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Background Microscopic colitis (MC), comprising lymphocytic colitis (LC) and collagenous colitis (CC), is an inflammatory bowel disease with increasing incidence. MC etiopathogenesis remains unknown; however, altered colonic epithelial integrity may underlie uncontrolled luminal antigen passage, triggering immuno‐inflammatory responses. Objective The aim of this study was to further define the involvement of the colonic epithelium in MC. Methods A paired transcriptomic and proteomic analysis followed by epithelial ultrastructural examination was performed on colonic biopsies from LC and CC patients, and from irritable bowel syndrome with a predominance of diarrhoea (IBS‐D) and healthy subjects (H) as control groups. The impact of budesonide therapy on the epithelial structure was also evaluated in CC. Results MC patients exhibited decreased expression of inter‐microvilli adhesion and actin‐bundling proteins, accompanied by increased expression of actin‐membrane connection proteins compared to both control groups. Distinct molecular differentiated CC and LC, which translated into differential ultrastructure abnormalities. The colonic microvilli in CC patients were shorter in length and fewer in number, with partial restoration following budesonide treatment, whereas LC showed a reduction solely in microvilli number. A negative correlation was found between daily stool frequency and SPATN1 and ATP8B1 protein levels in CC patients. Conclusions Molecular dysregulation and aberrant ultrastructure of the colonic brush border feature the colonic epithelium in LC and CC. These previously undescribed findings provide new perspectives for further defining MC pathogenesis and identifying biomarkers for diagnosis, prognosis and treatment of this debilitating and prevalent disease. Key Summary Summarise the established knowledge on this subject ◦ Microscopic colitis (MC) is a chronic immune‐mediated disease characterized by colonic mucosal inflammation and barrier dysfunction, but a deeper characterization of colonocytes is lacking. What are the significant and/or new findings of this study? ◦ This study is the first to MC identify molecular and ultrastructural alterations of the brush border in colonocytes in lymphocytic colitis (LC) and collagenous colitis (CC). ◦ The uniqueness of this study relies on the identification of a molecular phenotype of the brush border that differentiates from healthy controls and, notably, from the closest diarrhoeal disorder, irritable bowel syndrome with a predominance of diarrhoea. ◦ Given the fundamental role of the brush border in maintaining intestinal homoeostasis and regulating epithelial barrier function, our study sets the basis for the identification of new predictive diagnostic and/or prognostic biomarkers for both LC and CC, as well as new potential therapeutic targets.

Background The pathobiology of the non‐destructive inflammatory bowel disease (IBD) lymphocytic colitis (LC) is poorly understood. We aimed to define an LC‐specific mucosal transcriptome to gain insight into LC pathology, identify unique genomic signatures, and uncover potentially druggable disease pathways. Methods We performed bulk RNA‐sequencing of LC and collagenous colitis (CC) colonic mucosa from patients with active disease, and healthy controls (n = 4–10 per cohort). Differential gene expression was analyzed by gene‐set enrichment and deconvolution analyses to identify pathologically relevant pathways and cells, respectively, altered in LC. Key findings were validated using reverse transcription quantitative PCR and/or immunohistochemistry. Finally, we compared our data with a previous cohort of ulcerative colitis and Crohn's disease patients (n = 4 per group) to distinguish non‐destructive from classic IBD. Results LC can be subdivided into channelopathic LC, which is governed by organic acid and ion transport dysregulation, and inflammatory LC, which is driven by microbial immune responses. Inflammatory LC displays an innate and adaptive immunity that is limited compared to CC and classic IBD. Conversely, we noted a distinct induction of regulatory non‐coding RNA species in inflammatory LC samples. Moreover, compared with CC, water channel and cell adhesion molecule gene expression decreased in channelopathic LC, whereas it was accentuated in inflammatory LC and associated with reduced intestinal epithelial cell proliferation. Conclusions We conclude that LC can be subdivided into channelopathic LC and inflammatory LC that could be pathomechanistically distinct subtypes despite their shared clinical presentation. Inflammatory LC exhibits a dampened immune response compared to CC and classic IBDs. Our results point to regulatory micro‐RNAs as a potential disease‐specific feature that may be amenable to therapeutic intervention.

