and methanogenic pathways were increased in oral steroid users in patients with IBD. Due the importance of the gut microbiome in health and the widespread use of drugs, we here provide evidence for extensive changes in taxonomy, metabolic activity and resistome in relation to commonly used drugs. This research paves the way to further mechanistic studies for drug response and side effects and has implications on future microbiome studies, underlining the need for correcting for multiple drug use in both general population and in GI disease cohorts.