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    Current new challenges in the management of ulcerative colitis. Fukuda Tomohiro,Naganuma Makoto,Kanai Takanori Intestinal research Ulcerative colitis (UC) is a chronic inflammatory condition of the gastrointestinal tract. Although the cause of UC is postulated to be multifactorial in nature, including genetic predisposition, epithelial barrier defects, dysregulation of immune responses, and environmental factors, the specific pathogenesis of UC is still incompletely understood. In the treatment of UC so far, a method of suppressing immunity and treating it has been mainstream. Immunosuppressant drugs, including thiopurines (azathioprine or 6-mercaptopurine), anti-tumor necrosis factor-α (anti-TNF-α) antibody (infliximab and adalimumab), and calcineurin inhibitor, can be used in treat patients with corticosteroid-dependent and/or corticosteroid-refractory moderateto- severe UC. Recently, in addition to such a conventional therapeutic agent, golimumab, which is the first transgenic human monoclonal anti-TNF-α antibody to be fabricated, anti α-4/β-7 integrin antibody, and Janus kinase inhibitor have been reported to novel immunosuppressant therapy. Furthermore, other treatments with unique mechanisms different from immunosuppression, have also been suggested, including fecal microbiota transplantation and Indigo naturalis, which is a Chinese herbal medicine. We compared the features and efficacy of these new treatments. In this issue, the features and treatment options for these new treatments is reviewed. 10.5217/ir.2018.00126
    Pulmonary Arterial Hypertension Associated With the Chinese Herb Indigo Naturalis for Ulcerative Colitis: It May Be Reversible. Nishio Mayu,Hirooka Keiji,Doi Yasuji Gastroenterology 10.1053/j.gastro.2018.04.038
    Possible Association of Phlebitis-Induced Colitis With Indigo Naturalis. Matsuno Yuichi,Hirano Atsushi,Esaki Motohiro Gastroenterology 10.1053/j.gastro.2018.01.074
    Indigo naturalis-induced colitis. Yanai Shunichi,Nakamura Shotaro,Matsumoto Takayuki Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 10.1111/den.13226
    Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis. Naganuma Makoto,Sugimoto Shinya,Mitsuyama Keiichi,Kobayashi Taku,Yoshimura Naoki,Ohi Hidehisa,Tanaka Shinji,Andoh Akira,Ohmiya Naoki,Saigusa Keiichiro,Yamamoto Takayuki,Morohoshi Yuichi,Ichikawa Hitoshi,Matsuoka Katsuyoshi,Hisamatsu Tadakazu,Watanabe Kenji,Mizuno Shinta,Suda Wataru,Hattori Masahira,Fukuda Shinji,Hirayama Akiyoshi,Abe Takayuki,Watanabe Mamoru,Hibi Toshifumi,Suzuki Yasuo,Kanai Takanori, Gastroenterology BACKGROUND & AIMS:Indigo naturalis (IN) is a traditional Chinese medicine that contains ligands for the aryl hydrocarbon receptor and promotes regeneration of the mucosa by inducing production of interleukin 22. IN might induce mucosal healing in patients with ulcerative colitis (UC). We performed a randomized controlled trial to investigate the safety and efficacy of IN in patients with UC. METHODS:We performed a multicenter, double-blind trial evaluating the safety of 86 patients in Japan with active UC (Mayo scores of 6 or more), enrolled from March 30 through December 27, 2016. Patients were randomly assigned to groups and given a daily dose of 0.5, 1.0, or 2.0 g IN or placebo (1:1:1:1 ratio) for 8 weeks. The primary endpoint was the rate of clinical response at week 8, defined as a 3-point decrease in the Mayo score and a decrease of at least 30% from baseline, with a decrease of at least 1 point for the rectal bleeding subscore or absolute rectal bleeding score of 0-1. The main secondary endpoint was the rate of clinical remission at week 8, defined as a Mayo score or ≤2 and no subscores with a value >1. Mucosal healing was also assessed at week 8. RESULTS:The trial was terminated because of an external reason: a report of pulmonary arterial hypertension in a patient