Immunosuppressive effects of tacrolimus on macrophages ameliorate experimental colitis
Takuya YoshinoHiroshi NakaseYusuke HonzawaKayoko MatsumuraShuuji YamamotoYasuhiro TakedaSatoru UenoNorimitsu UzaSatohiro MasudaKen‐ichi InuiTsutomu Chiba
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Tacrolimus is a novel immunomodulator for inflammatory bowel diseases. Immunosuppressive effects of tacrolimus on T cells are well known; however, the effects of tacrolimus on macrophages remain unclear. The aim of this study was to investigate the effects of tacrolimus on activated macrophages and to examine its efficacy in murine colitis models.Proinflammatory cytokine production from lipopolysaccharide (LPS)-stimulated peritoneal macrophages of IL-10-knockout (KO) mice with and without tacrolimus was measured. We investigated the effects of tacrolimus on nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and caspase activation in macrophages and the induction of apoptosis in macrophages in vitro and examined the in vivo apoptotic effect of tacrolimus on colonic macrophages in IL-10-KO mice. We evaluated the effect of the rectal administration of tacrolimus on colonic inflammation in IL-10-KO mice and dextran sulfate sodium (DSS)-induced colitis in CB.17/SCID mice.Proinflammatory cytokine production from tacrolimus-treated macrophages was significantly lower than that from untreated cells. Tacrolimus suppressed LPS-induced activation of both NF-κB and MAPK in macrophages and induced apoptosis of macrophages via activation of caspases 3 and 9. Rectal administration of tacrolimus evoked apoptosis of colonic macrophages in IL-10-KO mice. Moreover, the rectal administration of tacrolimus ameliorated colitis in IL-10-KO mice and DSS-induced colitis in CB.17/SCID mice. Gene expression of inflammatory cytokines in colonic mucosa was significantly lower in tacrolimus-treated mice than in untreated mice.Tacrolimus suppresses the function of activated macrophages and promotes their apoptosis, which may lead to the amelioration of colonic inflammation.Keywords:
Inflammatory Bowel Diseases
Approximately 10% of patients with chronic diarrhea carry a diagnosis of microscopic colitis. The endoscopic appearance of both collagenous colitis and lymphocytic colitis may be normal; however, biopsies confirm the diagnosis. Available treatments include antidiarrheals, bismuth salicylate, and budesonide. Although most patients with fecal diversion may have endoscopic evidence of colitis, a much smaller percentage of patients are symptomatic. Some cases of diversion colitis respond to treatment with short-chain fatty acid enemas; however, return of the fecal stream is the most successful therapy. A variety of oral, intravenous, and per rectum chemicals may cause colitis; symptoms usually abate when chemical exposure is discontinued.
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Objective: Microscopic colitis is a chronic inflammatory disorder characterized by a triad of chronic diarrhea, endoscopy without significant abnormality, and distinct histopathological features.Histopathologically, microscopic colitis is divided into 3 subtypes; collagenous colitis, lymphocytic colitis, incomplete microscopic colitis.The main purpose of this study was to analyze the detailed clinicopathological parameters of microscopic colitis cases in the Turkish population. Material and Method:The clinicopathological parameters were evaluated in 53 microscopic colitis cases (37 collagenous colitis, 7 lymphocytic colitis, 9 incomplete microscopic colitis) diagnosed between 2010 and 2019.Results: All cases had lymphoplasmacytosis.The presence of ≥20 eosinophils/high power field in the lamina propria was remarkable in 75.7%, 57.1%, and 11.1% of collagenous colitis, lymphocytic colitis, and incomplete microscopic colitis cases, respectively.One of the striking findings was the presence of concomitant Celiac disease in 29% of the lymphocytic colitis cases.In terms of drug use, proton pump inhibitors and nonsteroidal anti-inflammatory drugs were the most commonly used drugs. Conclusion:The mean age in our series is lower than the literature and a distinct male predominance was observed in lymphocytic colitis and incomplete microscopic colitis, contrary to the literature.These suggest that susceptibility to microscopic colitis may differ between ethnic groups.The presence of overt lymphoplasmacytosis, eosinophilic infiltration and epithelial damage are the microscopic features which should alert the pathologist for the diagnosis of complete microscopic colitis.Given that microscopic colitis is a common treatable cause of chronic diarrhea, awareness of the aforementioned histopathological features is of utmost importance for accurate diagnosis and not to miss incomplete cases.
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Microscopic colitis is generally identified on random colon biopsies performed for chronic diarrhea, but rarely incidental polyps have histologic features of microscopic colitis. We compared patients with polypoid microscopic colitis to control patients with conventional polyps to determine the implications of polypoid microscopic colitis.
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Collagenous colitis and lymphocytic colitis, the two types of microscopic colitis, cause watery diarrhea. Budesonide, a glucocorticoid medication with limited systemic availability, is commonly used to treat these illnesses. Budesonide has proven efficacy in the induction of clinical remission in both collagenous colitis and lymphocytic colitis. Budesonide is effective as a maintenance drug for patients with collagenous colitis, but has not been studied for this indication in patients with lymphocytic colitis. This drug improves quality of life in patients while causing few mild adverse events. Budesonide is an effective treatment of microscopic colitis that is safe and well tolerated.
