Background and Aims: Familial mediterranean fever (FMF), an autoinflammatory disease, is characterized by periodic fever and serositis. An MEFV gene mutation has been identified as the cause of FMF. Recently, patients with MEFV gene mutations and chronic gastrointestinal mucosal inflammation mimicking inflammatory bowel disease (IBD) have been reported. In this retrospective study, we analyzed the clinical characteristics of patients with IBD unclassified (IBDU) with MEFV gene mutations. Methods: MEFV gene analysis was performed on 8 patients with IBDU among 710 patients with IBD who had been treated at Kyorin University Hospital from April 2016 to December 2018. Clinical manifestations, endoscopic findings, and serological markers were also analyzed. Results: The average of the 8 patients with IBDU (3 men, 5 women) was 32.7 ± 6.4 years (range 26-76 years). Their symptoms comprised diarrhea (n = 8, 100%), hematochezia (n = 3, 37.5%), abdominal pain (n = 3, 37.5%), high fever (n = 2, 16.5%), and other periodic symptoms (n = 2, 16.5%). MEFV gene mutation was confirmed in 4/8 of these patients. Colonoscopy showed various mucosal lesions, rectal sparing, right side dominant colitis, pseudopolyposis, and granular protrusions. Colchicine was administered to 5 of the 8 patients (4 with and 1 without MEFV mutation) who were resistant to conventional treatment for ulcerative colitis. Clinical and endoscopic improvement was observed in all of 5 patients treated with colchicine. Conclusions: Some patients diagnosed as having IBDU have enterocolitis related to MEFV gene mutation and respond to colchicine therapy.
Background Fecal biomarkers are considered to be useful surrogate markers for endoscopic activity. Given the mechanisms of fecal biomarkers, we hypothesized that the extent of ulcerative colitis (UC; pancolitis, left-sided colitis, and proctitis) could affect the usefulness of fecal biomarkers for assessing endoscopic and clinical disease activity; however, few studies have evaluated the utility of fecal biomarkers in the disease extent of UC. Methods Fecal calprotectin, a fecal immunochemical test for hemoglobin, and fecal lactoferrin were used as fecal biomarkers. UC patients, who underwent colonoscopy within 30 days of the fecal biomarker test, participated in this observational study. Clinical and endoscopic disease activity was assessed using the Lichtiger Index and Mayo endoscopic subscore (MES), respectively. Results A total of 162 colonoscopies were performed on 133 UC patients. A correlation analysis between each biomarker and the MES for each disease-extent subgroup showed a decreased correlation in the proctitis compared with the other groups. With the exception of proctitis, it was possible to distinguish between MES 0 and MES ≥ 1 with high area-under-the-curve values for fecal calprotectin and fecal lactoferrin. The fecal immunochemical test for hemoglobin was superior at discriminating MES 0 for proctitis. Conclusions For the practical application of fecal biomarkers for UC patients, it is necessary to consider disease extent before use. In particular, patients with proctitis exhibit a low correlation between stool biomarkers and endoscopic findings. The usefulness of these biomarkers for endoscopic remission is reduced, except for the fecal immunochemical test for hemoglobin.
Although many therapeutic options are available for inflammatory bowel disease (IBD), 5-aminosalicylic acid (5-ASA) is still the key medication, particularly for ulcerative colitis (UC). However, the mechanism of action of 5-ASA remains unclear. The intestinal microbiota plays an important role in the pathophysiology of IBD, and we hypothesized that 5-ASA alters the intestinal microbiota, which promotes the anti-inflammatory effect of 5-ASA. Because intestinal inflammation affects the gut microbiota and 5-ASA can change the severity of inflammation, assessing the impact of inflammation and 5-ASA on the gut microbiota is not feasible in a clinical study of patients with UC. Therefore, we undertook a translational study to demonstrate a causal link between 5-ASA administration and alterations of the intestinal microbiota. Furthermore, by rigorously controlling environmental confounders and excluding the effect of 5-ASA itself with a vertical transmission model, we observed that the gut microbiota altered by 5-ASA affected host mucosal immunity and decreased susceptibility to dextran sulfate sodium-induce colitis. Although the potential intergenerational transmission of epigenetic changes needs to be considered in this study, these findings suggested that alterations in the intestinal microbiota induced by 5-ASA directed the host immune system towards an anti-inflammatory state, which underlies the mechanism of 5-ASA efficacy.
Background 5-aminosalicylic acid (5-ASA) is widely used for the treatment of inflammatory bowel disease (IBD), while its anti-inflammatory mechanisms remain controversial. The intestinal microbiota plays a certain role in the pathogenesis of IBD. We hypothesised that 5-ASA exerts anti-inflammatory effects by altering the gut microbiota. Elucidating the effects of 5-ASA on gut microbiota and its contribution to anti-inflammatory effects can lead to the development of effective and economical IBD medications. Methods Specific-pathogen-free (SPF) mice were orally administered 5-ASA for 4 weeks. The fecal bacterial compositions were examined with 16S rRNA gene amplicon sequencing analysis in mice of the 5-ASA-treatment group (5-ASA group) and no-treatment group (NT group). The immune profiles of the colonic mucosa were assessed. The feces from female mice in both groups were gavaged into germ-free (GF) female mice in separated isolators. In each isolator, these female mice (5-ASA dams and NT dams) were mated with GF male mice. The populations of CD4+ T cells in mesenteric lymph nodes (MLN) and colonic mucosal immune profiles were analysed in their pups. The pups were used for the dextran sulfate sodium (DSS)-induced colitis model to evaluate the anti-inflammatory effects of the gut microbiota altered by 5-ASA. Results The fecal bacterial compositions changed with 5-ASA treatment over time in SPF mice. At the genus level, the relative abundance of Allobaculum increased significantly in the females of the 5-ASA group compared to the NT group (corrected p < 0.05). The same tendency was observed in male counterparts. The mRNA expression of IL-10 and IL-22 in the colonic mucosa increased significantly in mice of the 5-ASA group compared to their counterparts (p < 0.05 in both sexes). In each isolator, the fecal bacterial compositions were similar between the dams and pups, suggesting that the gut microbiota was vertically transmitted from the dams to the pups in each group. CD4+RORgt+ T cells increased in MLN in the pups of 5-ASA dams compared to those of NT dams (p < 0.01). The mRNA expression of TGF-b, claudin-2 and claudin-3 in the colonic mucosa increased significantly (p < 0.001). The colonic inflammation induced by DSS was milder in 5-ASA pups compared to NT pups (Figure 1). Conclusion Orally-administered 5-ASA altered the intestinal microbiota affecting the host immune system and leading to less susceptibility to DSS-induced colitis. Alteration of gut microbiota could be a part of the anti-inflammatory mechanisms of 5-ASA.
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