The basic principle for the treatment of idiopathic diarrhoea (functional diarrhoea K59.1) is to delay transit through the gut in order to promote the absorption of electrolytes and water. Under mild conditions, bulking agents may suffice. With increasing severity, antidiarrhoeal pharmaceuticals may be added in a stepwise manner. In diarrhoea of unknown aetiology, peripherally-acting opioid receptor agonists, such as loperamide, are first-line treatment and forms the pharmaceutical basis of antidiarrheal treatment. As second-line treatment opium drops have an approved indication for severe diarrhoea when other treatment options fail. Beyond this, various treatment options are built on experience with more advanced treatments using clonidine, octreotide, as well as GLP-1 and GLP-2 analogs which require specialist knowledge the field.

Background and Aims: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies.Methods: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied.Results: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 x 10(-23), odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [r(g) = 0.77; p = 0.048] and oesophageal diseases [r(g) = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 x 10(-8), OR = 1.31]. No significant association was detected for LC.Conclusion: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.

The basic principle for treatment of idiopathic diarrhea is to delay transit through the gut in order to promote absorption of electrolytes and water. Under mild conditions bulking agents may suffice. With increasing severity, antidiarrheal pharmaceuticals may be added in a stepwise manner. Bile salt malabsorption is a clear indication for adsorptive resins, while in idiopathic diarrhea peripherally-acting opioid receptor agonists, such as loperamide, is the first-line treatment. Second-line treatment with approved indication for severe diarrhea when other treatment options fail includes opium drops. More advanced treatments are to be used by clinicians with specialist knowledge and experience in the field.

Kronisk diarré är vanligt och förekommer hos 5 pro cent av befolkningen. Diagnostiken är ofta en utma ning, och behandling måste ofta initieras utan att sä ker orsak har konstaterats. Målsättningen med denna artikel är att ge rekommendationer om farmakologis ka behandlingssteg vid diarré. Det är viktigt att hålla i minnet att diarré kan ha olika innebörd för olika indi vider, från osäkerhet och rädsla för ofrivillig tömning till återkommande inkontinens. Det innebär alltid en påtagligt sänkt livskvalitet.

Objective

Microscopic colitis [MC], encompassing collagenous colitis [CC] and lymphocytic colitis [LC], is an increasingly prevalent gastrointestinal disease with an unknown aetiology. Previous research has reported significant differences in the incidence of MC within Denmark, with the lowest incidence found in the most populated region [Capital Region of Denmark]. Our aim was to elucidate the causes of these regional differences.

Design

All incident MC patients [n = 14 302] with a recorded diagnosis of CC [n = 8437] or LC [n = 5865] entered in The Danish Pathology Register between 2001 and 2016 were matched to 10 reference individuals [n = 142 481]. Information regarding drug exposure, including proton pump inhibitors [PPIs], selective serotonin reuptake inhibitors [SSRIs], statins, and nonsteroidal anti-inflammatory drugs [NSAIDs], were retrieved from The Danish National Prescription Registry. Information regarding endoscopy rate, smoking-related diseases, and immune-mediated inflammatory diseases were acquired from The Danish National Patient Registry.

Results

Smoking, immune-mediated inflammatory diseases, exposure to PPIs, SSRIs, statins, and NSAIDs were significantly associated with MC in all Danish regions. The association between drug exposure and MC was weakest in the Capital Region of Denmark with an odds ratio of 1.8 (95% confidence interval [CI]: 1.61-2.01). The relative risk of undergoing a colonoscopy with biopsy was significantly increased in sex- and age-matched controls in all regions compared with controls from the Capital Region of Denmark, with the greatest risk found in the Region of Southern Denmark, 1.37 [95% CI: 1.26-1.50].

Conclusions

The cause of the regional differences in MC incidence in Denmark seems to be multifactorial, including variations in disease awareness and distribution of risk factors.

Introduction Microscopic colitis is a chronic inflammatory bowel disease characterised by normal or almost normal endoscopic appearance of the colon, chronic watery, non-bloody diarrhoea and distinct histological abnormalities, which identify three histological subtypes, the collagenous colitis, the lymphocytic colitis and the incomplete microscopic colitis. With ongoing uncertainties and new developments in the clinical management of microscopic colitis, there is a need for evidence-based guidelines to improve the medical care of patients suffering from this disorder. Methods Guidelines were developed by members from the European Microscopic Colitis Group and United European Gastroenterology in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists, pathologists and basic scientists, and voted upon using the Delphi method. Results These guidelines provide information on epidemiology and risk factors of microscopic colitis, as well as evidence-based statements and recommendations on diagnostic criteria and treatment options, including oral budesonide, bile acid binders, immunomodulators and biologics. Recommendations on the clinical management of microscopic colitis are provided based on evidence, expert opinion and best clinical practice. Conclusion These guidelines may support clinicians worldwide to improve the clinical management of patients with microscopic colitis.

