Indigo naturalis has been considered mainly as an anti-fever and anti-inflammatory agent in Chinese textbooks since the tenth century, and has therefore been used to treat various inflammatory diseases for centuries [1, 2]. There have recently been studies suggesting the efficacy of indigo naturalis in patients with active ulcerative colitis [3,4,5,6]. The actual mechanisms of action of indigo naturalis still remain unknown, but one possible mechanism is that the active components of indigo naturalis can activate the aryl hydrocarbon receptor (AhR) by acting as an AhR ligand, and promote mucosal healing by the upregulation of interleukin-22 from innate lymphocytes cells that express AhR [2, 13].
The first study to evaluate the therapeutic efficacy of oral indigo naturalis in patients with intractable ulcerative colitis showed that clinical activity index scores and endoscopic grades decreased in the patients taking 2 g of indigo naturalis daily for 4 months [3]. In 2018, Naganuma et al. conducted a randomized controlled trial in Japan to investigate the clinical efficacy and safety of indigo naturalis in patients with moderate to severe ulcerative colitis [5]. Total of 86 patients were enrolled and randomized for each group, the results indicated that 8 weeks of oral indigo naturalis produced a significant clinical response in the indigo naturalis groups. The response rates at week 8 were 69.6% (16/23, 0.5 g/day group), 75.0% (15/20, 1.0 g/day group), 81.0% (17/21, 2.0 g/day group), and 13.6% (3/22, placebo group), respectively. However, this trial was terminated early because a case of pulmonary arterial hypertension was reported in a patient with ulcerative colitis who had used self-purchased indigo naturalis outside of this study [5, 7].
Some patients have recently started using indigo naturalis obtained over the Internet, but these patients do not always receive sufficient information regarding the adverse effects caused by indigo naturalis. Common mild adverse events of indigo naturalis include liver dysfunction, headache, epigastric or abdominal pain, and nausea [3,4,5,6]. Rare severe adverse events associated with indigo naturalis have included indigo naturalis-induced pulmonary arterial hypertension and acute colitis [7,8,9,10,11,12]. Nishio et al. reported the development of pulmonary arterial hypertension in a patient with ulcerative colitis who was taking indigo naturalis [7]. An experimental study suggested that a possible mechanism for triggering indigo naturalis-induced pulmonary arterial hypertension involves nitric oxide synthase inhibition and endothelial dysfunction in the pulmonary artery [8]. Recently, indigo naturalis-induced colitis has also been reported. A prospective study about clinical efficacy and safety of indigo naturalis in patients with ulcerative colitis described right-side colitis of obscure origin [4]. Kondo et al. also reported two patients with ulcerative colitis who developed colitis with wall thickening and edematous changes during oral administration of indigo naturalis [10].. In addition, Matsuno et al. reported two patients who developed phlebitis-induced colitis caused by indigo naturalis. They suggested that indigo naturalis might affect the venous system and cause adverse events such as phlebitis-induced colitis or pulmonary artery hypertension [12].
We herein described a case of ischemic colitis in a patient with ulcerative colitis after taking indigo naturalis. About 30 to 50% of patients with inflammatory bowel disease are known to use complementary and alternative medicines [14]. Thus, detailed medical history is needed when treating patients with inflammatory bowel disease. Indigo naturalis seems to be another therapeutic candidate for managing ulcerative colitis, but more research is needed to determine the optimal dose, standardized drug development, and indications for treatment. In addition, physicians should be aware of the possible risks of severe adverse events. Further basic studies and clinical investigation are needed to clarify the mechanisms of these possible adverse events of indigo naturalis.