who used self-purchased IN for 6 months. In the intent-to-treat analysis, we observed a significant, dose-dependent linear trend in proportions of patients with clinical responses (13.6% with a clinical response to placebo; 69.6% to 0.5 g IN; 75.0% to 1.0 g IN; and 81.0% to 2.0 g IN) (Cochran-Armitage trend test P < .0001 compared with placebo). Proportions of patients in clinical remission at week 8 were significantly higher in the 1.0 g IN group (55.0%, P = .0004) and the 2.0 g IN group (38.1%, (P = .0093) than in the placebo group (4.5%). Proportions of patients with mucosal healing were 13.6% in the placebo group, 56.5% in the 0.5 g IN group, 60.0% in the 1.0 g IN group, and 47.6% in the 2.0 g IN group (P = .0278 compared with placebo). Although mild liver dysfunction was observed in 10 patients who received IN, no serious adverse events were observed. CONCLUSIONS:In a randomized, placebo-controlled trial, we found 8 weeks of IN (0.5-2.0 g per day) to be effective in inducing a clinical response in patients with UC. However, IN should not yet be used because of the potential for adverse effects, including pulmonary arterial hypertension. Clinical Trials Registry no: UMIN000021439 (http://www.umin.ac.jp/ctr/). 10.1053/j.gastro.2017.11.024
    Indigo Naturalis Ameliorates Oxazolone-Induced Dermatitis but Aggravates Colitis by Changing the Composition of Gut Microflora. Adachi Soichiro,Hoshi Namiko,Inoue Jun,Yasutomi Eiichiro,Otsuka Takafumi,Dhakhwa Ramesh,Wang Zi,Koo Yuna,Takamatsu Toshihiro,Matsumura Yuriko,Yamairi Haruka,Watanabe Daisuke,Ooi Makoto,Tanahashi Toshihito,Nishiumi Shin,Yoshida Masaru,Azuma Takeshi International archives of allergy and immunology BACKGROUND:Indigo naturalis (IND) is an herbal medicine that has been used as an anti-inflammatory agent to treat diseases including dermatitis and inflammatory bowel disease in China. However, the mechanism by which IND exerts its immunomodulatory effect is not well understood. METHODS:A murine model of dermatitis and inflammatory bowel disease, both induced by oxazolone (OXA), was treated with IND. The severity of dermatitis was evaluated based on ear thickness measurements and histological scoring. The severity of colitis was evaluated by measuring body weight, histological scoring, and endoscopic scoring. The expression of inflammatory cytokines in ear and colon tissue was evaluated using real-time PCR. 16S rRNA DNA sequencing of feces from OXA-induced colitis mice was performed before and after IND treatment. The effects of IND on OXA-induced colitis were also evaluated after depleting the gut flora with antibiotics to test whether alteration of the gut flora by IND influenced the course of intestinal inflammation in this model. RESULTS:IND treatment ameliorated OXA dermatitis with a reduction in IL-4 and eosinophil recruitment. However, OXA colitis was significantly aggravated in spite of a reduction in intestinal IL-13, a pivotal cytokine in the induction of the colitis. It was found that IND dramatically altered the gut flora and IND no longer exacerbated colitis when colitis was induced after gut flora depletion. CONCLUSIONS:Our data suggest that IND could modify the inflammatory immune response in multiple ways, either directly (i.e., modification of the allergic immune cell activity) or indirectly (i.e., alteration of commensal compositions). 10.1159/000471923
