Journal Excerpt: Clinical Application of Indigo Naturalis
Indigo naturalis (IN), also known as qing dai, has a long history of use in Chinese medicine. This article examines evidence for the safety and efficacy of IN administration for the treatment of inflammatory bowel disease (IBD). IN appears to be a very effective induction therapy for patients with IBD, particularly those with ulcerative colitis (UC), though the likelihood of adverse events is significant and seems to increase with treatment length. Additional research shows a potential benefit of IN as a maintenance therapy.
Indigo naturalis is an ingredient in many Chinese herbal medicine formulas (notably xilei-san), and the first written record of its use comes from approximately 1,400 years ago, during the Tang Dynasty. To make IN, a rich blue pigment is extracted from dried foam from the fermented leaves and stems of several plants, including Isatis indigotica,1 Indigofera tinctoria, and Strobilanthes cusia.2 These plants have been used as blue dyes for thousands of years; and when IN has been used for UC, it has, as reported in 1 case report, induced a blue coloration of polypoid healing artifacts.3 Indigo and indirubin are the main active constituents responsible for IN’s healing properties. Considered to be energetically cooling in nature, IN has been traditionally used for “heat” conditions as an antipyretic, anti-inflammatory, and hemostatic remedy. Since the 1970s, IN has been widely used in Japan and South Korea to treat many gastrointestinal and skin conditions.4 A growing body of evidence, including human studies, supports the use of IN for the treatment of IBD, particularly ulcerative colitis.
Ulcerative colitis is a chronic condition characterized by relapsing and remitting inflammation of the mucosal layer of the colon.2,5 The goal of treatment is to achieve remission through mucosal healing and prevent the need for surgical removal of the affected tissue.2 Currently, conventional treatments rely on pharmaceuticals, including 5-aminosalicylic acid (5-ASA) preparations, steroids, immunomodulators, and biologics.6 Although the number of pharmaceutical options has increased, UC treatment outcomes remain poor. Over half of patients using first-line 5-ASA drugs as a solo initial therapy fail to enter remission,7 requiring escalation of therapy. Biologics have decreased UC patients’ lifetime risk of colectomy from ~25% to ~15%,8 but few patients maintain long-term remission despite biologic use,9 and biologics come with their own risks. Three-quarters of IBD patients on the most common biologics experience adverse events in the first year of therapy, and 15% to 20% of those adverse events are severe.10 With judicious use, IN is a potentially safe and effective treatment for the induction of and, possibly in some circumstances, for the maintenance of remission in UC.
Since 2013, several retrospective and open-label prospective studies have demonstrated the effectiveness of IN oral administration for the treatment of ulcerative colitis,2,5,11-13 all in Japanese populations. The first and largest double-blind study evaluating the safety and efficacy of oral IN for the treatment of UC was conducted in 2016 by Naganuma et al, and it was dubbed the INDIGO study.14 Patients were divided into 3 dosage groups (0.5, 1.0, or 2.0 g/day) or a placebo group and treated for 8 weeks. This study revealed a dose-dependent effect on clinical remission and mucosal healing. Clinical remission was substantially and significantly higher in the groups receiving 1.0 g daily (55%) and 2.0 g daily (38.1%) than in the placebo group (4.5%). Mucosal healing was achieved in 56.5% of patients in the 0.5 g group, 60.0% of patients in the 1.0 g group, 47.6% of patients in the 2.0 g group, and only 13.6% in the placebo group. No serious adverse effects were observed in this trial; however, the trial was discontinued because of
