Background and study aims: It has been suggested that smoking may be associated with microscopic colitis (MC) in some studies; however, there are conflicting results in the current literature with many of these studies having significant limitations. Our study aims to offer a meta-analysis evaluating the association between MC, including both its subtypes, and smoking. Patients and methods: A systemic review was conducted in PUBMED, Embase, PubMed Central, and ScienceDirect databases from inception through December 2019. Effect estimates from the individual studies were extracted and combined using the random effect, generic inverse variance method of DerSimonian and Laird and a pooled odds ratio (OR) was calculated. Forest plots were generated, and publication bias was assessed for using conventional techniques. Results: Eight observation studies with a total of 1461 patients with MC were included in this study, 383 of whom were active smokers (26.2%). Current smoking was significantly associated with MC (OR 3.58, 95% CI, 2.51–5.11), lymphocytic colitis (LC) (OR 3.64, 95% CI, 2.46–5.38), and collagenous colitis (CC) (OR 4.43, 95% CI, 2.68–7.32). Gender-specific subgroup analysis showed a significant association with smoking was found for CC in men (OR 4.53, 95% CI, 1.59–12.85), CC in women (OR 3.27, 95% CI, 2.35–4.54), LC in women (OR 2.27, 95% CI, 1.27–4.06) and MC in women (OR 2.93, 95% CI, 2.09–4.10). We found no publication bias as assessed by the funnel plots and Egger's regression asymmetry test. Conclusion: Our meta-analysis found a statistically significant association between smoking and both subtypes of MC.

Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC) is a common cause of chronic watery diarrhea. The diagnosis relies on typical histopathological changes observed upon microscopic examination. The studies in this thesis investigated innate and adaptive immune responses in the colonic mucosa of MC patients, also comparing patients with active disease (CC and LC) and histopathologically in remission (CC/LC-HR). We first analyzed expression of interleukin-1/Toll-like receptor (IL-1/TLR) signaling regulators in MC patients (Paper I). Our results showed enhanced IRAK-M, microRNA-146a, -155 and -21 expressions, whereas IL-37 gene expression was reduced in CC and LC patients as compared to non-inflamed controls. These results suggest different pathophysiological mechanisms in MC patients. The mixed inflammatory cell infiltrations seen in the lamina propria of MC patients might be a result of dysregulated expression of chemotactic mediators. In Paper II, we showed that MC patients display mainly an increased expression of chemokines and chemokine receptors in active disease as compared to noninflamed controls. In Paper III, we examined if the decreased IL-37 expression seen in Paper I could mediate the upregulation of chemokines seen in Paper II. We showed that a relatively small reduction in the ability of epithelial cells to produce IL-37 results in mainly increased chemokine expressions in a pattern similar to the findings in Paper II. In order to understand the nature of infiltrating T cells commonly observed in MC patients, we analyzed the T cell receptor (TCR) β chains in colonic biopsies of MC patients (Paper IV). Our results showed significant differences in TCRβ repertoire, which suggests selectively expanded T cell clones in active MC and histopathologically in remission patients. Altogether, these results i) increase the knowledge of MC pathogenesis by showing changes in TLR signaling regulators, enhanced chemokine and their receptor expressions involved in a mixed immune cell infiltrations and selectively expanded T cell clones in CC and LC patients, as well as in histopathological remission ii) might potentially increase the possibility of more target-specific therapies based on IL-37 induction, chemokines or chemokine receptor inhibitions, or hindering T cell infiltration according to TCR clonality.