    Indigo Naturalis ameliorates murine dextran sodium sulfate-induced colitis via aryl hydrocarbon receptor activation. Kawai Shoichiro,Iijima Hideki,Shinzaki Shinichiro,Hiyama Satoshi,Yamaguchi Toshio,Araki Manabu,Iwatani Shuko,Shiraishi Eri,Mukai Akira,Inoue Takahiro,Hayashi Yoshito,Tsujii Masahiko,Motooka Daisuke,Nakamura Shota,Iida Tetsuya,Takehara Tetsuo Journal of gastroenterology BACKGROUND:Indigo Naturalis (IN) is used as a traditional herbal medicine for ulcerative colitis (UC). However, the mechanisms of action of IN have not been clarified. We aimed to evaluate the efficacy of IN for ameliorating colonic inflammation. We further investigated the mechanisms of action of IN. METHODS:Colitis severity was assessed in dextran sodium sulfate-induced colitis and trinitrobenzene sulfonic acid-induced colitis models with or without the oral administration of IN or indigo, which is a known major component of IN. Colonic lamina propria (LP) mononuclear cells isolated from IN-treated mice were analyzed with quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry. LP and splenic mononuclear cells cultured in vitro with IN or indigo were also analyzed. The role of the candidate receptor for indigo, the aryl hydrocarbon receptor (AhR), was analyzed using Ahr-deficient mice. RESULTS:Colitis severity was significantly ameliorated in the IN and indigo treatment groups compared with the control group. The mRNA expression levels of interleukin (Il)-10 and Il-22 in the LP lymphocytes were increased by IN treatment. The treatment of splenocytes with IN or indigo increased the expression of anti-inflammatory cytokines and resulted in the expansion of IL-10-producing CD4 T cells and IL-22-producing CD3RORγt cells, but not CD4Foxp3 regulatory T cells. The amelioration of colitis by IN or indigo was abrogated in Ahr-deficient mice, in association with diminished regulatory cytokine production. CONCLUSIONS:IN and indigo ameliorated murine colitis through AhR signaling activation, suggesting that AhR could be a promising therapeutic target for UC. 10.1007/s00535-016-1292-z
    Short-term and long-term outcomes of indigo naturalis treatment for inflammatory bowel disease. Matsuno Yuichi,Hirano Atsushi,Torisu Takehiro,Okamoto Yasuharu,Fuyuno Yuta,Fujioka Shin,Umeno Junji,Moriyama Tomohiko,Nagai Shuntaro,Hori Yoshifumi,Fujiwara Minako,Kitazono Takanari,Esaki Motohiro Journal of gastroenterology and hepatology BACKGROUND AND AIM:Indigo naturalis (IN) is a traditional Chinese herbal medicine reported to be effective in inducing remission in ulcerative colitis (UC). We conducted a retrospective observational study to investigate the efficacy and safety of IN for induction and maintenance therapy in patients with inflammatory bowel disease. METHODS:Data were collected from the electric medical records of patients with inflammatory bowel disease who had started IN treatment between March 2015 and April 2017 at Kyushu University Hospital. Clinical response and remission rates were assessed based on the clinical activity index determined by Rachmilewitz index or Crohn's disease (CD) activity index. Cumulative IN continuation rates were estimated using the Kaplan-Meier method. Overall adverse events (AEs) during follow-up were also analyzed. RESULTS:Seventeen UC patients and eight CD patients were enrolled. Clinical response and remission rates at week 8 were 94.1% and 88.2% in UC patients and 37.5% and 25.0% in CD patients, respectively. Clinical remission rates, as assessed through non-responders imputation analyses at weeks 52 and 104, were 76.4% and 70.4% in UC patients and 25.0% and 25.0% in CD patients, respectively. Ten patients (40%) experienced AEs during follow-up. Three patients (12%) experienced severe AEs, including acute colitis requiring hospitalization in two patients and acute colitis with intussusception requiring surgery in one patient. CONCLUSIONS:Indigo naturalis showed favorable therapeutic efficacy in UC, whereas its therapeutic efficacy in CD appeared to be modest. The risk of severe AEs should be recognized for IN treatment. 10.1111/jgh.14823