The same team performed a post hoc analysis of the INDIGO study to determine the efficacy of IN in patients with treatment-refractory UC; this included patients with steroid-dependent disease, previous use of anti-TNF-α (tumor necrosis factor alpha) drugs, concomitant use of immunomodulators, or a Mayo score of 9 to 11 at baseline. The clinical response of refractory UC patients was significantly higher in the IN group than in the placebo group; 77% of patients with steroid-dependent disease, 77.5% of patients with previous use of anti-TNF-α drugs, 70.8% of patients with concomitant use of immunomodulators (thiopurine), and 76.7% of patients with a Mayo score of 9 to 11 at baseline achieved a clinical response. No patients in the placebo group showed clinical response. In the steroid-dependent group, 50% of the patients showed mucosal healing vs 0% in the placebo group.16
An open-label, dose-escalation study in 2021 found a similar efficacy of oral IN for treatment-refractory UC. The study followed 11 treatment-refractory patients, 10 of whom achieved a significant clinical response by 8 weeks, as assessed by the Mayo score, a standardized disease activity index for UC. Three patients achieved clinical remission.5
A 2020 randomized, controlled trial (RCT) evaluated the efficacy and safety of short-term oral IN administration in patients with mild-to-moderately active UC. After 2 weeks of treatment, the placebo group showed no change in score, while the intervention group improved significantly (Lichtiger Index scores decreasing from 9.04 to 4.48). Clinical response was seen in 60.9% of the intervention group, compared to 26.3% in the placebo group. Only mild headaches were reported in the intervention group with no serious adverse effects.6
One open-label study followed 33 patients with moderate-to-severe UC, as determined by the clinical activity index (CAI), over 52 weeks, evaluating the efficacy and safety of IN as a possible maintenance therapy. Patients received doses of 2 g/day (1 g orally twice daily). Clinical remission was observed in 67%, 75%, and 73% of the patients at weeks 4, 8, and 52, respectively; however, 17 patients (51.5%) experienced adverse events, 4 of which (12.1%) were considered severe. This rate of SAEs in maintenance therapy is comparable to the rates observed with the use of biologics.10 Although treatment for UC with IN for a year was effective, indicating its potential benefit as a maintenance therapy, side effects were seen at a significantly higher rate than shorter-term studies.2
One retrospective study has shown IN to be beneficial in the treatment of Crohn disease (CD). However, the benefit appeared to be modest in comparison to UC, and the sample size was small; only 8 patients with CD were enrolled. After 8 weeks of treatment, 37.5% of patients achieved clinical response, and 25.0% achieved clinical remission.17
No RCTs have been conducted in pediatric populations. In 2021, 29 high-volume centers treating pediatric IBD patients in Japan completed a survey and systematic review to determine IN’s efficacy and safety in the pediatric population. Of the 107 pediatric patients reported to have used IN, 80.2% achieved clinical remission within 6 months. Of these patients, 64.1% had no relapses, whereas 31.5% experienced only 1 to 2 relapses annually. The adverse event rate was comparable to that in the adult group (8%), with 1 pediatric patient developing pulmonary arterial hypertension, an SAE. However, no dosages were reported.18
One open-label trial studied the effects of 50 mg IN suppositories in 10 patients with active UC with moderate-to-severe inflammation in the rectum to the sigmoid colon. IN was found to promote mucosal healing, and 3 patients achieved clinical remission; however, the efficacy was dependent on severity. Patients with less severe proctitis and colitis were more likely to respond. Common side effects of oral administration, such as headache, epigastric/abdominal pain, and nausea, were not observed.19
Xilei-san (which is about 1/3 IN) has been studied in RCTs for patients with intractable ulcerative proctitis, both in: 1) 100-mg suppository form compared to placebo20 and 2) as a rectal suspension (1 gram of xilei-san in 60 mL fluid) compared to rectal dexamethasone.21 Xilei-san was found to be dramatically superior to placebo and noninferior to dexamethasone at inducing remission, with fewer adverse events than dexamethasone and no SAEs.
Editor's note: This article was originally published in Natural Medicine Journal. Click here to read the complete original article with references.
- Feng J, Huang D, Yang Y, et al. Isatis indigotica: from (ethno) botany, biochemistry to synthetic biology. Mol Horticulture. 2021;1(1):17.
