Reviewing not Homer’s Iliad, but “Kai Bao Ben Cao”: indigo dye—the past, present, and future

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Intest Res. 2023;21(2):174-176
Publication date (electronic) : 2022 June 14
doi : https://doi.org/10.5217/ir.2022.00018
1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
2Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan
Correspondence to Takanori Kanai, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel: +81-3-5843-7090, Fax: +81-3-3353-6247, E-mail: takagast@keio.jp
Received 2022 February 7; Revised 2022 April 19; Accepted 2022 April 23.

Heinrich Schliemann read Homer’s Iliad and believed in the story of Troy. He was a successful businessman in the United States, cornering the market in indigo dye. He first traveled to China and Japan in 1865 after his lucrative career in the dye business. Subsequently, he found the Troy site while visiting sites in Greece, where he established himself as a pioneer in the field of archeology 6 years after traveling through Eastern countries. If he could have read the old literature “Kai Bao Ben Cao” and believed in the importance of the indigo dye for ulcerative colitis (UC), he would have become a pioneer in the field of medicine. Or, in the present, we might be the second Schliemann in the field of UC.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that provides a response for toxic effects, such as dioxin. Recently, specific dietary compounds present in vegetables and metabolites digested by microbes act as the AhR ligand, and they promote intestine immune homeostasis through AhR signaling [1-4]. AhR is expressed by several kinds of immune cells [5-10], epithelial cells [11], and neurons [12] in the intestine. AhR enters the nucleus by binding to its ligand and forms a heterodimer with the AhR nuclear translocator, which binds to the xenobiotic response element on DNA and triggers the transcriptional activation of target genes, such as drug-metabolizing enzymes [9,13].

UC is a chronic intestinal disease, which has increased worldwide over the last few decades, especially in Asia [14,15]. Western drugs, such as anti-tumor necrosis factor α and anti-IL-12/23 p40 antibody that provide systemic immunity, are currently used for UC [16-22]. However, the old Chinese literature “Kai Bao Ben Cao” reported that an indigo compound was used for patients who expressed chronic blood stools around 900 AD.

Because we believed in the literature of the past like Schliemann, and Suzuki et al. [23] reported the retrospective study about the efficacy of indigo naturalis (IN), which mainly contains AhR ligands, on patients with UC in Japan, we conducted prospective clinical trial of IN for them [24], followed by a randomized controlled trial (INDIGO study) [25]. As a result, we demonstrated that 8 weeks of IN is safe and effective in patients with UC, even if in treatment refractory patients [25,26]. Recent Western technologies revealed that AhR ligands lead to innovative treatments that promote the regeneration of mucosal epithelial cells [27,28]. Of note, IN causes adverse effects, such as headaches, gastrointestinal symptoms, mild liver dysfunction, nonspecific enteritis, bowel intussusception, and pulmonary arterial hypertension [29-31]. As a consequence, inspired by the anti-colitic effect of the AhR ligand, both clinical and basic research studies on the efficacy and safety of IN are being conducted [24,32-34]. Based on these verifications, we are preparing a consensus statement on the appropriate use of IN based on the fact-finding survey, while developing indigo containing capsule that disintegrates in the large intestine for the clinical trial (first in human) in order to reduce side effects because indigo is extracted as the active ingredient of IN [34] and is assumed to be absorbed in the small intestine due to its insolubility.

Safe AhR ligand-based drugs will become a novel treatment strategy for inflammatory bowel diseases in the near future. Although the precise mechanism is still unknown, new technology will illuminate the truth in the ancient documents.

Notes

Funding Source

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Data Availability Statement

Not applicable.

Author Contributions

Conceptualization: all authors. Project administration: Kanai T. Resources: all authors. Software: Yoshimatsu Y. Supervision: Sujino T. Validation: Kanai T. Writing original draft: Yoshimatsu Y. Writing review & editing: Sujino T, Kanai T. Approval of final manuscript: all authors.

