Treatment-refractory ulcerative colitis responsive to indigo naturalis
Background Indigo naturalis (IN) is an herbal medicine that has been used for ulcerative colitis with an unclear mechanism of action. Indigo and indirubin, its main constituents, are ligands of the aryl hydrocarbon receptor (AhR). We assessed the safety, efficacy, and colon AhR activity of IN given...
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BMJ Publishing Group
2021-10-01
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| Series: | BMJ Open Gastroenterology |
| Online Access: | https://bmjopengastro.bmj.com/content/8/1/e000813.full |
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| author | Berkeley Limketkai Julie P Saiki Johan OL Andreasson Kevin V Grimes Lyn R Frumkin Elvi Sanjines Matthew G Davidson KT Park |
| author_facet | Berkeley Limketkai Julie P Saiki Johan OL Andreasson Kevin V Grimes Lyn R Frumkin Elvi Sanjines Matthew G Davidson KT Park |
| author_sort | Berkeley Limketkai |
| collection | DOAJ |
| description | Background Indigo naturalis (IN) is an herbal medicine that has been used for ulcerative colitis with an unclear mechanism of action. Indigo and indirubin, its main constituents, are ligands of the aryl hydrocarbon receptor (AhR). We assessed the safety, efficacy, and colon AhR activity of IN given orally to patients with treatment-refractory ulcerative colitis. The role of AhR in IN benefit was further evaluated with an AhR antagonist in a murine colitis model.Methods This open-label, dose-escalation study sequentially treated 11 patients with ulcerative colitis with either IN 500 mg/day or 1.5 g/day for 8 weeks, followed by a 4-week non-treatment period. The primary efficacy endpoint was clinical response at week 8, assessed by total Mayo score. Secondary endpoints included clinical remission, Ulcerative Colitis Endoscopic Index of Severity, quality of life, and colon AhR activity measured by cytochrome P450 1A1 (CYP1A1) RNA expression.Results Ten of 11 (91%) patients, including 8/9 (89%) with moderate-to-severe disease, achieved a clinical response. Among these 10 patients, all had failed treatment with 5-aminosalicylic acid, 8 patients with a tumour necrosis factor (TNF)-alpha inhibitor, and 6 patients with TNF-alpha inhibitor and vedolizumab. Five patients were corticosteroid dependent. Clinical response was observed in all five patients who had been recommended for colectomy. Three patients achieved clinical remission. All patients experienced improved endoscopic severity and quality of life. Four weeks after treatment completion, six patients had worsened partial Mayo scores. Four patients progressed to colectomy after study completion. Colon CYP1A1 RNA expression increased 12 557-fold at week 8 among six patients evaluated. No patient discontinued IN due to an adverse event. Concomitant administration of 3-methoxy-4-nitroflavone, an AhR antagonist, in a murine colitis model abrogated the benefit of IN.Conclusion IN is a potentially effective therapy for patients with treatment-refractory ulcerative colitis. This benefit is likely through AhR activation.Trial registration number NCT02442960. |
| format | Article |
| id | doaj-art-e32da20674574097be31039148bf366e |
| institution | OA Journals |
| issn | 2054-4774 |
| language | English |
| publishDate | 2021-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | BMJ Open Gastroenterology |
| spelling | doaj-art-e32da20674574097be31039148bf366e2025-08-20T02:21:01ZengBMJ Publishing GroupBMJ Open Gastroenterology2054-47742021-10-018110.1136/bmjgast-2021-000813Treatment-refractory ulcerative colitis responsive to indigo naturalisBerkeley Limketkai0Julie P Saiki1Johan OL Andreasson2Kevin V Grimes3Lyn R Frumkin4Elvi Sanjines5Matthew G Davidson6KT Park7Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USADepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USADepartment of Genetics, Department of Biochemistry, Stanford University School of Medicine, Stanford, California, USADepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USADepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USADivision of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USAAzora Therapeutics Inc, Encino, California, USADivision of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, California, USABackground Indigo naturalis (IN) is an herbal medicine that has been used for ulcerative colitis with an unclear mechanism of action. Indigo and indirubin, its main constituents, are ligands of the aryl hydrocarbon receptor (AhR). We assessed the safety, efficacy, and colon AhR activity of IN given orally to patients with treatment-refractory ulcerative colitis. The role of AhR in IN benefit was further evaluated with an AhR antagonist in a murine colitis model.Methods This open-label, dose-escalation study sequentially treated 11 patients with ulcerative colitis with either IN 500 mg/day or 1.5 g/day for 8 weeks, followed by a 4-week non-treatment period. The primary efficacy endpoint was clinical response at week 8, assessed by total Mayo score. Secondary endpoints included clinical remission, Ulcerative Colitis Endoscopic Index of Severity, quality of life, and colon AhR activity measured by cytochrome P450 1A1 (CYP1A1) RNA expression.Results Ten of 11 (91%) patients, including 8/9 (89%) with moderate-to-severe disease, achieved a clinical response. Among these 10 patients, all had failed treatment with 5-aminosalicylic acid, 8 patients with a tumour necrosis factor (TNF)-alpha inhibitor, and 6 patients with TNF-alpha inhibitor and vedolizumab. Five patients were corticosteroid dependent. Clinical response was observed in all five patients who had been recommended for colectomy. Three patients achieved clinical remission. All patients experienced improved endoscopic severity and quality of life. Four weeks after treatment completion, six patients had worsened partial Mayo scores. Four patients progressed to colectomy after study completion. Colon CYP1A1 RNA expression increased 12 557-fold at week 8 among six patients evaluated. No patient discontinued IN due to an adverse event. Concomitant administration of 3-methoxy-4-nitroflavone, an AhR antagonist, in a murine colitis model abrogated the benefit of IN.Conclusion IN is a potentially effective therapy for patients with treatment-refractory ulcerative colitis. This benefit is likely through AhR activation.Trial registration number NCT02442960.https://bmjopengastro.bmj.com/content/8/1/e000813.full |
| spellingShingle | Berkeley Limketkai Julie P Saiki Johan OL Andreasson Kevin V Grimes Lyn R Frumkin Elvi Sanjines Matthew G Davidson KT Park Treatment-refractory ulcerative colitis responsive to indigo naturalis BMJ Open Gastroenterology |
| title | Treatment-refractory ulcerative colitis responsive to indigo naturalis |
| title_full | Treatment-refractory ulcerative colitis responsive to indigo naturalis |
| title_fullStr | Treatment-refractory ulcerative colitis responsive to indigo naturalis |
| title_full_unstemmed | Treatment-refractory ulcerative colitis responsive to indigo naturalis |
| title_short | Treatment-refractory ulcerative colitis responsive to indigo naturalis |
| title_sort | treatment refractory ulcerative colitis responsive to indigo naturalis |
| url | https://bmjopengastro.bmj.com/content/8/1/e000813.full |
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