Microscopic colitis is an inflammatory bowel disease (IBD) comprising two clinically undiscernible entities: collagenous colitis and lymphocytic colitis. Collagenous colitis associates with HLA genes and displays a Th1/Tc1–Th17/Tc17 profile with pericryptal myofibroblast activity, water malabsorption and secondary fluid loss due to altered osmoregulation. Conversely, lymphocytic colitis lacks genetic associations and displays a Th1/Th2 profile and paracellular/transcellular permeability. Lymphocytic colitis subclassifies into channelopathic lymphocytic colitis due to unique alteration of ion and organic acid transport that could result from drug exposure, and inflammatory lymphocytic colitis due to the involvement of moderate immune responses compared to collagenous colitis. As microscopic colitis mucosa remains intact and immune cells seem to stay inactive, microscopic colitis is an ideal model to explore early stages of IBD if collagenous colitis and lymphocytic colitis are studied as distinct entities. Exploiting multiomic approaches and established biobanks will ensure validation of microscopic colitis patient stratification, and deepening into pathomechanisms which could enable precision medicine.

Lymphocytic colitis (LC) causes watery diarrhea. We aimed to identify mechanisms of altered Na+ absorption and regulatory inputs in patients with LC by examining the epithelial Na+ channel (ENaC) function as the predominant Na+ transport system in human distal colon.MethodsEpithelial Na+ channel function and regulation was analyzed in biopsies from sigmoid colon of patients with LC and in rat distal colon in Ussing chambers. ENaC-subunit expression was measured by real-time PCR and RNA sequencing. Correction factors for subepithelial resistance contributions were determined by impedance spectroscopy. Upstream regulators in LC were determined by RNA sequencing.ResultsEpithelial Na+ channel-mediated electrogenic Na+ transport was inhibited despite aldosterone stimulation in human sigmoid colon of patients with LC. The increase in γ-ENaC mRNA expression in response to aldosterone was MEK1/2-dependently reduced in LC, since it could be restored toward normal by MEK1/2 inhibition through U0126. Parallel experiments for identification of signaling in rat distal colon established MEK1/2 to be activated by a cytokine cocktail of TNFα, IFNγ, and IL-15, which were identified as the most important regulators in the upstream regulator analysis in LC.ConclusionsIn the sigmoid colon of patients with LC, the key effector cytokines TNFα, IFNγ, and IL-15 inhibited γ-ENaC upregulation in response to aldosterone through a MEK1/2-mediated pathway. This prevents ENaC to reach its maximum transport capacity and results in Na+ malabsorption which contributes to diarrhea.

Matrix metalloproteinases play an important role in extracellular matrix remodelling. It has been proposed that matrix metalloproteinase-9 (MMP-9) is involved in epithelial damage in ulcerative colitis (UC). However, to our knowledge, no data are available in terms of MMP-9 expression in microscopic colitis. Determination of mucosal protein expression levels of MMP-9 in lymphocytic colitis (LC), collagenous colitis (CC) and UC. MMP-9 immunohistochemical expressions were analyzed in paraffin-embedded tissue samples by immunohistochemistry including patients with LC, CC, UC, active diverticulitis, inactive diverticular disease and healthy control subjects. UC was also subgrouped according to the severity of inflammation. Immunostaining was determined semiquantitatively. Independent colonic biopsies from healthy and severe UC cases were used for gene expression analyses. For further comparison MMP-9 serum antigen levels were also determined in patients with UC and control patients without macroscopic or microscopic changes during colonoscopy. MMP-9 mucosal expression was significantly higher in UC (26.7 ± 19.5%) compared to LC (6.6 ± 9.3%), CC (6.4 ± 7.6%), active diverticulitis (5.33 ± 2.4%), inactive diverticular disease (5.0 ± 2.2%) and controls (6.3 ± 2.6%) ( P  < 0.001). The immunohistochemical expression of MMP-9 in LC and CC was similar as compared to controls. MMP-9 expression was significantly higher in each inflammatory group of UC compared to controls (mild: 11.0 ± 2.8%, moderate: 23.9 ± 3.7%, severe UC: 52.6 ± 3.9% and 6.3 ± 2.6%, respectively, P  < 0.005). The gene expression microarray data and RT-PCR results demonstrated a significantly higher expression of MMP-9 in severely active UC compared to healthy controls ( P  < 0.001). Significantly higher MMP-9 serum antigen concentrations were observed in UC patients compared with the control group ( P  < 0.05). MMP-9 seems to play no role in the inflammatory process of LC and CC. In contrast, the mucosal up-regulation of MMP-9 correlated with the severity of inflammation in UC. The increased MMP-9 expression could contribute to the severity of mucosal damage in active UC.