Background Microscopic colitis (MC) is a common cause of chronic watery diarrhea. Biopsies with characteristic histological features are crucial for establishing the diagnosis. The two main subtypes are collagenous colitis (CC) and lymphocytic colitis (LC) but incomplete forms exist. The disease course remains unpredictable varying from spontaneous remission to a relapsing course.

Aim To identify possible histological predictors of course of disease.

Methods Sixty patients from the European prospective MC registry (PRO-MC Collaboration) were included. Digitised histological slides stained with CD3 and Van Gieson were available for all patients. Total cell density and proportion of CD3 positive lymphocytes in lamina propria and surface epithelium were estimated by automated image analysis, and measurement of the subepithelial collagenous band was performed. Histopathological features were correlated to the number of daily stools and daily watery stools at time of endoscopy and at baseline as well as the clinical disease course (quiescent, achieved remission after treatment, relapsing or chronic active) at 1-year follow-up.

Results Neither total cell density in lamina propria, proportion of CD3 positive lymphocytes in lamina propria or surface epithelium, or thickness of collagenous band showed significant correlation to the number of daily stools or daily watery stools at any point of time. None of the assessed histological parameters at initial diagnosis were able to predict clinical disease course at 1-year follow-up.

Conclusions Our data indicate that the evaluated histological parameters were neither markers of disease activity at the time of diagnosis nor predictors of disease course.

Introduction: Microscopic colitis (MC) is an inflammatory bowel condition with two subtypes, lymphocytic colitis (LC) and collagenous colitis (CC). Unlike patients with ulcerative colitis (UC) and non-inflamed individuals, MC patients have reduced risk of developing colorectal cancer, possibly due to increased immune surveillance in MC patients.

Aim: To examine differences in levels of immunomodulatory molecules, including those involved in immune checkpoint mechanisms, in sera from patients with MC and in colonic biopsies from patients with MC and UC compared with controls.

Methods: Using Luminex, 23 analytes (4-1BB, 4-1BBL, APRIL, BAFF, BTLA, CD27, CD28, CD80, CTLA-4, E-cadherin, Galectin-3, GITR, HVEM, IDO, IL-2R alpha, LAG-3, MICA, MICB, PD-1, PD-L1, PD-L2, sCD40L and TIM-3) were studied in serum from patients with active MC (n = 35) and controls (n = 23), and in colonic biopsies from patients with active LC (n = 9), active CC (n = 16) and MC in histological remission (LC n = 6, CC n = 6), active UC (n = 15) and UC in remission (n = 12) and controls (n = 58).

Results: In serum, IDO, PD-1, TIM-3, 4-1BB, CD27, and CD80 were decreased whereas 4-1BBL and IL-2R alpha were increased in MC patients compared with controls. In contrast, in biopsies, levels of PD-L2 and 4-1BB were increased in MC and UC patients with active disease. Furthermore, in biopsies from CC and UC but not LC patients with active disease, CTLA-4, PD-1, APRIL, BAFF, and IL-2R alpha were increased compared with controls. PD-L1 was increased in CC but not UC or LC patients. CD27 and TIM-3 were decreased in biopsies from MC patients in comparison to controls whereas levels of MICB were decreased in patients with active UC compared with controls.

Conclusions: Compared with non-inflamed controls, levels of soluble and membrane-bound immunomodulatory molecules were systemically and locally altered in MC and UC patients, with most analytes being decreased in serum but enhanced in colonic biopsies. These findings contribute to knowledge about checkpoint molecules and their role as biomarkers in MC and may also contribute to knowledge about possible mechanisms behind the seemingly protective effects of MC against colorectal cancer.

BACKGROUND AND AIMS: The pathophysiology of the inflammatory bowel disease collagenous colitis (CC) is poorly described. Our aim was to use RNA sequencing of mucosal samples from patients with active CC, CC in remission, refractory CC, ulcerative colitis (UC), and controls to gain insight into CC pathophysiology, identify genetic signatures linked to CC, and uncover potentially druggable disease pathways.

