Gut Microbiota-Mediated Transformation of Coptisine Into a Novel Metabolite 8-Oxocoptisine: Insight Into Its Superior Anti-Colitis Effect.

Gaoxiang Ai,Juanjuan Cheng,Yuhong Liu,Yucui Li,Huifang Zeng,Xiaoqi Huang,Jiannan Chen,Jianhui Xie,Ziwei Huang,Ziren Su

doi:10.3389/fphar.2021.639020

Abstract

Coptisine (COP) is a bioactive isoquinoline alkaloid derived from Coptis Chinemsis Franch, which is traditionally applied for the management of colitis. However, the blood concentration of COP was extremely low, and its gut microbiota-mediated metabolites were thought to contribute to its prominent bioactivities. To comparatively elucidate the protective effect and underlying mechanism of COP and its novel gut microbiota metabolite (8-oxocoptisine, OCOP) against colitis, we used dextran sulfate sodium (DSS) to induce colitis in mice. Clinical symptoms, microscopic alternation, immune-inflammatory parameters for colitis were estimated. The results indicated that OCOP dramatically ameliorated disease activity index (DAI), the shortening of colon length and colonic histopathological deteriorations. OCOP treatment also suppressed the mRNA expression and release of inflammatory mediators (TGF-β, TNF-α, IL-6, IL-18, IL-1β and IFN-γ) and elevated the transcriptional and translational levels of anti-inflammatory cytokine (IL-10) as well as the mRNA expression levels of adhesion molecules (ICAM-1 and VCAM-1). Besides, the activation of NF-κB pathway and NLRP3 inflammasome was markedly inhibited by OCOP. Furthermore, OCOP displayed superior anti-colitis effect to COP, and was similar to MSZ with much smaller dosage. Taken together, the protective effect of OCOP against DSS-induced colitis might be intimately related to inhibition of NF-κB pathway and NLRP3 inflammasome. And the findings indicated that OCOP might have greater potential than COP to be further exploited as a promising candidate in the treatment of colitis.

Highlights

Ulcerative colitis (UC), a major form of inflammatory bowel disease (IBD), is an idiopathic long-term inflammatory disorder of the colon and rectum characterized by abdominal pain, fatigue, rectal bleeding, persistent diarrhea and abdominal cramps (Feuerstein and Cheifetz, 2014)
Our results indicated that OCOP eminently alleviated acute colitis elicited by dextran sulfate sodium (DSS), which exhibited similar anti-UC effect to the reference drug mesalazine (MSZ) with much smaller dosage and superior to COP via regulation of NF-κB pathway and NLRP3 inflammasome
Since gut microflora-mediated conversion plays a crucial role in reducing the toxicities of some drugs or modulating their metabolism, especially those with poor bioavailability, gut metabolism was considered to be one of the main factors contributing to the pronounced pharmacological effects of drugs

Summary

Introduction

Ulcerative colitis (UC), a major form of inflammatory bowel disease (IBD), is an idiopathic long-term inflammatory disorder of the colon and rectum characterized by abdominal pain, fatigue, rectal bleeding, persistent diarrhea and abdominal cramps (Feuerstein and Cheifetz, 2014). For medical management of UC, current therapeutic agents mainly focus on nonsteroidal anti-inflammatory agents, corticosteroids and immunosuppressants, which can be effective in the early stage of disease. These pharmaceutical therapies would be compromised due to incomplete efficacy and frequent side effects (Kellermayer, 2017; Ahmad and Kumar, 2018). Coptisine (COP), the characteristic active constituent of Rhizoma Coptidis with typical natural benzyltherahydroisoquinoline-type alkaloids skeleton as berberine, possesses a broad spectrum of prominent bioactivities including anti-inflammatory (Zielinska et al, 2020), anti-diabetes (Shi et al, 2019), anti-malaria (Lang et al, 2018) and anti-cancer effects (Ya et al, 2020), which is a promising active component to treat UC. Low oral bioavailability of COP is difficult to expound its various pharmacological activities (Wu et al, 2019)

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Conclusion