Microscopic colitis (MC) is comprised of two entities, lymphocytic (LC) and collagenous colitis. Up to 20% of patients with chronic diarrhea that have a normal appearing colonoscopy will be diagnosed with MC. Since MC was first described less than 40 years ago, little is known about the mechanisms involved in disease pathogenesis. Nonsteroidal anti-inflammatory drugs are associated with an increased risk of MC and some reports suggest a dysregulation in prostaglandin production. Recent genome wide screens have found an association between prostaglandin receptor EP4 expression and inflammatory bowel disease; however, EP4 expression has never been studied in MC. The aim of this study was to assess colonic mucosal inflammatory cytokine profiles in patients with LC and to assess expression of the prostaglandin receptor EP4. Colonic mucosal biopsies were obtained from patients undergoing colonoscopy for investigation of diarrhea and in those undergoing colon cancer screening. Following histological assessment, expression of cytokines and the prostaglandin receptor EP4 was analyzed using real-time reverse transcriptase-PCR and immunohistochemistry. Patients with LC had markedly increased mRNA expression for TNF-α, IFN-γ and IL-8 compared to normal controls (p<0.001). No significant differences were noted for IL-1β, IL-4, IL-10 or IL-12/23. Interestingly, those with LC had increased EP4 receptor expression, which positively correlated with increased TNF-α expression. This is the first report to demonstrate that LC is associated with increased TNF-α, INF-γ and IL-8 concurrent with a marked up-regulation of EP4. These findings add to our knowledge on the pathogenesis of LC and may give rise to possible new therapeutic and/or diagnostic tools in the management of MC.

Microscopic colitis (MC) is a relatively common cause of chronic watery diarrhea, especially in older persons. Associated symptoms, including abdominal pain and arthralgias, are common. The diagnosis is based upon characteristic histological findings in the presence of diarrhea. The two types of MC, collagenous and lymphocytic colitis, share similar clinical features, with the main difference being the presence or absence of a thickened subepithelial collagen band. There are several treatment options for patients with MC, although only budesonide has been well studied in multiple controlled clinical trials. This review will describe the clinical features, epidemiology, pathophysiology, diagnostic criteria, and treatment of patients with MC.

T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment 1 . The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction 2 . However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy. Tolerant T cells display characteristic patterns of gene expression and epigenetics that are distinct from other types of T cells and are orchestrated by the transcription factor NR4A1.

Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non-B cell functions. Here, we explored the function of this kinase in macrophages with studies of its regulation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. We found that bone marrow-derived macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome activity; this was also the case for BMDMs exposed to low doses of BTK inhibitors such as ibrutinib and for monocytes from patients with chronic lymphocytic leukemia being treated with ibrutinib. In mechanistic studies, we found that BTK bound to NLRP3 during the priming phase of inflammasome activation and, in doing so, inhibited LPS- and nigericin-induced assembly of the NLRP3 inflammasome during the activation phase of inflammasome activation. This inhibitory effect was caused by BTK inhibition of protein phosphatase 2A-mediated (PP2A-mediated) dephosphorylation of Ser5 in the pyrin domain of NLRP3. Finally, we show that BTK-deficient mice were subject to severe experimental colitis and that such colitis was normalized by administration of anti-IL-β or anakinra, an inhibitor of IL-1β signaling. Together, these studies strongly suggest that BTK functions as a physiologic inhibitor of NLRP3 inflammasome activation and explain why patients with XLA are prone to develop Crohn's disease.