- Matsuno Y, Torisu T, Umeno J, et al. One-year clinical efficacy and safety of indigo naturalis for active ulcerative colitis: a real-world prospective study. Intest Res. 2022;20(2):260-268.
- Kato J, Yoshida T, Niwa T. Blue polypoid colorectal lesions in a woman with ulcerative colitis taking qing-dai. Clin Gastroenterol Hepatol. 2016;14(8):A32.
- Sun Q, Leng J, Tang L, Wang L, Fu C. A comprehensive review of the chemistry, pharmacokinetics, pharmacology, clinical applications, adverse events, and quality control of indigo naturalis. Front Pharmacol. 2021;12:664022.
- Saiki JP, Andreasson JO, Grimes KV, et al. Treatment-refractory ulcerative colitis responsive to indigo naturalis. BMJ Open Gastroenterol. 2021;8(1):e000813.
- Uchiyama K, Takami S, Suzuki H, et al. Efficacy and safety of short-term therapy with indigo naturalis for ulcerative colitis: an investigator-initiated multicenter double-blind clinical trial. PLoS One. 2020;15(11):e0241337.
- Murray A, Nguyen TM, Parker CE, Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2020;8(8):CD000543.
- Barnes EL, Jiang Y, Kappelman MD, et al. Decreasing colectomy rate for ulcerative colitis in the United States between 2007 and 2016: a time trend analysis. Inflamm Bowel Dis. 2020;26(8):1225-1231.
- Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723-1736.
- Peyrin-Biroulet L, Arkkila P, Armuzzi A, et al. Comparative efficacy and safety of infliximab and vedolizumab therapy in patients with inflammatory bowel disease: a systematic review and meta-analysis. BMC Gastroenterol. 2022;22(1):291.
- Urushikubo J, Yanai S, Nakamura S, et al. Efficacy of indigo naturalis therapy for ulcerative colitis: a case series. Intern Med. 2019;58(16):2299-2304.
- Suzuki H, Kaneko T, Mizokami Y, et al. Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis. World J Gastroenterol. 2013;19(17):2718-2722.
- Sugimoto S, Naganuma M, Kiyohara H, et al. Clinical efficacy and safety of oral qing-dai in patients with ulcerative colitis: a single-center open-label prospective study. Digestion. 2016;93(3):193-201.
- Naganuma M, Sugimoto S, Mitsuyama K, et al. Efficacy of indigo naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis. Gastroenterol. 2018;154(4):935-947.
- Nishio M, Hirooka K, Doi Y. Chinese herbal drug natural indigo may cause pulmonary artery hypertension. Eur Heart J. 2016;37(25):1992.
- Naganuma M, Sugimoto S, Fukuda T, et al. Indigo naturalis is effective even in treatment-refractory patients with ulcerative colitis: a post hoc analysis from the INDIGO study. J Gastroenterol. 2020;55(2):169-180.
- Matsuno Y, Hirano A, Torisu T, et al. Short-term and long-term outcomes of indigo naturalis treatment for inflammatory bowel disease. J Gastroenterol Hepatol. 2020;35(3):412-417.
- Kudo T, Jimbo K, Shimizu H, et al. Qing-Dai for pediatric ulcerative colitis multicenter survey and systematic review. Pediatr Int. 2022;64(1):e15113.
- Yoshimatsu Y, Naganuma M, Sugimoto S, et al. Development of an indigo naturalis suppository for topical induction therapy in patients with ulcerative colitis. Digestion. 2020;101(4):492-498.
- Fukunaga K, Ohda Y, Hida N, et al. Placebo controlled evaluation of Xilei San, a herbal preparation in patients with intractable ulcerative proctitis. J Gastroenterol Hepatol. 2012;27(12):1808-1815.
- Zhang F, Li Y, Xu F, Chu Y, Zhao W. Comparison of Xilei-san, a Chinese herbal medicine, and dexamethasone in mild/moderate ulcerative proctitis: a double-blind randomized clinical trial. J Altern Complement Med. 2013;19(10):838-842.