    Indigo Naturalis Suppresses Colonic Oxidative Stress and Th1/Th17 Responses of DSS-Induced Colitis in Mice. Xiao Hai-Tao,Peng Jiao,Wen Bo,Hu Dong-Dong,Hu Xiao-Peng,Shen Xiang-Chun,Liu Zhi-Gang,He Zhen-Dan,Bian Zhao-Xiang Oxidative medicine and cellular longevity Indigo naturalis (also known as Qing-dai, or QD), a traditional Chinese medicine, has been widely used as an anticolitis regimen in the clinical practice of Chinese medicine. However, the precise mechanisms behind its efficacy remain unknown. We investigated the protective effects and associated molecular mechanisms of QD in DSS-induced colitis in mice. We found that QD administration attenuated DSS-induced colon shortening, tissue damage, and the disease activity index during the onset of colitis. Moreover, QD administration significantly suppressed colonic MPO activity and increased the activities of colonic T-SOD, CAT, and GSH-Px, as well the expression of p-AMPK and Nrf-2 in colon tissues of colitic mice. In addition, QD was capable of reducing the colonic Th1 and Th17 cell cytokines, the frequencies of Th1 and Th17 cells, and the phosphorylation of p-STAT1 and p-STAT3 in the mesenteric lymph nodes of colitic mice. An assay showed that QD significantly suppressed the differentiation of Th1 and Th17 cells. These findings suggest that QD has the potential to alleviate experimental colitis by suppressing colonic oxidative stress and restraining colonic Th1/Th17 responses, which are associated with activating AMPK/Nrf-2 signals and inhibiting STAT1/STAT3 signals, respectively. These findings also support QD as an effective regimen in the treatment of IBD. 10.1155/2019/9480945
    Treatment with indigo naturalis for inflammatory bowel disease and other immune diseases. Naganuma Makoto Immunological medicine Indigo naturalis (IN) is a herbal medicine extracted from leaves and stems of plants and is a component of crude drugs used in China. Recently, IN was reported to be effective for treating (UC) and psoriasis. The mechanisms of IN for UC is not clear, but aryl hydrocarbon receptor ligand, the active components of IN, can promote mucosal healing by inducing the production of interleukin-22 from type-3 innate lymphocytes cells. Although IN is effective even for refractory cases, critical adverse effects including IN-induced colitis and pulmonary arterial hypertension should be concerned. Due to adverse effects of IN, topical treatment of IN is useful for distal UC as well as psoriasis to secure patients' safeties. Many refractory patients may be helped by IN if it becomes available in appropriate forms for clinical practice. In the near future, the mechanism that underlies the adverse effects of IN needs to be determined, and extraction of active ingredients with fewer side effects, investigated. 10.1080/25785826.2019.1599158
    Indole compounds may be promising medicines for ulcerative colitis. Sugimoto Shinya,Naganuma Makoto,Kanai Takanori Journal of gastroenterology Indole compounds are extracted from indigo plants and have been used as blue or purple dyes for hundreds of years. In traditional Chinese medicine, herbal agents in combination with Qing-Dai (also known as indigo naturalis) have been used to treat patients with ulcerative colitis (UC) and to remedy inflammatory conditions. Recent studies have noted that indole compounds can be biosynthesized from tryptophan metabolites produced by various enzymes derived from intestinal microbiota. In addition to their action on indole compounds, the intestinal microbiota produce various tryptophan metabolites that mediate critical functions through distinct pathways and enzymes. Furthermore, some indole compounds, such as indigo and indirubin, act as ligands for the aryl hydrocarbon receptor. This signaling pathway stimulates mucosal type 3 innate lymphoid cells to produce interleukin-22, which induces antimicrobial peptide and tight junction molecule production, suggesting a role for indole compounds during the mucosal healing process. Thus, indole compounds may represent a novel treatment strategy for UC patients. In this review, we describe the origin and function of this indole compound-containing Chinese herb, as well as the drug development of indole compounds. 10.1007/s00535-016-1220-2