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Pseudomembranous colitis
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Summary Background Colitis is a significant complication of immune checkpoint inhibitors (ICI). Currently, clinical and endoscopic severity are used to guide therapy. Aims To investigate associations between clinical, endoscopic, and histological features with outcomes Methods We identified 149 patients from seven institutions with biopsy‐proven ICI colitis. Biopsies were evaluated for histological features including the Geboes score, and the Robarts histopathological index (RHI) was calculated. Clinical, endoscopic, and histological data were tested for associations with biological use and adverse colitis outcomes (biological‐refractory colitis, colectomy or death from colitis). Results Three mutually exclusive histological patterns were identified: acute colitis, chronic active colitis and microscopic colitis. Microscopic colitis was associated with older age (68.5 vs 61 years for acute colitis pattern, P = 0.02) and longer time to colitis (5.5 vs 3 months for the other patterns, P = 0.05). Biological use was associated with earlier time to colitis (2 vs 3 months, P = 0.04) and higher RHI (18 vs 12, P = 0.007). On multivariate analysis, RHI ≥14 was associated with biological use with an odds ratio of 4.5 (95% CI 1.4‐13.8; P = 0.01). Adverse colitis outcomes were associated with shorter time to colitis (2 vs 3 months, P = 0.008) and higher RHI (24 vs 14, P = 0.001). On multivariate analysis, RHI ≥24 was associated with adverse colitis outcomes with an odds ratio 9.5 (95% CI 2.1‐42.3 P = 0.003). Conclusion Histological activity as measured by RHI is the only factor independently associated with biological use and adverse colitis outcomes. Prospective studies are needed to validate these findings to determine if histological activity should be incorporated into therapeutic algorithms.
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Purpose of review Microscopic colitis is an inflammatory disease of the colon that presents as watery diarrhea with minimal to normal endoscopic changes on colonoscopy. It encompasses two common subtypes, lymphocytic colitis and collagenous colitis, which are both treated similarly. Immune checkpoint inhibitor colitis is among the most common immune-related adverse events. Endoscopic and histological findings range from normal colonic mucosa to inflammatory bowel like changes. This review article provides update in treatment and management of microscopic colitis and immune checkpoint inhibitor colitis (ICPi colitis). Recent findings Recent studies on microscopic colitis have focused on the successful use of immunomodulators such as biologics for treatment of budesonide refractory microscopic colitis cases. Microscopic colitis does not confer an added risk for colorectal cancer. With the increasing usage of immunotherapy agents, immune checkpoint inhibitor colitis is becoming more common. ICPi colitis can be successfully managed with steroids, with treatment stepped up to biologics for moderate to severe cases or for mild cases that do not respond to steroids. Immunotherapy agents can be carefully re-introduced in mild cases, after treatment of ICPi colitis. Summary Biologics can be used to treat budesonide refractory microscopic colitis. ICPi colitis can be managed with steroids and biologics in moderate to severe cases.
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Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestinal tract and is primarily comprised of Crohn's disease (CD) and ulcerative colitis (UC). Several murine models that include both chemical induced and genetic models have been developed that mimic some aspects of either CD or UC. These models have been instrumental in our understanding of IBD. Of the chemical induced colitis models, dextran sodium sulfate (DSS) induced colitis model is a relatively simple and very widely used model of experimental colitis.
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Purpose: To study the changing prevalence of microscopic colitis over the past 16 years. Methods: A retrospective computerized list of all patients with either lymphocytic colitis or collagenous colitis was obtained from our private community GI practice data base in Orlando, Fl from 1/90- 4/30/06. A breakdown was made of new diagnoses by year. Results: 92 cases of microscopic colitis were identified, 31 (35%) with collagenous colitis, 54 (57%) with lymphocytic colitis, and 7 (8%) with both lymphocytic and collagenous colitis. 14 had remission, then recrudescent disease, an average of 4 years apart, with a range of 1–8 years. There was a distinct change in the prevalence of microscopic colitis from 2004 onward. Whereas 1–5 cases were found annually from 1990 – 2003, (a mean of 3.4cases/year), in 2004 there were 15, in 2005 there were 20 patients, and in the first third of 2006 there were 10 patients. Patients were predominently female, comprising 78% of lymphocytic colitis, 90% of collageous colitis and 83% of those that had both lymphocytic and collagenous colitis. Conclusions: 1. There has been a marked increase in prevalence of microscopic colitis beginning in 2004 with a 200% increase, then a 25% rise in 2005 and a projected 50% rise in 2006. The reasons for this observation are as yet unknown. 2. Lymphocytic colitis is > 3 times as prevalent as collagenous colitis. 3. 15% (N = 14) of patients had remission and then recurrence of symptomatic colitis (8 patients with collagenous and 6 with lymphocytic colitis), an average of 4 years apart. 4. There is a marked female predominance in all forms of microscopic colitis.
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Animal models of experimentally induced inflammatory bowel disease (IBD) are useful for understanding more about the mechanistic basis of the disease, identifying new targets for therapeutic intervention, and testing novel therapeutics. This unit provides detailed protocols for five widely used mouse models of experimentally induced intestinal inflammation: chemical induction of colitis by dextran sodium sulfate (DSS), hapten-induced colitis via 2,4,6-trinitrobenzene sulfonic acid (TNBS), Helicobacter-induced colitis in mdr1a(-/-) mice, the CD4(+) CD45RB(hi) SCID transfer colitis model, and the IL-10(-/-) colitis model. © 2016 by John Wiley & Sons, Inc.
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