METHODS: We performed whole transcriptome sequencing of CC samples from patients before and during treatment with the corticosteroid drug budesonide, CC steroid-refractory patients, UC patients, and healthy controls (n=9-13). Bulk mucosa and laser-captured microdissected intestinal epithelial cell (IEC) gene expression were analyzed by gene-set enrichment and gene-set variation analyses to identify significant pathways and cells, respectively, altered in CC. Leading genes and cells were validated using reverse transcription quantitative PCR and/or immunohistochemistry.

RESULTS: We identified an activation of the adaptive immune response to bacteria and viruses in active CC that could be mediated by dendritic cells. Moreover, IECs display hyperproliferation and increased antigen presentation in active CC. Further analysis revealed that genes related to the immune response (DUOX2, PLA2G2A, CXCL9), DNA transcription (CTR9), protein processing (JOSD1, URI1) and ion transport (SLC9A3) remained dysregulated even after budesonide-induced remission. Budesonide-refractory CC patients fail to restore normal gene expression, and displayed a transcriptomic profile close to UC.

CONCLUSIONS: Our study confirmed the implication of innate and adaptive immune responses in CC, governed by IECs and dendritic cells, respectively; and identified ongoing epithelial damage. Refractory CC could share pathomechanisms with UC.

Background and Aims: Epidemiological studies suggest an increasing global incidence of microscopic colitis, including collagenous colitis and lymphocytic colitis. We aimed to investigate the incidence and prevalence of microscopic colitis in Denmark. Methods: In a nationwide cohort study, we included all incident patients with a recorded diagnosis of collagenous colitis or lymphocytic colitis in the Danish Pathology Register between 2001 and 2016. Results: A total of 14 302 patients with microscopic colitis-8437 [59%] with collagenous and 5865 [41%] with lymphocytic colitis-were identified during the study period. The prevalence in December 2016 was estimated to be 197.9 cases per 100 000 inhabitants. Microscopic colitis was more prevalent among females (n = 10 127 [71%]), with a mean annual incidence of 28.8, compared with 12.3 per 100 000 person-years among males. The overall mean incidence during the study period was 20.7 per 100 000 person-years. Mean age at time of diagnosis was 65 years (standard deviation [SD]:14) for microscopic colitis, 67 [SD:13] for collagenous colitis, and 63 [SD:15] for lymphocytic colitis. The overall incidence increased significantly from 2.3 cases in 2001 to 24.3 cases per 100 000 person-years in 2016. However, the highest observed incidence of microscopic colitis was 32.3 cases per 100 000 person-years in 2011. Large regional differences were found, with the highest incidence observed in the least populated region. Conclusions: The incidence of microscopic colitis in Denmark has increased 10-fold during the past 15 years and has now surpassed that of Crohns disease and ulcerative colitis. However, incidence has stabilised since 2012, suggesting that a plateau has been reached.

BACKGROUND AND AIMS: Diarrhoea is a common, debilitating symptom of gastrointestinal disorders. Pathomechanisms probably involve defects in trans-epithelial water transport, but the role of aquaporin [AQP] family water channels in diarrhoea-predominant diseases is unknown. We investigated the involvement of AQPs in the pathobiology of collagenous colitis [CC], which features chronic, watery diarrhoea despite overtly normal intestinal epithelial cells [IECs].

METHODS: We assessed the expression of all AQP family members in mucosal samples of CC patients before and during treatment with the corticosteroid drug budesonide, steroid-refractory CC patients and healthy controls. Samples were analysed by genome-wide mRNA sequencing [RNA-seq] and quantitative real-time PCR [qPCR]. In some patients, we performed tissue microdissection followed by RNA-seq to explore the IEC-specific CC transcriptome. We determined changes in the protein levels of the lead candidates in IEC by confocal microscopy. Finally, we investigated the regulation of AQP expression by corticosteroids in model cell lines.

RESULTS: Using qPCR and RNA-seq, we identified loss of AQP8 expression as a hallmark of active CC, which was reverted by budesonide treatment in steroid-responsive but not refractory patients. Consistently, decreased AQP8 mRNA and protein levels were observed in IECs of patients with active CC, and steroid drugs increased AQP8 expression in model IECs. Moreover, low APQ8 expression was strongly associated with higher stool frequency in CC patients.

CONCLUSION: Down-regulation of epithelial AQP8 may impair water resorption in active CC, resulting in watery diarrhoea. Our results suggest that AQP8 is a potential drug target for the treatment of diarrhoeal disorders.