References

1. Lamas B, Richard ML, Leducq V, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med 2016;22:598–605.
2. Goettel JA, Gandhi R, Kenison JE, et al. AHR activation is protective against colitis driven by T cells in humanized mice. Cell Rep 2016;17:1318–1329.
3. Kim YH, Kwon HS, Kim DH, et al. 3,3’-diindolylmethane attenuates colonic inflammation and tumorigenesis in mice. Inflamm Bowel Dis 2009;15:1164–1173.
4. Sugimoto S, Naganuma M, Kanai T. Indole compounds may be promising medicines for ulcerative colitis. J Gastroenterol 2016;51:853–861.
5. Qiu J, Heller JJ, Guo X, et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 2012;36:92–104.
6. Gutiérrez-Vázquez C, Quintana FJ. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity 2018;48:19–33.
7. Quintana FJ, Basso AS, Iglesias AH, et al. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008;453:65–71.
8. Ye J, Qiu J, Bostick JW, et al. The aryl hydrocarbon receptor preferentially marks and promotes gut regulatory T cells. Cell Rep 2017;21:2277–2290.
9. Stockinger B, Di Meglio P, Gialitakis M, Duarte JH. The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol 2014;32:403–432.
10. Quintana FJ, Murugaiyan G, Farez MF, et al. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2010;107:20768–20773.
11. Schiering C, Wincent E, Metidji A, et al. Feedback control of AHR signalling regulates intestinal immunity. Nature 2017;542:242–245.
12. Obata Y, Castaño Á, Boeing S, et al. Neuronal programming by microbiota regulates intestinal physiology. Nature 2020;578:284–289.
13. Rothhammer V, Quintana FJ. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol 2019;19:184–197.
14. Murakami Y, Nishiwaki Y, Oba MS, et al. Estimated prevalence of ulcerative colitis and Crohn’s disease in Japan in 2014: an analysis of a nationwide survey. J Gastroenterol 2019;54:1070–1077.
15. Ananthakrishnan AN, Kaplan GG, Ng SC. Changing global epidemiology of inflammatory bowel diseases: sustaining health care delivery into the 21st century. Clin Gastroenterol Hepatol 2020;18:1252–1260.
16. Fukuda T, Naganuma M, Kanai T. Current new challenges in the management of ulcerative colitis. Intest Res 2019;17:36–44.
17. Lee SH, Kwon JE, Cho ML. Immunological pathogenesis of inflammatory bowel disease. Intest Res 2018;16:26–42.
18. Oh SJ, Shin GY, Soh H, et al. Long-term outcomes of infliximab in a real-world multicenter cohort of patients with acute severe ulcerative colitis. Intest Res 2021;19:323–331.
19. Nakamura S, Asano T, Tsuchiya H, et al. Real-world data for golimumab treatment in patients with ulcerative colitis in Japan: interim analysis in post-marketing surveillance. Intest Res 2022;20:329–341.
20. Ogata H, Hagiwara T, Kawaberi T, Kobayashi M, Hibi T. Safety and effectiveness of adalimumab in the treatment of ulcerative colitis: results from a large-scale, prospective, multicenter, observational study. Intest Res 2021;19:419–429.
21. Shin SY, Park SJ, Kim Y, et al. Clinical outcomes and predictors of response for adalimumab in patients with moderately to severely active ulcerative colitis: a KASID prospective multicenter cohort study. Intest Res 2022;20:350–360.
22. Hisamatsu T, Kim HJ, Motoya S, et al. Efficacy and safety of ustekinumab in East Asian patients with moderately to severely active ulcerative colitis: a subpopulation analysis of global phase 3 induction and maintenance studies (UNIFI). Intest Res 2021;19:386–397.
23. Suzuki H, Kaneko T, Mizokami Y, et al. Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis. World J Gastroenterol 2013;19:2718–2722.
24. 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;93:193–201.
25. Naganuma M, Sugimoto S, Mitsuyama K, et al. Efficacy of indigo naturalis in a multicenter randomized controlled trial of patients with ulcerative colitis. Gastroenterology 2018;154:935–947.
26. 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;55:169–180.
27. Metidji A, Omenetti S, Crotta S, et al. The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 2018;49:353–362.
28. Stockinger B, Shah K, Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function. Nat Rev Gastroenterol Hepatol 2021;18:559–570.
29. Naganuma M, Sugimoto S, Suzuki H, et al. Adverse events in patients with ulcerative colitis treated with indigo naturalis: a Japanese nationwide survey. J Gastroenterol 2019;54:891–896.
30. Hiraide T, Teratani T, Uemura S, et al. Pulmonary arterial hypertension caused by AhR signal activation protecting against colitis. Am J Respir Crit Care Med 2021;203:385–388.
31. Masaki T, Okazawa M, Asano R, et al. Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci U S A 2021;118e2023899118.
32. 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;101:492–498.
33. Sun Z, Li J, Dai Y, et al. Indigo naturalis alleviates dextran sulfate sodium-induced colitis in rats via altering gut microbiota. Front Microbiol 2020;11:731.
34. Kawai S, Iijima H, Shinzaki S, et al. Indigo naturalis ameliorates murine dextran sodium sulfate-induced colitis via aryl hydrocarbon receptor activation. J Gastroenterol 2017;52:904–919.

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