Abstract The aims of this study were to investigate the clinical features, the endoscopic and histological abnormalities of ileocolonic and gastroduodenal mucosa and immunogenetic background of microscopic colitis (MC) and its subtypes collagenous colitis (CC) and lymphocytic colitis (LC). 30 patients with CC and 54 with LC were examined with different control groups used according to the study. The mean age at diagnosis was in the sixties in both CC and LC, with a female preponderance in both Autoimmune conditions such as celiac diseased (CD) were common in MC. Bronchial asthma associated with LC. Lactose intolerance associated with MC but colonic diverticulosis was rare. Ileal histological changes were common in MC. Focal gastritis did not associate with MC. Lymphocytic gastritis was found only in LC. Gastric endoscopic erosions were more prevalent in CC than in LC. The age at diagnosis of MC was higher in H. pylori positive than negative patients. The patients with MC had shorter duodenal villi than controls even when patients with CD were excluded. HLA-DR3-DQ2 haplotype and TNF2 allele carriage were more frequent in patients with MC compared to controls. The genotype GG of IL-6-174 was more prevalent in MC compared to the controls. IL-6 genotype did not associate with the serum IL-6 concentration. The concentration of IL-6 was higher in patients with CC than in LC. In conclusion, in addition to colonic typical inflammation, histological abnormalities were detected also in gastric, duodenal and ileal mucosa. CD was common in MC, but there was no association with specific types of gastritis. HLA association was found in MC. Polymorphism in the proinflammatory IL-6-174 gene displayed a possible association with MC. Although CC and LC share many clinical features, the differences in the occurrence of immune conditions, gastric abnormalities and IL-6 response point to differences in their pathogenesis. / Tiivistelmä Tutkimuksen tavoitteena oli tutkia mikroskooppisen koliitin sekä sen alaryhmien, kollageenikoliitin ja lymfosyyttisen koliitin kliinisiä piirteitä, mahalaukun ja ohutsuolen limakalvon muutoksia sekä immunogeneettistä taustaa. Tutkimukseen osallistui 30 kollageeni- ja 54 lymfosyyttikoliittipotilasta sekä verrokkeja. Sekä kollageenikoliitti että lymfosyyttinen koliitti diagnosoitiin keskimäärin 50–60 v iässä, ja molemmissa tautiryhmissä naisia oli enemmän kuin miehiä. Autoimmuunisairaudet kuten keliakia olivat yleisiä liitännäissairauksia. Astmaa esiintyi lymfosyyttistä koliittia sairastavilla verrokkeja enemmän. Laktoosi-intoleranssi oli yleistä, mutta paksusuolen divertikuloosia oli harvoin mikroskooppista koliittia sairastavilla potilailla. Ileumin muutokset olivat yleisiä. Mikroskooppinen koliitti ei assosioitunut fokaaliseen gastriittiin. Lymfosyyttigastriittia todettiin vain lymfosyyttisessä koliitissa. Mahalaukun eroosioita esiintyi enemmän kollageenikoliitissa kuin lymfosyyttisessa koliitissa. Mikroskooppinen koliitti ilmeni iäkkäämpänä niillä, joilla todettiin helikobakteeri. Pohjukaissuolen suolinukka oli keliakiasta riippumatta matalampaa kuin verrokeilla. HLA-DR3-DQ2 haplotyyppiä, TNF-2 alleelia ja IL-6-174-GG genotyyppiä esiintyi enemmmän mikroskooppista koliittia sairastavilla potilailla kuin verrokeilla. IL-6 genotyyppi ei vaikuttanut seerumin IL-6-pitoisuuteen. IL-6 pitoisuus oli korkeampi kollageenikoliitissa kuin lymfosyyttisessä koliitissa. Havainnot osoittavat, että mikroskooppisessa koliitissa limakalvomuutoksia on paksusuolen lisäksi myös muualla mahasuolikanavassa. Keliakia on tavallinen liitännäistauti. HLA-DR3-DQ2 on yleinen mikroskooppista koliittia sairastavilla myös ilman keliakiaa. IL-6-174-GG genotyypin yleisyys viittaa siihen, että tämä polymorfismi saattaa altistaa mikroskooppiselle koliitille. Vaikka kollageenikoliitti ja lymfosyyttinen koliitti ovat kliinisesti samankaltaisia sairauksia, erot tautiassosiaatioissa, mahan limakalvon muutoksissa ja seerumin IL-6-tasoissa viittaavat erilaisiin syntymekanismeihin.